α‐Thalassemia X‐linked intellectual disability (ATR‐X) syndrome is a neurodevelopmental disorder caused by mutations in the ATRX gene that encodes a SNF2‐type chromatin‐remodeling protein. The ATRX protein regulates chromatin structure and gene expression in the developing mouse brain and early inactivation leads to DNA replication stress, extensive cell death, and microcephaly. However, the outcome of Atrx loss of function postnatally in neurons is less well understood. We recently reported that conditional inactivation of Atrx in postnatal forebrain excitatory neurons (ATRX‐cKO) causes deficits in long‐term hippocampus‐dependent spatial memory. Thus, we hypothesized that ATRX‐cKO mice will display impaired hippocampal synaptic transmission and plasticity. In the present study, evoked field potentials and current source density analysis were recorded from a multichannel electrode in male, urethane‐anesthetized mice. Three major excitatory synapses, the Schaffer collaterals to basal dendrites and proximal apical dendrites, and the temporoammonic path to distal apical dendrites on hippocampal CA1 pyramidal cells were assessed by their baseline synaptic transmission, including paired‐pulse facilitation (PPF) at 50‐ms interpulse interval, and by their long‐term potentiation (LTP) induced by theta‐frequency burst stimulation. Baseline single‐pulse excitatory response at each synapse did not differ between ATRX‐cKO and control mice, but baseline PPF was reduced at the CA1 basal dendritic synapse in ATRX‐cKO mice. While basal dendritic LTP of the first‐pulse excitatory response was not affected in ATRX‐cKO mice, proximal and distal apical dendritic LTP were marginally and significantly reduced, respectively. These results suggest that ATRX is required in excitatory neurons of the forebrain to achieve normal hippocampal LTP and PPF at the CA1 apical and basal dendritic synapses, respectively. Such alterations in hippocampal synaptic transmission and plasticity could explain the long‐term spatial memory deficits in ATRX‐cKO mice and provide insight into the physiological mechanisms underlying intellectual disability in ATR‐X syndrome patients.

中文翻译：

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前脑兴奋性神经元中 ATRX 的失活影响海马突触可塑性。

α-地中海贫血 X 连锁智力障碍 (ATR-X) 综合征是一种神经发育障碍，由编码 SNF2 型染色质重塑蛋白的ATRX基因突变引起。ATRX 蛋白调节发育中的小鼠大脑中的染色质结构和基因表达，早期失活会导致 DNA 复制应激、广泛的细胞死亡和小头畸形。然而，对出生后神经元中Atrx功能丧失的结果知之甚少。我们最近报道了Atrx 的条件失活出生后前脑兴奋性神经元 (ATRX-cKO) 导致长期海马依赖性空间记忆缺陷。因此，我们假设 ATRX-cKO 小鼠会表现出海马突触传递和可塑性受损。在本研究中，从雄性聚氨酯麻醉小鼠的多通道电极记录诱发场电位和电流源密度分析。三个主要的兴奋性突触，基底树突和近端树突的 Schaffer 侧枝，以及海马 CA1 锥体细胞上远端树突的颞侧通路通过它们的基线突触传递进行评估，包括 50 毫秒脉冲间的配对脉冲促进 (PPF)间隔，以及由θ频率突发刺激诱导的长期增强（LTP）。每个突触的基线单脉冲兴奋反应在 ATRX-cKO 小鼠和对照小鼠之间没有差异，但 ATRX-cKO 小鼠的 CA1 基底树突突触的基线 PPF 降低。虽然 ATRX-cKO 小鼠的第一脉冲兴奋反应的基底树突 LTP 没有受到影响，但近端和远端根尖树突 LTP 分别略有降低和显着降低。这些结果表明，前脑的兴奋性神经元需要 ATRX，以分别在 CA1 顶端和基底树突突触处实现正常的海马 LTP 和 PPF。海马突触传递和可塑性的这种改变可以解释 ATRX-cKO 小鼠的长期空间记忆缺陷，并提供对 ATR-X 综合征患者智力障碍生理机制的深入了解。