Podcasts about gabab

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.06.547738v1?rss=1 Authors: Ahmed, M., Campbell, S. A. Abstract: Objective: Childhood absence epilepsy (CAE) is a paediatric generalized epilepsy disorder with a confounding feature of resolving in adolescence in a majority of cases. In this study, we modelled how the small-scale (synapse-level) effect of progesterone metabolite allopregnanolone induces a large-scale (network-level) effect on a thalamocortical circuit associated with this disorder. In particular, our goal was to understand the role of sex steroid hormones in the spontaneous remission of CAE. Methods: The conductance-based computational model consisted of single-compartment cortical pyramidal, cortical interneurons, thalamic reticular and thalamocortical relay neurons, each described by a set of ordinary differential equations. Excitatory and inhibitory synapses were mediated by AMPA, GABAa and GABAb receptors. The model was implemented using the NetPyne modelling tool and the NEURON simulator. Results: The action of allopregnanolone on individual GABAa-receptor mediated synapses has an ameliorating effect on spike-wave discharges (SWDs) associated with absence seizures. This effect is region-specific and most significant in the thalamus, particularly the synapses between thalamic reticular neurons.Significance: The remedying effect of allopregnanolone on SWDs may possibly be true only for individuals that are predisposed to remission due to intrinsic connectivity differences or differences in tonic inhibition. These results are a useful first-step and prescribe directions for further investigation into the role of ALLO together with these differences to distinguish between models for CAE-remitting and non-remitting individuals. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.06.23.546323v1?rss=1 Authors: Ngodup, T., Irie, T., Elkins, S., Trussell, L. O. Abstract: Cartwheel interneurons of the dorsal cochlear nucleus (DCN) potently suppress multisensory signals that converge with primary auditory afferent input, and thus regulate auditory processing. Noradrenergic fibers from locus coeruleus project to the DCN, and 2-adrenergic receptors inhibit spontaneous spike activity but simultaneously enhance synaptic strength in cartwheel cells, a dual effect leading to enhanced signal-to-noise for inhibition. However, the ionic mechanism of this striking modulation is unknown. We generated a glycinergic neuron-specific knockout of the Na less than + leak channel NALCN, and found that its presence was required for spontaneous firing in cartwheel cells. Activation of 2-adrenergic receptors inhibited both NALCN and spike generation, and this modulation was absent in the NALCN knockout. Moreover, 2-dependent enhancement of synaptic strength was also absent in the knockout. GABAB receptors mediated inhibition through NALCN as well, acting on the same population of channels as 2 receptors, suggesting close apposition of both receptor subtypes with NALCN. Thus, multiple neuromodulatory systems determine the impact of synaptic inhibition by suppressing the excitatory leak channel, NALCN. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.01.10.523440v1?rss=1 Authors: Masri, S., Fair, R., Mowery, T. M., Sanes, D. H. Abstract: Even transient periods of developmental hearing loss during the developmental critical period have been linked to long-lasting deficits in auditory perception, including temporal and spectral processing, which correlate with speech perception and educational attainment. In gerbils, hearing loss-induced perceptual deficits are correlated with a reduction of both ionotropic GABAA and metabotropic GABAB receptor-mediated synaptic inhibition in auditory cortex, but most research on critical period plasticity has focused on GABAA receptors. We developed viral vectors to express both endogenous GABAA or GABAB receptor subunits in auditory cortex and tested their capacity to restore perception of temporal and spectral auditory cues following critical period hearing loss in the Mongolian gerbil. HL significantly impaired perception of both temporal and spectral auditory cues. While both vectors similarly increased IPSCs in auditory cortex, only overexpression of GABAB receptors improved perceptual thresholds after HL to be similar to those of animals without developmental hearing loss. These findings identify the GABAB receptor as an important regulator of sensory perception in cortex and point to potential therapeutic targets for developmental sensory disorders. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.12.14.520067v1?rss=1 Authors: RIONDEL, P., JURCIC, N., TROUSLARD, J., WANAVERBECQ, N., SEDDIK, R. Abstract: Spinal cerebrospinal fluid-contacting neurons (CSF-cNs) form an evolutionary conserved bipolar cells population localized around the central canal of all vertebrates. CSF-cNs were shown to express molecular markers of neuronal immaturity into adulthood, however the functional relevance of their incomplete maturation remains unknown. Neuronal maturation is classically associated with the expression of the K+-Cl- cotransporter 2 (KCC2), allowing chloride (Cl-) extrusion and hyperpolarising GABA transmission. Here, we show no detectable expression of KCC2 in CSF-cNs of adult mouse spinal cord. Accordingly, lack of KCC2 expression results in low Cl- extrusion capacity in CSF-cNs under high Cl- load in whole-cell patch-clamp. Using cell-attached recordings, we found that activation of ionotropic GABAA receptors induced a dominant depolarising effect in 70% of CSF-cNs recorded with intact intracellular chloride concentration. Moreover, in these cells, depolarising GABA-responses can drive action potentials as well as intracellular calcium elevations by activating voltage-gated calcium channels. CSF-cNs express the Na+-K+-Cl- cotransporter 1 (NKCC1) involved in Cl- uptake and its inhibition by bumetanide blocked the GABA-induced calcium transients in CSF-cNs. Finally, we show that activation of metabotropic GABAB receptors did not mediate hyperpolarisation in spinal CSF-cNs, presumably due to the lack of expression of G protein-coupled inwardly rectifying potassium (GIRK) channels. Together, these findings outline CSF-cNs as a unique neuronal population in adult spinal cord with immature Cl- homeostasis and no hyperpolarising GABAergic signalling but rather generation of excitation and intracellular calcium modulation. GABA may therefore promote CSF-cNs maturation and integration into the existing spinal circuit. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.28.514202v1?rss=1 Authors: Koppensteiner, P., Bhandari, P., Önal, C., Borges-Merjane, C., Le Monnier, E., Nakamura, Y., Sadakata, T., Sanbo, M., Hirabayashi, M., Brose, N., Jonas, P., Shigemoto, R. Abstract: GABAB receptor (GBR) activation inhibits neurotransmitter release in axon terminals in the brain, except in medial habenula (MHb) terminals, which show robust potentiation. However, mechanisms underlying this enigmatic potentiation remain elusive. Here, we report that GBR activation induces a transition from tonic to phasic release accompanied by a 4-fold increase in readily releasable pool (RRP) size in MHb terminals, mirrored by a similar increase in the docked vesicle number at the presynaptic active zone (AZ). The tonic and phasic release vesicles have distinct coupling distances. We identified two vesicle-associated molecules, synaptoporin and CAPS2, selectively involved in tonic and phasic release, respectively. Synaptoporin mediates augmentation of tonic release and CAPS2 stabilizes readily releasable vesicles during phasic release. A newly developed Flash and Freeze-fracture method revealed selective recruitment of CAPS2 to the AZ during phasic release. Thus, we propose a novel two-pool mechanism underlying the GBR-mediated potentiation of release from MHb terminals. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.25.505296v1?rss=1 Authors: Vandrey, B., Armstrong, J., Brown, C. M., Garden, D. L. F., Nolan, M. F. Abstract: Standard models for spatial and episodic memory suggest that the lateral entorhinal cortex (LEC) and medial entorhinal cortex (MEC) send parallel independent inputs to the hippocampus, each carrying different types of information. Here, we evaluate the possibility that information is integrated between divisions of the entorhinal cortex prior to reaching the hippocampus. We demonstrate that fan cells in layer 2 (L2) of LEC that receive neocortical inputs, and that project to the hippocampal dentate gyrus, also send axon collaterals to layer 1 (L1) of the MEC. Activation of fan cell inputs evokes monosynaptic glutamatergic excitation of stellate and pyramidal cells in L2 of the MEC, typically followed by inhibition that contains fast and slow components mediated by GABAA and GABAB receptors, respectively. Fan cell inputs also directly activate interneurons in L1 and L2 of MEC, with synaptic connections from L1 interneurons accounting for slow feedforward inhibition of L2 principal cell populations. The relative strength of excitation and inhibition following fan cell activation differs substantially between neurons and is largely independent of anatomical location. Our results demonstrate that the LEC, in addition to directly influencing the hippocampus, can activate or inhibit major hippocampal inputs arising from the MEC. Thus, local circuits in the superficial MEC may combine spatial information with sensory and higher order signals from the LEC, providing a substrate for integration of what and where components of episodic memories. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

FM脑科学新闻 | 适应新环境的神经基础是什么？前额叶Gamma波有重要作用。电极假体可以给失明患者带来光明吗？ 导读：无信号仪器 皮皮佳责编：Zhu Xiao配音：行者背景音乐：lovely piano song-Guru排版：KinoNature Neuroscience | 前额叶PV神经元间跨半脑的Gamma同步波支持规则转换学习中的行为调整生物体在适应变化的环境时，经常会遇到已有的行为策略不再有效的情况，因此它们需要及时停止无效的策略并学习新的策略。在精神分裂症中，这种能力的缺失标志着前额叶功能紊乱，而特殊神经元之间的同步活动则可以使大脑进入一种有活力的状态，并促进行为策略的调整。Vikaas Sohal教授的团队近期发现，在规则转换学习（rule shift learning）中，在左右半球的内侧前额叶皮质（medial prefrontal cortex, mPFC）里的小清蛋白中间神经元（parvalbumin interneuron）会产生Gamma同步波（频率约30-80Hz）来支持行为调整。该团队设计了巧妙的行为学实验来令小鼠学习“规则转换”，他们先让小鼠在训练中学会将特定的气味与埋在培养基里的食物奖励关联，再把获取奖励的规则改为识别特定的培养基质地，最后观察小鼠在规则转换后的表现，测试小鼠学习新规则的能力。他们发现小清蛋白中间神经元之间的跨半球Gamma同步活动会在小鼠发现旧规则不适用时增强，而当他们用光遗传学手段扰乱Gamma同步后，小鼠便难以学会新规则。因此，他们认为Gamma同步对重新评价外部线索的行为学意义是必不可少的。（导读：无信号仪器） 文章链接：https://www.nature.com/articles/s41593-020-0647-1图片来源：https://www.dreamstime.com/closeup-small-vole-mouse-digs-hole-near-grains-rye-field-closeup-small-vole-mouse-digs-hole-near-grains-rye-image102969982 Cell | 定向激活特定的位置细胞能改变小鼠的行为认知地图（Cognitive map）一直都是海马领域的研究热点，发表在《Cell》上的一篇工作首次通过活体钙成像和单细胞光遗传技术，证实激活特定的位置细胞，能让小鼠产生记忆引导的空间行为变化。作者首先将带有荧光蛋白的病毒注射在小鼠右侧海马区，随后让小鼠在一个虚拟的跑道中探索。跑道分为开始区域（start zone)和奖赏区域（reward zone），作者发现，激活开始区域的位置细胞，能让小鼠出现超速跑的行为，而激活奖赏区域的位置细胞，小鼠则会提前终止任务。此外，这一过程是由位置细胞网络去调节的。这项工作第一次在功能学层面证实了认知地图存在的重要性，为日后的研究带来了新的思路。（导读：皮皮佳） 原文地址：https://www.cell.com/cell/pdf/S0092-8674(20)31302-7.pdf图片地址：https://in.pinterest.com/pin/335518240971381405/ Science | 视皮层上的电极假体有望治疗失明 失明影响着全世界四千万人的生活，但是这一疾病目前尚未有明确的治疗手段。于是科学家就想：能在他们的脑内植入神经假体，实现重建功能学视觉的效果嘛？之前有研究将电极放在大脑表面，并施以高电流刺激，结果发现不仅同时能被刺激的电极数目有限，而且电极会激活很区域，空间分辨率低。近期《Science》上的一篇研究，解决了低空间分辨率的问题。他们在猴子V1和V4这两块视皮层植入了有1024个通道的神经假体，并对视皮层进行了电刺激，发现猴子对电极产生的光点幻觉（phosphenes）与被刺激的神经元的实际感受野相匹配。其中，V4的活动成功预测了将在V1产生的光幻觉。他们同时刺激了多个电极，来产生一些视觉图案（如简单的形状、运动或字母），发现猴子能立刻识别出这些图案。这项研究证实了电刺激具有重建功能性视觉的可能性。（导读：皮皮佳） 原文链接：http://science.sciencemag.org/content/370/6521/1191图片链接：https://kyeye.com/near-or-far-what-does-20-40-vision-mean/ Nature Neuroscience | 前额叶皮层中星形胶质细胞的GABA能信号能维持目标定向行为 星形胶质细胞会与全脑的突触相互作用，并被认作是兴奋性突触传递的调控性元件。但是，关于GABA能中间神经元与星形胶质细胞之间的相互作用对行为的影响，一直都不是很清楚。发表在《Nature Neuroscience》上的一篇文章发现，对内前额叶皮层的星形胶质细胞内的GABAB型受体进行敲除后，改变了low-gamma震荡和皮层神经元的放电特性，最终影响了目标定向性行为。值得一提的是，工作记忆受损是可以通过光遗传激活星形胶质细胞被重建的。此外，研究人员发现，在野生型小鼠内，通过视黑素激活星形胶质细胞，能够提高皮层神经元的放电速率和Gama震荡，并且对认知功能也有促进作用。该工作鉴定了星形胶质细胞是一个控制皮层环路的抑制性中心，为皮层信息处理和目标定向性运动提供了一个全新的通路解释。（导读：皮皮佳） 原文链接：https://www.nature.com/articles/s41593-020-00752-x图片链接：https://brainxell.com/cortical-gabaergic-neurons Neuron | 初级视皮层的去抑制通路 在日常生活中，情境（context）通过影响刺激的显著性来指导我们的感知觉。同样，在视皮层中，神经元对一个特定刺激的响应也受到视觉情境的调节。不过，这背后的机制一直都未被揭示。发表在《Neuron》上的一篇文章通过利用光学记录、操纵和计算建模等方法，发现由表达血管活性肠肽（VIP）和表达生长激素抑制素（SOM）的神经元组成的去抑制通路，能够调节小鼠视皮层的神经元应答，并且这种应答依赖于视觉刺激与刺激周边的差异性。当一个刺激与刺激周边很相似，那么VIP神经元就处于失活的状态，同时SOM神经元会抑制兴奋性神经元的活性。但当刺激与刺激周边差异显著时，VIP神经元就会变得十分活跃，抑制SOM神经元，从而解除其对兴奋行神经元的抑制。该研究为视皮层神经元活性的调节带来了新的思路。（导读：皮皮佳） 原文链接：https://www.sciencedirect.com/science/article/abs/pii/S0896627320308916?dgcid=rss_sd_all图片链接：https://guardian.ng/guardian-woman/everything-begins-with-a-vision/ Current Biology | 幼鱼利用嗅觉躲避盐水 盐度限制了所有水生生物的栖息环境，幼年斑马鱼也不例外。作为地道的淡水鱼，它们无法在高盐环境中生存。因此，研究人员就推测它们的脑内可能存在某些依赖于盐度定位的神经环路。考虑到斑马鱼没有表皮钠离子通道，故它们可能采取了一种人类未知的探测盐分的机制。在该篇研究中，研究人员利用钙成像技术找到了探测盐分的主要嗅觉系统，并明确了一群编码绝对盐度的嗅觉受体神经元。这项工作首次提出幼年斑马鱼拥有嗅觉导航能力，为嗅觉相关的研究带来了新思路。（导读：皮皮佳）原文链接：https://www.sciencedirect.com/science/article/pii/S0960982220317644图片链接：https://www.foodnavigator.com/Article/2014/11/25/Quiet-salt-reduction-is-vital-but-gourmet-salt-growth-may-stifle-industry-efforts

FM脑科学新闻 | 适应新环境的神经基础是什么？前额叶Gamma波有重要作用。电极假体可以给失明患者带来光明吗？ 导读：无信号仪器 皮皮佳责编：Zhu Xiao配音：行者背景音乐：lovely piano song-Guru排版：KinoNature Neuroscience | 前额叶PV神经元间跨半脑的Gamma同步波支持规则转换学习中的行为调整生物体在适应变化的环境时，经常会遇到已有的行为策略不再有效的情况，因此它们需要及时停止无效的策略并学习新的策略。在精神分裂症中，这种能力的缺失标志着前额叶功能紊乱，而特殊神经元之间的同步活动则可以使大脑进入一种有活力的状态，并促进行为策略的调整。Vikaas Sohal教授的团队近期发现，在规则转换学习（rule shift learning）中，在左右半球的内侧前额叶皮质（medial prefrontal cortex, mPFC）里的小清蛋白中间神经元（parvalbumin interneuron）会产生Gamma同步波（频率约30-80Hz）来支持行为调整。该团队设计了巧妙的行为学实验来令小鼠学习“规则转换”，他们先让小鼠在训练中学会将特定的气味与埋在培养基里的食物奖励关联，再把获取奖励的规则改为识别特定的培养基质地，最后观察小鼠在规则转换后的表现，测试小鼠学习新规则的能力。他们发现小清蛋白中间神经元之间的跨半球Gamma同步活动会在小鼠发现旧规则不适用时增强，而当他们用光遗传学手段扰乱Gamma同步后，小鼠便难以学会新规则。因此，他们认为Gamma同步对重新评价外部线索的行为学意义是必不可少的。（导读：无信号仪器） 文章链接：https://www.nature.com/articles/s41593-020-0647-1图片来源：https://www.dreamstime.com/closeup-small-vole-mouse-digs-hole-near-grains-rye-field-closeup-small-vole-mouse-digs-hole-near-grains-rye-image102969982 Cell | 定向激活特定的位置细胞能改变小鼠的行为认知地图（Cognitive map）一直都是海马领域的研究热点，发表在《Cell》上的一篇工作首次通过活体钙成像和单细胞光遗传技术，证实激活特定的位置细胞，能让小鼠产生记忆引导的空间行为变化。作者首先将带有荧光蛋白的病毒注射在小鼠右侧海马区，随后让小鼠在一个虚拟的跑道中探索。跑道分为开始区域（start zone)和奖赏区域（reward zone），作者发现，激活开始区域的位置细胞，能让小鼠出现超速跑的行为，而激活奖赏区域的位置细胞，小鼠则会提前终止任务。此外，这一过程是由位置细胞网络去调节的。这项工作第一次在功能学层面证实了认知地图存在的重要性，为日后的研究带来了新的思路。（导读：皮皮佳） 原文地址：https://www.cell.com/cell/pdf/S0092-8674(20)31302-7.pdf图片地址：https://in.pinterest.com/pin/335518240971381405/ Science | 视皮层上的电极假体有望治疗失明 失明影响着全世界四千万人的生活，但是这一疾病目前尚未有明确的治疗手段。于是科学家就想：能在他们的脑内植入神经假体，实现重建功能学视觉的效果嘛？之前有研究将电极放在大脑表面，并施以高电流刺激，结果发现不仅同时能被刺激的电极数目有限，而且电极会激活很区域，空间分辨率低。近期《Science》上的一篇研究，解决了低空间分辨率的问题。他们在猴子V1和V4这两块视皮层植入了有1024个通道的神经假体，并对视皮层进行了电刺激，发现猴子对电极产生的光点幻觉（phosphenes）与被刺激的神经元的实际感受野相匹配。其中，V4的活动成功预测了将在V1产生的光幻觉。他们同时刺激了多个电极，来产生一些视觉图案（如简单的形状、运动或字母），发现猴子能立刻识别出这些图案。这项研究证实了电刺激具有重建功能性视觉的可能性。（导读：皮皮佳） 原文链接：http://science.sciencemag.org/content/370/6521/1191图片链接：https://kyeye.com/near-or-far-what-does-20-40-vision-mean/ Nature Neuroscience | 前额叶皮层中星形胶质细胞的GABA能信号能维持目标定向行为 星形胶质细胞会与全脑的突触相互作用，并被认作是兴奋性突触传递的调控性元件。但是，关于GABA能中间神经元与星形胶质细胞之间的相互作用对行为的影响，一直都不是很清楚。发表在《Nature Neuroscience》上的一篇文章发现，对内前额叶皮层的星形胶质细胞内的GABAB型受体进行敲除后，改变了low-gamma震荡和皮层神经元的放电特性，最终影响了目标定向性行为。值得一提的是，工作记忆受损是可以通过光遗传激活星形胶质细胞被重建的。此外，研究人员发现，在野生型小鼠内，通过视黑素激活星形胶质细胞，能够提高皮层神经元的放电速率和Gama震荡，并且对认知功能也有促进作用。该工作鉴定了星形胶质细胞是一个控制皮层环路的抑制性中心，为皮层信息处理和目标定向性运动提供了一个全新的通路解释。（导读：皮皮佳） 原文链接：https://www.nature.com/articles/s41593-020-00752-x图片链接：https://brainxell.com/cortical-gabaergic-neurons Neuron | 初级视皮层的去抑制通路 在日常生活中，情境（context）通过影响刺激的显著性来指导我们的感知觉。同样，在视皮层中，神经元对一个特定刺激的响应也受到视觉情境的调节。不过，这背后的机制一直都未被揭示。发表在《Neuron》上的一篇文章通过利用光学记录、操纵和计算建模等方法，发现由表达血管活性肠肽（VIP）和表达生长激素抑制素（SOM）的神经元组成的去抑制通路，能够调节小鼠视皮层的神经元应答，并且这种应答依赖于视觉刺激与刺激周边的差异性。当一个刺激与刺激周边很相似，那么VIP神经元就处于失活的状态，同时SOM神经元会抑制兴奋性神经元的活性。但当刺激与刺激周边差异显著时，VIP神经元就会变得十分活跃，抑制SOM神经元，从而解除其对兴奋行神经元的抑制。该研究为视皮层神经元活性的调节带来了新的思路。（导读：皮皮佳） 原文链接：https://www.sciencedirect.com/science/article/abs/pii/S0896627320308916?dgcid=rss_sd_all图片链接：https://guardian.ng/guardian-woman/everything-begins-with-a-vision/ Current Biology | 幼鱼利用嗅觉躲避盐水 盐度限制了所有水生生物的栖息环境，幼年斑马鱼也不例外。作为地道的淡水鱼，它们无法在高盐环境中生存。因此，研究人员就推测它们的脑内可能存在某些依赖于盐度定位的神经环路。考虑到斑马鱼没有表皮钠离子通道，故它们可能采取了一种人类未知的探测盐分的机制。在该篇研究中，研究人员利用钙成像技术找到了探测盐分的主要嗅觉系统，并明确了一群编码绝对盐度的嗅觉受体神经元。这项工作首次提出幼年斑马鱼拥有嗅觉导航能力，为嗅觉相关的研究带来了新思路。（导读：皮皮佳）原文链接：https://www.sciencedirect.com/science/article/pii/S0960982220317644图片链接：https://www.foodnavigator.com/Article/2014/11/25/Quiet-salt-reduction-is-vital-but-gourmet-salt-growth-may-stifle-industry-efforts

Fiona Marshall got fascinated with GPCRs after attending a lecture on how the beta-adrenergic receptor in the heart is activated by adrenaline, during her undergraduate studies at Bath University. She then pursued her Ph.D. in neuroscience from Cambridge University. An expert in GPCR biology, Fiona published the first description of the cloning and structural requirements of the GABAB receptor. One of her career path defining moments came from when she visited Dr. Chris Tate and Dr. Richard Henderson at the Laboratory of Molecular Biology in Cambridge, UK. As a co-founder of Heptares Therapeutics, now called Sosei Heptares, a GPCR focused drug discovery and development biotechnology company, Fiona and her team made considerable breakthroughs in the field of GPCR stabilization and structure-based drug design. Today, Dr. Marshall is the VP Head of Neuroscience Discovery and Head of Discovery UK, Global Head of Neuroscience discovery research leading teams in West Point, Boston, and London at MSD. Join me and learn more about her fascinating career trajectory.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.12.362491v1?rss=1 Authors: Church, E., Hamid, E., Zurawski, Z. P., Alford, S. Abstract: Presynaptic terminals have been little studied as sites of synaptic integration because of inaccessibility. Gi/o-mediated presynaptic inhibition is ubiquitous and either reduces release probability (Pr) by inhibiting Ca2+ entry or inhibits directly at SNARE complexes. At CA1-subicular presynapses, 5-HT1B and GABAB receptors colocalize. GABABRs inhibit Ca2+ entry, whereas 5-HT1BRs Ca2+-dependently target SNARE complexes. We demonstrate that GABABRs, alter Pr, but 5-HT1BRs reduce cleft glutamate concentrations allowing strong inhibition of AMPA- but not NMDA-receptor responses. Simulations of glutamate release and receptor binding demonstrates that experimental effects on release and low affinity antagonism are well-fit by reduced release rates. Train-dependent presynaptic Ca2+ accumulation forces frequency-dependent recovery of neurotransmission during 5-HT1BR activation, consistent with competition between Ca2+-synaptotagmin and G{beta}{gamma} at SNARE complexes. Thus, stimulus trains in 5-HT unveil dynamic synaptic modulation and a sophisticated hippocampal output filter, that itself is modulated by colocalized GABABRs which alter presynaptic Ca2+ allowing complex presynaptic integration. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.10.01.322131v1?rss=1 Authors: Cramer, N. P., Silva-Cardoso, G. K., Keller, A. Abstract: The parabrachial nucleus (PB) is a hub for aversive behaviors, including those related to pain. We have shown that the expression of chronic pain is causally related to amplified activity of PB neurons, and to changes in synaptic inhibition of these neurons. These findings indicate that regulation of synaptic activity in PB may modulate pain perception and be involved in the pathophysiology of chronic pain. Here, we identify the roles in PB of signaling pathways that modulate synaptic functions. In pharmacologically isolated lateral PB neurons in acute mouse slices, we find that baclofen, a GABAB receptor agonist, suppresses the frequency of miniature inhibitory and excitatory postsynaptic currents (mIPSCs and mEPSC). Activation of -opioid peptide receptors with DAMGO had similar effects, while the {kappa}-opioid peptide receptor agonist U-69593 suppressed mIPSC release but had no consistent effects on mEPSCs. Activation of cannabinoid type 1 receptors with WIN 55,212-2 reduced the frequency of both inhibitory and excitatory synaptic events, while the CB1 antagonist AM251 had opposite effects on mIPSC and mEPSC frequencies. AM251 increased the frequency of inhibitory events but led to a reduction in excitatory events through a GABAB mediated mechanism. Although none of the treatments produced a consistent effect on mIPSC or mEPSC amplitudes, baclofen and DAMGO both reliably activated a postsynaptic conductance. Together, these results demonstrate that signaling pathways known to modulate nociception, alter synaptic transmission and neuronal excitability in the lateral parabrachial nucleus and provide a basis for investigating the contributions of these systems to the development and maintenance of chronic pain. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.03.235044v1?rss=1 Authors: Holly, E. N., Davatolhagh, M. F., Espana, R. A., Fuccillo, M. V. Abstract: Low-threshold spiking interneurons (LTSIs) in the dorsomedial striatum are potent modulators of goal-directed learning. Here, we uncover a novel function for LTSIs in locally and directly gating striatal dopamine, using in vitro fast scan cyclic voltammetry as well as in vivo GRAB-DA sensor imaging and pharmacology during operant learning. We demonstrate that LTSIs, acting via GABAB signaling, attenuate dopamine release, thereby serving as local coordinators of striatal plasticity. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.28.219600v1?rss=1 Authors: Paci, M., Di Cosmo, G., Ferri, F., Costantini, M. Abstract: Inhibitory control is the ability to suppress unwanted actions. At the behavioral level,this ability can be measured via the Stop-Signal Task (stop-signal reaction time,SSRT). At the neural level, Transcranial Magnetic Stimulation provides electrophysiological measures of motor inhibition within the primary motor cortex (M1),such as the Cortical Silent period (CSP), a biomarker of proactive intracortical inhibition mainly mediated by GABAB receptors. Individual differences in this biomarker might contribute to behavioral differences in inhibitory control. Hence, we explored the relationship between intracortical inhibition and behavioral inhibition. Levels of intracortical inhibition were determined by measuring the length of individuals CSP, while inhibitory capacities were assessed by the SSRT. We found a significant positive correlation between CSP and SSRT, namely that individuals with greater GABABergic-mediated proactive inhibition seems to perform worse in inhibiting behavioral responses. These results suggest that individual differences in intracortical inhibitionare mirrored by differences in motor-inhibitory ability. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.13.200113v1?rss=1 Authors: Dzyubenko, E., Fleischer, M., Manrique-Castano, D., Borbor, M., Kleinschnitz, C., Faissner, A., Hermann, D. M. Abstract: Maintaining the balance between excitation and inhibition is essential for the appropriate control of neuronal network activity. Sustained excitation-inhibition (E-I) balance relies on the orchestrated adjustment of synaptic strength, neuronal activity and network circuitry. While growing evidence indicates that extracellular matrix (ECM) of the brain is a crucial regulator of neuronal excitability and synaptic plasticity, it remains unclear whether and how ECM contributes to neuronal circuit stability. Here we demonstrate that the integrity of ECM supports the maintenance of E-I balance by retaining inhibitory connectivity. Depletion of ECM in mature neuronal networks preferentially decreases the density of inhibitory synapses and the size of individual inhibitory postsynaptic scaffolds. After ECM depletion, inhibitory synapse strength homeostatically increases via the reduction of presynaptic GABAB receptors. However, the inhibitory connectivity reduces to an extent that inhibitory synapse scaling is no longer efficient in controlling neuronal network state. Our results indicate that the brain ECM preserves the balanced network state by stabilizing inhibitory control. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.06.29.178236v1?rss=1 Authors: Marti-Prats, L., Belin-Rauscent, A., Fouyssac, M., Puaud, M., Cocker, P. J., Everitt, B. J., Belin, D. Abstract: While most individuals with access to alcohol drink it recreationally, about 5% lose control over their intake and progressively develop an alcohol use disorder (AUD), characterised by compulsive alcohol drinking accompanied by decreased interest in alternative sources of reinforcement. The neural and molecular mechanisms underlying the vulnerability to switch from controlled to compulsive alcohol intake have not been fully characterized, so limiting the development of new treatments for AUD. It has recently been shown that rats having reduced levels of expression of the gamma-aminobutyric acid (GABA) transporter, GAT-3, in the amygdala tend to persist in seeking and drinking alcohol even when adulterated with quinine, suggesting that pharmacological interventions aimed at restoring GABA homeostasis in these individuals may provide a targeted treatment to limit compulsive alcohol drinking. Here, we tested the hypothesis that the GABAB receptor agonist baclofen, which decreases GABA release, specifically decreases compulsive alcohol drinking in vulnerable individuals. In a large cohort of Sprague-Dawley rats allowed to drink alcohol under an intermittent two-bottle choice procedure, a cluster of individuals was identified that persisted in drinking alcohol despite adulteration or the availability of an alternative ingestive reinforcer, saccharin. In these rats, that were characterised by decreased GAT-3 mRNA levels in the central amygdala, acute baclofen administration (1.5 mg/kg, intraperitoneal) resulted in a decrease in compulsive drinking. These results indicate that low GAT-3 mRNA levels in the central amygdala represent an endophenotype of AUD and that the associated compulsive alcohol drinking characteristic is sensitive to baclofen. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.06.06.137844v1?rss=1 Authors: Bernstein, H. L., Lu, Y.-L., Botterill, J. J., Duffy, A. M., LaFrancois, J. J., Scharfman, H. E. Abstract: Glutamatergic dentate gyrus (DG) mossy cells (MCs) innervate the primary cell type, granule cells (GCs), and GABAergic neurons which inhibit GCs. Prior studies suggest that the net effect of MCs is mainly to inhibit GCs, leading one to question why direct excitation of GCs is often missed. We hypothesized that MCs do have excitatory effects, but each GC is only excited weakly, at least under most experimental conditions. To address this hypothesis, MC axons were stimulated optogenetically in slices. A brief optogenetic stimulus to MC axons in the inner molecular layer (IML) led to a short-latency field EPSP (fEPSP) in the IML, suggesting there was a direct excitatory effect on GCs. Population spikes were negligible however, consistent with weak excitation. FEPSPs reflected AMPA/NMDA receptor-mediated EPSPs in GCs. EPSPs reached threshold after GC depolarization or facilitating NMDA receptors. GABAA and GABAB receptor-mediated IPSPs often followed EPSPs. At the network level, an optogenetic stimulus led to a brief, small facilitation of the PP-evoked population spike followed by a longer, greater inhibition. These data are consistent with rapid and selective GC firing by MCs (MC [->] GC) and disynaptic inhibition (MC [->] GABAergic neuron [->] GC). Notably, optogenetic excitation was evoked for both dorsal and ventral MCs, ipsilateral and contralateral MC axons, and two Cre lines. Together the results suggest a way to reconcile past studies and provide new insight into the balance of excitation and inhibition of GCs by MCs. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.06.02.129601v1?rss=1 Authors: Lu, A. C., Lee, C. K., Kleiman-Weiner, M., Truong, B., Wang, M., Huguenard, J. R., Beenhakker, M. P. Abstract: Absence seizures result from 3-5 Hz generalized thalamocortical oscillations that depend on highly regulated inhibitory neurotransmission in the thalamus. Efficient reuptake of the inhibitory neurotransmitter GABA is essential, and reuptake failure worsens seizures. Here, we show that blocking GABA transporters (GATs) in acute brain slices containing key parts of the thalamocortical seizure network modulates epileptiform activity. As expected, we found that blocking either GAT1 or GAT3 prolonged oscillations. However, blocking both GATs unexpectedly suppressed oscillations. Integrating experimental observations into single-neuron and network-level computational models shows how a non-linear dependence of T-type calcium channel opening on GABAB receptor activity regulates network oscillations. Receptor activity that is either too brief or too protracted fails to sufficiently open T-type channels necessary for sustaining oscillations. Only within a narrow range does prolonging GABAB receptor activity promote channel opening and intensify oscillations. These results have implications for therapeutics that modulate GABA transporters. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.05.25.114389v1?rss=1 Authors: Liu, J.-J., Tsien, R. W., Pang, Z. P. Abstract: Neuropeptide melanin-concentrating hormone (MCH) plays important roles in the brain including control of energy homeostasis, sleep, learning and memory. However, the synaptic and circuitry mechanisms underlying MCH-mediated regulations remain largely unknown. Here, we uncover that MCH modulates the hippocampo (HP)-dorsal lateral septum (dLS)-lateral hypothalamus neural circuit to facilitate spatial learning and memory. MCH achieves this function by enhancing both excitatory and inhibitory synaptic transmission via presynaptic mechanisms. The dLS neuronal spiking activity in response to HP CA3 excitatory inputs is strongly controlled by feed-forward inhibition (FFI) mediated by both GABAA and GABAB receptors. Endogenous MCH signaling enhances Signal/Noise (S/N) ratio of dLS neurons by increase the excitatory strengths, meanwhile decrease the overall dLS excitability by enhance inhibition which reduces dLS FFI, and consequentially enables dLS neurons to fire with high fidelity with HP synaptic inputs. Our data unravel the multifaceted synaptic mechanisms of MCH in the defined HP-dLS circuitry which may contribute to learning and memory. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.04.30.069682v1?rss=1 Authors: Ramakrishna, Y., Sadeghi, S. G. Abstract: GABAergic sources have been identified in the vestibular sensory neuroepithelium, mainly in the supporting cells. However, existence of GABA receptors or any possible GABAergic effects on vestibular nerve afferents has not been investigated. The current study was conducted to determine whether activation of GABAB receptors affects calyx afferent terminals in the central region of the cristae of the semicircular canals in rats. We used patch clamp recording in P13 to P18 Sprague Dawley rats of either sex. Application of GABA-B receptor agonist baclofen inhibited voltage activated outward potassium currents. This effect was blocked by selective GABAB receptor antagonist CGP 35348. Antagonists of small (SK) and large (BK) current potassium channels resulted in an almost complete block of baclofen effect. The remaining baclofen effect was due to inhibition of voltage gated calcium channels and was blocked by cadmium chloride. Furthermore, baclofen had no effect in the absence of calcium in the extracellular fluid. Inhibition of potassium currents by GABAB activation resulted in an excitatory effect on calyx terminal action potential firing. While in the control condition calyces could only fire a single action potential during step depolarizations, in the presence of baclofen they fired continuously during steps and a few even showed spontaneous discharge. We also found a decrease in threshold for action potential generation and a decrease in first spike latency during step depolarization. These results provide the first evidence for the presence of GABAB receptors on calyx terminals, show that their activation results in an unusual excitatory effect and that GABA inputs could be used to modulate calyx response properties. Copy rights belong to original authors. Visit the link for more info

1. Featured Article: Long-term neuropsychological outcome following pediatric anti-NMDAR encephalitis2.What's Trending: Amateur fundus photographyThis podcast begins and closes with Dr. Robert Gross, Editor-in-Chief, briefly discussing highlighted articles from the May 29, 2018 issue of Neurology. In the first segment, Dr. David Lapides talks with Dr. Maarten Titulaer about his paper on long-term neuropsychological outcome following pediatric anti-NMDAR encephalitis. Next, Dr. Roy Strowd talks with Dr. Saman Zafar about her paper on amateur fundus photography for our “What’s Trending” feature of the week. DISCLOSURES: Dr. Titulaer serves on the editorial board of Neurology: Neuroimmunology & Neuroinflammation; filed a patent for "methods for typing neurological disorders and cancer, and devices for use therein" specifically about diagnostics for anti-GABAB receptor antibodies and KCTD antibodies; and has received research support from Medimmune LLC, Guidepoint Global LLC, Novartis, Euroimmun AG, the Netherlands Organisation for Scientific Research, an ErasmusMC fellowship, and the Dutch Epilepsy Foundations. Dr. Strowd serves on the editorial board for Neurology (Resident & Fellow section); and has received research support from the Wake Forest School of Medicine Center for Translational Sciences Award, the KL2 Career Development Award, and the American Academy of Neurology. Dr. Lapides and Dr. Zafar report no disclosures.

1) Neurology® Neuroimmunology & Neuroinflammation: Next-generation sequencing in neuropathological diagnosis of infections of the nervous system2) e-Pearl topic: GABAb receptor encephalitis3) Topic of the month: Neurology Today story about the global burden of strokeThis podcast for the Neurology Journal begins and closes with Dr. Robert Gross, Editor-in-Chief, briefly discussing highlighted articles from the print issue of Neurology. In the second segment Dr. Heather Harle interviews Dr. Carlo Pardo about his Neurology® Neuroimmunology & Neuroinflammation paper on next-generation sequencing in neuropathological diagnosis of infections of the nervous system. Dr. Steve O'Donnell is reading our e-Pearl of the week about GABAb receptor encephalitis. Dr. Andy Southerland interviews Dr. Vladimir Hachinski about a Neurology Today story on the topic of the global burden of stroke.DISCLOSURES: Dr. Pardo receive research support from the Bart McLean Fund for Neuroimmunology Research-Project Restore and the NIH.Dr. O'Donnell serves on the editorial team for the Neurology® Resident and Fellow Section.Dr. Southerland serves as Podcast Deputy Editor for Neurology; receives research support from the American Heart Association-American Stroke Association National Clinical Research Program, American Academy of Neurology, American Board of Psychiatry and Neurology, Health Resources Services Administration and the NIH; has a provisional patent application titled: “Method, system and computer readable medium for improving treatment times for rapid evaluation of acute stroke via mobile telemedicine;” and gave legal expert review.NO CME WILL BE OFFERED THIS WEEK.

1) GABAB receptor autoantibody frequency in-service serological evaluation and 2) This week's topic: About Ted Burns about being diagnosed with a serious cancer. This podcast for the Neurology Journal begins and closes with Dr. Robert Gross, Editor-in-Chief, briefly discussing highlighted articles from the print issue of Neurology. In the second segment Dr. Zsofia Hole interviews Dr. Andrew McKeon about his paper on GABAB receptor autoantibody frequency in-service serological evaluation. Dr. Roy Strowd is reading our e-Pearl of the week about Fazio-Londe syndrome. In the next part of the podcast Dr. Alberto Espay interviews Dr. Ted Burns about being diagnosed with a serious cancer and how he has gained insight into what it's like being a patient. The participants had nothing to disclose except Drs. McKeon, Strowd, Espay, and Burns.Dr. McKeon receives research support from the Guthy Jackson Charitable Foundation.Dr. Strowd serves on the editorial team for the Neurology® Resident and Fellow Section. Dr. Espay is supported by the K23 career development award (NIMH, 1K23MH092735); has received grant support from CleveMed/Great Lakes Neurotechnologies, Davis Phinney Foundation, and Michael J Fox Foundation; is a consultant for Chelsea Therapeutics; serves on the scientific advisory boards for Solvay Pharmaceuticals, Inc., Abbott (now Abbie), Chelsea Therapeutics, TEVA Pharmaceutical Industries Ltd, Impax Pharmaceuticals, Merz Pharmaceuticals, LLC, Solstice Neurosciences, and Eli Lilly and Company, USWorldMeds; serves as Assistant Editor of Movement Disorders and on the editorial boards of The European Neurological Journal and Frontiers in Movement Disorders; serves on the speakers' bureaus of Novartis, UCB, TEVA Pharmaceutical Industries Ltd, American Academy of Neurology, Movement Disorder Society and receives royalties from Lippincott, Williams & Wilkins and Cambridge University Press.Dr. Burns serves as Podcast Editor for Neurology®; and has received research support for consulting activities with CSL Behring and Alexion Pharmaceuticals.

1) Fingolimod-associated macular edema and 2) Topic of the month: Paraneoplastic syndromes in neurology. This podcast for the Neurology Journal begins and closes with Dr. Robert Gross, Editor-in-Chief, briefly discussing highlighted articles from the print issue of Neurology. In the second segment Dr. Mark Keegan interviews Dr. M. Tariq Bhatti about his paper on fingolimod-associated macular edema. Dr. Jennifer Fugate is reading our e-Pearl of the week about omega 3 fatty acids: Good for the brain. In the next part of the podcast Dr. Chafic Karam interviews Dr. Josep Dalmau about disease specific paraneoplastic disorders. In concluding, there is a brief statement where to find other up-to date patient information and current Patient Page. The participants had nothing to disclose except Drs. Keegan, Bhatti, Fugate, Karam and Dalmau.Dr. Keegan serves as a Section Editor for Neurology® and as Chief Editor for eMedicine and has served as a consultant for Novartis, Bionest Parners, and the FDA.Dr. Bhatti has received consultancy fees, speaker fees or honoraria from Pfizer Inc, EMD Serono, Inc., Novartis and Bayer Schering Pharma.Dr. Fugate serves on the editorial team for the Neurology® Resident and Fellow Section. Dr. Karam serves on the editorial team for the Neurology® Resident and Fellow Section.Dr. Dalmau serves on the editorial board of Neurology®; receives royalties from the editorial board of Up-To-Date; has filed a patent application for the use of LGI1 as a diagnostic test; has received royalties from Athena Diagnostics, Inc. for a patent re: Ma2 autoantibody test and has patents pending re: NMDA and GABAB receptor autoantibody tests (license fee payments received from EUROIMMUN AG); and receives research support from funding from EUROIMMUN AG, the NIH/NCI, and a McKnight Neuroscience of Brain Disorders award.

1) Treatment of spinocerebellar ataxia and 2) Topic of the month: Paraneoplastic syndromes in neurology. This podcast for the Neurology Journal begins and closes with Dr. Robert Gross, Editor-in-Chief, briefly discussing highlighted articles from the print issue of Neurology. In the second segment Dr. Bryan Cupka interviews Dr. Theresa Zesiewicz about her paper on treatment of spinocerebellar ataxia. Dr. Jennifer Fugate is reading our e-Pearl of the week about hereditary angioedema. In the next part of the podcast Dr. Chafic Karam interviews Dr. Josep Dalmau about NMDA encephalitis. Next week, you will hear the last interview by Dr. Karam with Dr. Dalmau about other paraneoplastic syndromes in neurology. The participants had nothing to disclose except Drs. Zesiewicz, Fugate, Karam and Dalmau.Dr. Zesiewicz serves on the speakers' bureau for and has received funding for travel and speaker honoraria from Teva Pharmaceutical Industries Ltd.; serves on the editorial board of Tremor and Other Hyperkinetic Movement Disorders; serves/has served as a consultant for Boehringer Ingelheim, Teva Pharmaceutical Industries Ltd., Allergan, Inc., UCB, and Novartis; is listed as an inventor on a provisional patent on the use of nicotinic modulators in treating ataxia and imbalance held by the University of South Florida; and receives/has received research support from Pfizer Inc, the National Ataxia Foundation, the Friedreich's Ataxia Research Association, and the Bobby Allison Ataxia Research Center.Dr. Fugate serves on the editorial team for the Neurology® Resident and Fellow Section. Dr. Karam serves on the editorial team for the Neurology® Resident and Fellow Section.Dr. Dalmau serves on the editorial board of Neurology®; receives royalties from the editorial board of Up-To-Date; has filed a patent application for the use of LGI1 as a diagnostic test; has received royalties from Athena Diagnostics, Inc. for a patent re: Ma2 autoantibody test and has patents pending re: NMDA and GABAB receptor autoantibody tests (license fee payments received from EUROIMMUN AG); and receives research support from funding from EUROIMMUN AG, the NIH/NCI, and a McKnight Neuroscience of Brain Disorders award.

1) Absent brainstem reflexes and 2) Topic of the month: Paraneoplastic syndromes in neurology. This podcast for the Neurology Journal begins and closes with Dr. Robert Gross, Editor-in-Chief, briefly discussing highlighted articles from the print issue of Neurology. In the second segment Dr. Ted Burns interviews Dr. Shin Chien Beh about his paper on a 41-year-old comatose man. Dr. Jennifer Fugate is reading our e-Pearl of the week about gait freezing. In the next part of the podcast Dr. Chafic Karam interviews Dr. Josep Dalmau about common central nervous system paraneoplastic disorders. Over the next two weeks, Dr. Karam will interview Dr. Dalmau about other paraneoplastic syndromes in neurology. The participants had nothing to disclose except Drs. Burns, Fugate, Karam and Dalmau.Dr. Burns serves as Podcast Editor for Neurology®; performs EMG studies in his neuromuscular practice (30% effort); and has received research support from the Myasthenia Gravis Foundation of America and Knopp Neurosciences Inc..Dr. Fugate serves on the editorial team for the Neurology® Resident and Fellow Section. Dr. Karam serves on the editorial team for the Neurology® Resident and Fellow Section.Dr. Dalmau serves on the editorial board of Neurology®; receives royalties from the editorial board of Up-To-Date; has filed a patent application for the use of LGI1 as a diagnostic test; has received royalties from Athena Diagnostics, Inc. for a patent re: Ma2 autoantibody test and has patents pending re: NMDA and GABAB receptor autoantibody tests (license fee payments received from EUROIMMUN AG); and receives research support from funding from EUROIMMUN AG, the NIH/NCI, and a McKnight Neuroscience of Brain Disorders award.

1) Ophelia syndrome and 2) Topic of the month: Hypoxic-ischemic encephalopathy. This podcast for the Neurology Journal begins and closes with Dr. Robert Gross, Editor-in-Chief, briefly discussing highlighted articles from the print issue of Neurology. In the second segment Dr. Jennie Taylor interviews Dr. Josep Dalmau about his paper on Ophelia syndrome. In the next segment, Dr. Jennifer Fugate is reading our e-Pearl of the week about How long must an athlete wait before returning to play after a concussion? In the next part of the podcast Dr. Ted Burns interviews Dr. Eelco Wijdicks about operational issues related to post-cardiac arrest patients. Over the following weeks, Dr. Burns will interview Dr. Wijdicks about neurologic evaluation of the post-cardiac arrest patient. The participants had nothing to disclose except Drs. Dalmau, Fugate, Burns and Wijdicks.Dr. Dalmau serves on the editorial board of Neurology®; receives royalties from the editorial board of Up-To-Date; has filed a patent application for the use of LGI1 as a diagnostic test; has received royalties from Athena Diagnostics, Inc. for a patent re: Ma2 autoantibody test and has patents pending re: NMDA and GABAB receptor autoantibody tests (license fee payments received from EUROIMMUN AG); and receives research support from funding from EUROIMMUN AG, the NIH/NCI, and a McKnight Neuroscience of Brain Disorders award.Dr. Fugate serves on the editorial team for the Neurology® Resident and Fellow Section. Dr. Burns serves as Podcast Editor for Neurology®; performs EMG studies in his neuromuscular practice (30% effort); and has received research support from the Myasthenia Gravis Foundation of America and Knopp Neurosciences Inc..Dr. Wijdicks serves as Editor-in-Chief for Neurocritical Care; and receives royalties for books published by Oxford University Press.

1) NMDA receptor antibodies and 2) Topic of the month: Neuro-muscular disease. This podcast for the Neurology Journal begins and closes with Dr. Robert Gross, Editor-in-Chief, briefly discussing highlighted articles from the print issue of Neurology. In the second segment Dr. Ted Burns interviews Drs. Harald Pruss, Josep Dalmau and Klaus-Peter Wandinger about their paper on NMDA receptor antibodies. In the next segment, Dr. Ryan Overman is reading our e-Pearl of the week about acute intermittent porphyria as a mimic of Guillain-Barré syndrome. In the next part of the podcast Dr. Beau Bruce interviews Dr. Ted Burns for the next part of our discussion on diagnostic testing for myasthenia gravis for our Lesson of the Week. Over the subsequent three weeks, we will continue to highlight other areas of the frontal cortex. The participants had nothing to disclose except Drs. Dalmau, Wandinger, Overman, and Burns. Dr. Dalmau has received royalties from a patent re: Ma2 autoantibody test and has patents pending re: NMDA and GABAB receptor autoantibody tests (license fee payments received from EUROIMMUN AG); and receives research support from funding from EUROIMMUN AG and the NIH/NCI [RO1CA107192 (PI) and RO1CA89054-06A2 (PI)].Dr. Wandinger is a full-time employee of and holds stock in EUROIMMUN AG. Dr. Overman serves as Deputy Editor on the Neurology® Resident and Fellow Section editorial team and the Neurology® Podcast Committee.Dr. Burns receives a stipend as Podcast Editor for Neurology®, and performs EMG studies in his neuromuscular practice (30% effort).

Aside from recognizing and distinguishing sound patterns, the ability to localize sounds in the horizontal plane is an essential component of the mammalian auditory system. It facilitates approaching potential mating partners and allows avoiding predators. The superior olivary complex (SOC) within the auditory brainstem is the first site of binaural interaction and its major projections and inputs are well investigated. The adult input pattern, however, is not set from the beginning but changes over the period of development. Mammals including humans experience different stages and conditions of hearing during auditory development. The human brain for instance has to perform a transition after birth from the perception of sound waves transmitted in amniotic fluid to the perception of airborne sounds. Furthermore, small mammals like rodents, which are common model organisms for auditory research, perceive airborne sounds for the first time some days after birth, when their ear canals open. The basic neuronal projections and the intrinsic properties of neurons, such as the expression of specific ion channels, are already established and adjusted in the SOC during the perinatal period of partial deafness. An additional refinement of inputs and further adaptations of intrinsic characteristics occur with the onset of hearing in response to the new acoustic environment. It is likely that with ongoing maturation well-established inputs within the sound localization network need these adaptations to balance anatomical changes such as an increasing head size. In addition, short-term adjustments of synaptic inputs in the adult auditory system are equally necessary for a faithful representation of auditory space. A recent study suggests that these short-term adaptations are partially represented at the auditory brainstem level. The question of how intrinsic properties change during auditory development, to what extent auditory experience is involved in these changes and the functional implications of these changes on the sound localization circuitry is only partially answered. I used the hyperpolarization-activated and cyclic nucleotide-gated cation channels (HCN channels), which are a key determinant of the intrinsic properties of auditory brainstem neurons, as a target to study the influence of auditory experience on the intrinsic properties of neurons in the auditory brainstem. Another important question still under discussion is how neurons in the auditory brainstem might fine-tune their firing behavior to cope optimally with an altered acoustic environment. Recent data suggest that auditory processing is also affected by modulatory mechanisms at the brainstem level, which for instance change the input strength and thus alter the spike output of these neurons. One possible candidate is the metabotropic GABAB receptor (GABABR) which has been shown to be abundant in the adult auditory brainstem, although GABAergic projections are scarce in the mature auditory brainstem. These questions were investigated by performing whole-cell patch-clamp recordings of SOC neurons from Mongolian gerbils at different developmental stages in the acute brain slice preparation. Specific currents and receptors were isolated using pharmacological means. Immmunohistochemical results additionally supported physiological findings. In the first study, I investigated the developmental regulation of HCN channels in the SOC and their underlying depolarizing current Ih, which has been shown to regulate the excitability of neurons and to enhance the temporally precise analysis of binaural acoustic cues. I characterized the developmental changes of Ih in neurons of the lateral superior olive (LSO) and the medial nucleus of the trapezoid body (MNTB), which in the adult animals show different HCN subunit composition. I showed that right after hearing onset there was a strong increase of Ih in the LSO and just a minor increase in the MNTB. In addition, the open probability of HCN channels was shifted towards more positive voltages in both nuclei and the activation time constants accelerated during the first days of auditory experience. These results implicate that Ih is actively regulated by sensory input activity. I tested this hypothesis by inducing auditory deprivation which was achieved by surgically removing the cochlea in gerbils before hearing onset. The effect was opposite in neurons of the MNTB and the LSO. Whereas in LSO neurons auditory deprivation resulted in increased Ih amplitude, MNTB neurons displayed a moderate decrease in Ih. These results suggest that auditory experience differentially changes the amount of HCN channels dependent on the subunit composition or possibly alters intracellular cAMP levels, thereby shifting the voltage dependence of Ih. This regulatory mechanism might thus maintain adequate excitability levels within the SOC. A second study was carried out to investigate the role of GABABRs in the medial superior olive (MSO). Upon activation, these metabotropic receptors are known to decrease the release probability of neurotransmitters at the presynapse thereby altering excitatory and inhibitory currents at the postsynaptic site. Neurons in the MSO analyze interaural time differences (ITDs) by comparing the relative timing of the excitatory inputs from the two ears using a coincidence mechanism. In addition, these neurons receive a precisely timed inhibitory input from each ear which shifts ITDs in the physiological relevant range. Since the major inhibitory input changes its transmitter type from mixed GABA/glycinergic to only glycinergic after hearing onset it was now interesting to examine the mediated effects of GABABRs, which have been shown to be abundant in the prehearing and adult MSO of gerbils. Furthermore, revealing the precise expression pattern of GABABRs and their influence on excitatory and inhibitory currents in the MSO during auditory development should provide further evidence of their functional relevance. Performing pharmacological experiments I could now demonstrate that the activation of GABABRs before hearing onset decreases the current of excitatory inputs stronger than that of inhibitory inputs whereas a switch is performed after hearing onset and inhibitory currents are stronger decreasedcompared to excitatory currents. In a similar way, also the expression pattern of GABABRs changes before and after hearing onset as revealed by immunohistochemistry. Since the main inhibitory inputs to the adult MSO are purely glycinergic, it was commonly assumed that GABABRs occupy only a minor role in the mature auditory brainstem. Contradictory to this, it was possible to activate presynaptic GABABRs by synaptic stimulation even in adult animals and to observe a profound decrease of inhibitory current in MSO neurons. These results suggest GABAergic projections of yet unknown origin targeting the MSO. It is therefore quite likely that GABABRs modulate and possibly improve the localization of low frequency sounds even in adult mammals. Summarized, the outcome of this thesis contributes to a better understanding of the developmental adaptation in the auditory system and demonstrates that the orderly specification of intrinsic properties within the SOC is dependent on auditory experience. Moreover, I show that even in mature animals the synaptic strength of MSO inputs can be modulated by synaptic GABA release. This should emphasize the importance of modulatory mechanisms and could be the basis for future studies concerning the field of sound localization.

Durch die Kombination verschiedener experimenteller Methoden konnten in der vorliegenden Arbeit zahlreiche Elemente eines bislang unbekannten GABAergen Steuerungssystems in der Nebennierenrinde nachgewiesen werden. Neben Markern neuroendokriner Differenzierung wie Syntaxin und VAMP-2 konnten sowohl endogene GABA-Produktion als auch GABA-Rezeptoren in steroidproduzierenden Zellen der Nebenniere identifiziert werden. Die Schlüsselenzyme GAD und VIAAT, die für die Synthese und Speicherung von GABA verantwortlich sind, wurden mittels immunologischer und molekularbiologischer Verfahren in adrenokortikalen Zellen lokalisiert. Außerdem wurde die Aktivität von GAD in einem in vitro-Assay nachgewiesen. Daneben wurden GABAA-Rezeptor-Untereinheiten und GABAB-Rezeptoren, darunter die Spleissvariante GABAB(1e), in der Nebennierenrinde vorgefunden. Diese Befunde wurden durch Untersuchung menschlicher und tierischer Gewebe sowie einer menschlichen Nebennierenrinden-Tumorzelllinie (NCI-H295R) gewonnen. Die ausgeprägten Übereinstimmungen zwischen den verschiedenen Modellsystemen unterstreichen dabei die Relevanz der Ergebnisse. Weitergehende Untersuchungen haben zudem ergeben, dass den GABAB-Rezeptoren in der Nebennierenrinde funktionelle Signifikanz zukommt: durch die Modulation von T-Typ Calcium-Strömen interagieren sie mit einem wichtigen Signalweg, dessen Bedeutung für die Steuerung der Steroid-Biosynthese gut belegt ist. In diesem Zusammenhang wurden in der vorliegenden Arbeit auch bereits publizierte Erkenntnisse zur Expression von Calciumkanälen in der Zona glomerulosa bestätigt und durch die Untersuchung humanen Gewebes erweitert. Die in der Ratte festgestellte Lokalisation des GABAergen Systems in der Zona glomerulosa, in Kombination mit dem beobachteten Einfluss von GABAB-Rezeptoren auf Calciumkanäle, deckt sich unter funktionellen Gesichtspunkten gut mit der besonderen Bedeutung des Calcium-Signalwegs für die Regulation der Aldosteronproduktion. Hingegen konnte in der vorliegenden Arbeit weder ein deutlicher Einfluss von adrenokortikalen GABAB-Rezeptoren auf die cAMP-Signaltransduktionskaskade, noch eine Beeinflussung des Proliferationsverhaltens von NCI-H295R-Zellen durch GABAerge Stimulantien festgestellt werden. Die Klärung der physiologischen Rolle von GABA im Kortex der Nebennieren bedarf noch weiterer Forschungsanstrengungen. Insbesondere ist die Frage, ob eine GABAerge Modulation des Calciumeinstroms durch T-Typ-Kanäle tatsächlich die Produktion von Steroidhormonen beeinflusst, noch unbeantwortet. Zudem existieren auffällige Unterschiede in der Verteilung von GAD, VIAAT und GABAB(2) zwischen der Nebennierenrinde der Ratte, verglichen mit der des Menschen. Daher muss noch genauer untersucht werden, ob sich auch die funktionelle Bedeutung von GABA in diesen Spezies unterscheidet. In vivo-Experimente in Ratten, die akutem Stress ausgesetzt wurden, zeigten aber, dass die Verabreichung von Baclofen die Kortikosteron-Konzentration im Blut beeinflusst [95] und unterstreichen somit eine mögliche Rolle von GABA in der Kontrolle der Nebennieren-Funktion. Zusammengefasst zeigen die in dieser Arbeit präsentierten Ergebnisse, dass in der Nebennierenrinde ein bislang unbekanntes, lokales GABAerges Signaltransduktionssystem existiert. Dieser Befund sollte zusammen mit ähnlichen, gut dokumentierten Befunden aus anderen endokrin aktiven Geweben wie der Adenohypophyse, dem endokrinen Pankreas und dem Hoden betrachtet werden. In diesen breiteren Kontext gestellt, unterstützt die vorliegende Arbeit das Konzept, dass GABA nicht nur ein wichtiger Neurotransmitter im ZNS ist, sondern auch ein weit verbreitetes Signalmolekül in peripheren Organen darstellt.

The major neurotransmitter of the central nervous system, gamma-aminobutyric acid (GABA), exerts its actions through GABA(A), GABA(B) and GABA(C) receptors. GABA and GABA receptors are, however, also present in several non-neural tissues, including the endocrine organs pituitary, pancreas and testis. In the case of the rat testis, GABA appears to be linked to the regulation of steroid synthesis by Leydig cells via GABA(A) receptors, but neither testicular sources of GABA, nor the precise nature of testicular GABA receptors are fully known. We examined these points in rat, mouse, hamster and human testicular samples. RT-PCR followed by sequencing showed that the GABA-synthesizing enzymes glutamate decarboxylase (GAD) 65 and/or GAD67, as well as the vesicular GABA transporter vesicular inhibitory amino acid transporter (VIAAT/VGAT) are expressed. Testicular GAD in the rat was shown to be functionally active by using a GAD assay, and Western blot analysis confirmed the presence of GAD65 and GAD67. Interstitial cells, most of which are Leydig cells according to their location and morphological characteristics, showed positive immunoreaction for GAD and VIAAT/VGAT proteins. In addition, several GABA(A) receptor subunits (alpha1-3, beta1-3, gamma1-3), as well as GABAB receptor subunits R1 and R2, were detected by RT-PCR. Western blot analysis confirmed the results for GABA(A) receptor subunits beta2/3 in the rat, and immunohistochemistry identified interstitial Leydig cells to possess immunoreactive GABA(A) receptor subunits beta2/3 and alpha1. The presence of GABA(A) receptor subunit alpha1 mRNA in interstitial cells of the rat testis was further shown after laser microdissection followed by RT-PCR analysis. In summary, these results describe molecular details of the components of an intratesticular GABAergic system expressed in the endocrine compartment of rodent and human testes. While the physiological significance of this peripheral neuroendocrine system conserved throughout species remains to be elucidated, its mere presence in humans suggests the possibility that clinically used drugs might be able to interfere with testicular function. Copyright (C) 2003 S. Karger AG, Basel.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.04.16.045112v1?rss=1 Authors: Bhandari, P., Vandael, D., Fernandez-Fernandez, D., Fritzius, T., Kleindienst, D., Montanaro, J., Gassmann, M., Kulik, A., Jonas, P., Bettler, B., Shigemoto, R., Koppensteiner, P. Abstract: The connection from medial habenula (MHb) to interpeduncular nucleus is critical for aversion- and addiction-related behaviors. This pathway is unique in selective expression of R-type voltage-gated Ca2+ channels (Cav2.3) in its terminals, and robust potentiation of release via presynaptic GABAB receptors (GBRs). To understand the mechanism underlying this peculiar GBR effect, we examined the presynaptic localization and function of Cav2.3, GBR, and its auxiliary subunits, K+-channel tetramerization domain-containing (KCTD) proteins. We found selective co-expression of KCTD12b and Cav2.3 at the presynaptic active zone. GBR-mediated potentiation remained intact in KCTD12b KO mice but lasted significantly shorter. This impairment was associated with increased release and an insertion of KCTD8 into the active zone. In heterologous cells, we found direct binding of KCTD8 and KCTD12b to Cav2.3, and potentiation of Cav2.3 currents by KCTD8. The unexpected interaction of Cav2.3 with KCTDs therefore provides a means to scale synaptic strength independent of GBR activation. Copy rights belong to original authors. Visit the link for more info