Holford Timothy W, Letourneau Kaitlyn N, Von-Walter Carolyn, Moncaleano Daniela, Loomis Cody L, Bolton M McLean
Disorders of Neural Circuit Function, Max Planck Florida Institute for Neuroscience, Jupiter, FL, United States.
Front Cell Neurosci. 2025 Jun 26;19:1597131. doi: 10.3389/fncel.2025.1597131. eCollection 2025.
The phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a negative regulator of the mTOR pathway and is strongly associated with autism spectrum disorder (ASD), with up to 25% of ASD patients with macrocephaly harboring PTEN mutations. Mice with germline PTEN haploinsufficiency show behavioral characteristics resembling ASD, as do various mouse models with conditional knockouts of PTEN. Human tissue studies and those from multiple genetic mouse models suggest that dysfunction of GABAergic interneurons may play a role in the development of ASD, but the precise mechanisms remain elusive. PTEN provides a target for investigation because it regulates the development of inhibitory neurons arising from the medial ganglionic eminence, promoting the survival and maturation of parvalbumin (PV+) neurons at the expense of somatostatin (SOM+) neurons.
Here, we investigate how PTEN regulates SOM+ neurons at the cellular and circuit level in the central lateral amygdala (CeL), an area that governs the key ASD behavioral symptoms of social anxiety and altered emotional motivation for social engagement using behavioral analysis, electrophysiology, and two-photon local circuit mapping.
We found that knocking out PTEN in SOM+ neurons results in elevated levels of fear and anxiety and decreases CeL local circuit connectivity. Specifically, this manipulation decreased the strength of connections between individual neurons and altered the distribution of local connections in a cell-type specific manner. In contrast to the deficit in local inhibitory connections within CeL, the excitatory drive from the major CeL input, the basolateral amygdala (BLA) was enhanced.
This combined imbalance of enhanced excitation and diminished local inhibition likely underlies the heightened fear learning and anxiety we observed in the PTEN-SOM-KO mice.
10号染色体缺失的磷酸酶和张力蛋白同源物（PTEN）是mTOR通路的负调节因子，与自闭症谱系障碍（ASD）密切相关，高达25%的大头畸形ASD患者携带PTEN突变。种系PTEN单倍体不足的小鼠表现出类似于ASD的行为特征，各种条件性敲除PTEN的小鼠模型也是如此。人体组织研究和多个基因小鼠模型的研究表明，GABA能中间神经元功能障碍可能在ASD的发展中起作用，但其确切机制仍不清楚。PTEN是一个研究靶点，因为它调节来自内侧神经节隆起的抑制性神经元的发育，以生长抑素（SOM+）神经元为代价促进小白蛋白（PV+）神经元的存活和成熟。
在这里，我们使用行为分析、电生理学和双光子局部回路映射，研究PTEN如何在中央外侧杏仁核（CeL）的细胞和回路水平上调节SOM+神经元，CeL是一个控制社交焦虑和社交参与中情绪动机改变等关键ASD行为症状的区域。
我们发现，在SOM+神经元中敲除PTEN会导致恐惧和焦虑水平升高，并降低CeL局部回路的连通性。具体而言，这种操作降低了单个神经元之间连接的强度，并以细胞类型特异性方式改变了局部连接的分布。与CeL内局部抑制性连接的缺陷相反，CeL的主要输入——基底外侧杏仁核（BLA）的兴奋性驱动增强。
这种增强的兴奋性和减弱的局部抑制性的综合失衡可能是我们在PTEN-SOM-KO小鼠中观察到的恐惧学习增强和焦虑加剧的基础。
