Center for Learning and Memory, University of Texas at Austin, Austin, TX, USA.
Department of Neuroscience, University of Texas at Austin, Austin, TX, USA.
J Physiol. 2023 Feb;601(4):831-845. doi: 10.1113/JP283311. Epub 2023 Jan 29.
Patients with Fragile X syndrome, the leading monogenetic cause of autism, suffer from impairments related to the prefrontal cortex, including working memory and attention. Synaptic inputs to the distal dendrites of layer 5 pyramidal neurons in the prefrontal cortex have a weak influence on the somatic membrane potential. To overcome this filtering, distal inputs are transformed into local dendritic Na spikes, which propagate to the soma and trigger action potential output. Layer 5 extratelencephalic (ET) prefrontal cortex (PFC) neurons project to the brainstem and various thalamic nuclei and are therefore well positioned to integrate task-relevant sensory signals and guide motor actions. We used current clamp and outside-out patch clamp recording to investigate dendritic spike generation in ET neurons from male wild-type and Fmr1 knockout (FX) mice. The threshold for dendritic spikes was more depolarized in FX neurons compared to wild-type. Analysis of voltage responses to simulated in vivo 'noisy' current injections showed that a larger dendritic input stimulus was required to elicit dendritic spikes in FX ET dendrites compared to wild-type. Patch clamp recordings revealed that the dendritic Na conductance was significantly smaller in FX ET dendrites. Taken together, our results suggest that the generation of Na -dependent dendritic spikes is impaired in ET neurons of the PFC in FX mice. Considering our prior findings that somatic D-type K and dendritic hyperpolarization-activated cyclic nucleotide-gated-channel function is reduced in ET neurons, we suggest that dendritic integration by PFC circuits is fundamentally altered in Fragile X syndrome. KEY POINTS: Dendritic spike threshold is depolarized in layer 5 prefrontal cortex neurons in Fmr1 knockout (FX) mice. Simultaneous somatic and dendritic recording with white noise current injections revealed that larger dendritic stimuli were required to elicit dendritic spikes in FX extratelencephalic (ET) neurons. Outside-out patch clamp recording revealed that dendritic sodium conductance density was lower in FX ET neurons.
患有脆性 X 综合征的患者，这是自闭症的主要单基因病因，他们的前额叶皮层相关功能受到损伤，包括工作记忆和注意力。前额叶皮层第 5 层锥体神经元的远端树突上的突触传入对体细胞膜电位的影响较弱。为了克服这种过滤，远端输入被转化为局部树突 Na 峰，它传播到体并触发动作电位输出。第 5 层额外皮质（ET）前额叶皮层（PFC）神经元投射到脑干和各种丘脑核，因此非常适合整合与任务相关的感觉信号并指导运动动作。我们使用电流箝位和胞外贴附式膜片钳记录来研究雄性野生型和 Fmr1 敲除（FX）小鼠 ET 神经元中的树突棘产生。与野生型相比，FX 神经元中的树突棘阈值更去极化。对模拟体内“嘈杂”电流注入的电压响应分析表明，与野生型相比，FX ET 树突中需要更大的树突输入刺激来引发树突棘。膜片钳记录显示，FX ET 树突中的树突 Na 电导明显较小。总的来说，我们的结果表明，FX 小鼠 PFC 中的 ET 神经元中 Na 依赖性树突棘的产生受损。考虑到我们之前的发现，即 D 型钾通道和树突超极化激活环核苷酸门通道功能在 ET 神经元中减少，我们认为 PFC 回路的树突整合在脆性 X 综合征中发生了根本改变。关键点：Fmr1 敲除（FX）小鼠第 5 层前额叶皮层神经元的树突棘阈值去极化。通过白噪声电流注入进行的同时体和树突记录显示，FX 外皮质（ET）神经元中需要更大的树突刺激来引发树突棘。胞外贴附式膜片钳记录显示，FX ET 神经元中的树突钠电导密度较低。
