Ordemann Gregory J, Apgar Christopher J, Chitwood Raymond A, Brager Darrin H
Department of Neuroscience, Institute for Neuroscience, Center for Learning and Memory, University of Texas at Austin, Austin, Texas 78712.
Department of Neuroscience, Institute for Neuroscience, Center for Learning and Memory, University of Texas at Austin, Austin, Texas 78712
J Neurosci. 2021 Jul 7;41(27):5947-5962. doi: 10.1523/JNEUROSCI.0082-21.2021.
Fragile X syndrome (FXS) is the leading monogenetic cause of cognitive impairment and autism spectrum disorder. Area CA1 of the hippocampus receives current information about the external world from the entorhinal cortex via the temporoammonic (TA) pathway. Given its role in learning and memory, it is surprising that little is known about TA long-term potentiation (TA-LTP) in FXS. We found that TA-LTP was impaired in male KO mice. Although there were no significant differences in basal synaptic transmission, synaptically evoked dendritic calcium signals were smaller in KO neurons. Using dendritic recording, we found no difference in complex spikes or pharmacologically isolated Ca spikes; however, the threshold for fast, Na-dependent dendritic spikes was depolarized in KO mice. Cell-attached patch-clamp recordings found no difference in Na channels between wild-type and KO CA1 dendrites. Dendritic spike threshold and TA-LTP were restored by blocking A-type K channels with either 150 µm Ba or the more specific toxin AmmTx3. The impairment of TA-LTP shown here, coupled with previously described enhanced Schaffer collateral LTP, may contribute to spatial memory alterations in FXS. Furthermore, as both of these LTP phenotypes are attributed to changes in A-type K channels in FXS, our findings provide a potential therapeutic target to treat cognitive impairments in FXS. Alterations in synaptic function and plasticity are likely contributors to learning and memory impairments in many neurologic disorders. Fragile X syndrome is marked by dysfunctional learning and memory and changes in synaptic structure and function. This study shows a lack of LTP at temporoammonic synapses in CA1 neurons associated with biophysical differences in A-type K channels in KO CA1 neurons. Our results, along with previous findings on A-type K channel effects on Schaffer collateral LTP, reveal differential effects of a single ion channelopathy on LTP at the two major excitatory pathways of CA1 pyramidal neurons. These findings expand our understanding of memory deficits in FXS and provide a potential therapeutic target for the treatment of memory dysfunction in FXS.
脆性X综合征（FXS）是认知障碍和自闭症谱系障碍的主要单基因病因。海马体CA1区通过颞叶-海马通路（TA）从内嗅皮质接收有关外部世界的当前信息。鉴于其在学习和记忆中的作用，令人惊讶的是，对于FXS中的TA长时程增强（TA-LTP）知之甚少。我们发现雄性KO小鼠的TA-LTP受损。尽管基础突触传递没有显著差异，但KO神经元中突触诱发的树突状钙信号较小。使用树突记录，我们发现复合峰电位或药理学分离的钙峰电位没有差异；然而，KO小鼠中快速、钠依赖性树突状峰电位的阈值去极化。细胞贴附式膜片钳记录发现野生型和KO CA1树突之间的钠通道没有差异。用150 µm Ba或更特异的毒素AmmTx3阻断A型钾通道可恢复树突状峰电位阈值和TA-LTP。此处显示的TA-LTP损伤，加上先前描述的增强的沙费尔侧支LTP，可能导致FXS中的空间记忆改变。此外，由于这两种LTP表型都归因于FXS中A型钾通道的变化，我们的发现为治疗FXS中的认知障碍提供了一个潜在的治疗靶点。突触功能和可塑性的改变可能是许多神经系统疾病中学习和记忆障碍的原因。脆性X综合征的特征是学习和记忆功能障碍以及突触结构和功能的变化。这项研究表明，与KO CA1神经元中A型钾通道的生物物理差异相关的CA1神经元颞叶-海马突触处缺乏LTP。我们的结果，连同先前关于A型钾通道对沙费尔侧支LTP影响的发现，揭示了单一离子通道病对CA1锥体神经元两条主要兴奋性通路LTP的不同影响。这些发现扩展了我们对FXS中记忆缺陷的理解，并为治疗FXS中的记忆功能障碍提供了一个潜在的治疗靶点。
