Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, CA 94720, USA.
Cell Rep. 2021 Aug 10;36(6):109511. doi: 10.1016/j.celrep.2021.109511.
Tuberous sclerosis complex (TSC) is a neurodevelopmental disorder that often presents with psychiatric conditions, including autism spectrum disorder (ASD). ASD is characterized by restricted, repetitive, and inflexible behaviors, which may result from abnormal activity in striatal circuits that mediate motor learning and action selection. To test whether altered striatal activity contributes to aberrant motor behaviors in the context of TSC, we conditionally deleted Tsc1 from direct or indirect pathway striatal projection neurons (dSPNs or iSPNs, respectively). We find that dSPN-specific loss of Tsc1 impairs endocannabinoid-mediated long-term depression (eCB-LTD) at cortico-dSPN synapses and strongly enhances corticostriatal synaptic drive, which is not observed in iSPNs. dSPN-Tsc1 KO, but not iSPN-Tsc1 KO, mice show enhanced motor learning, a phenotype observed in several mouse models of ASD. These findings demonstrate that dSPNs are particularly sensitive to Tsc1 loss and suggest that enhanced corticostriatal activation may contribute to altered motor behaviors in TSC.
结节性硬化症复合征（TSC）是一种神经发育障碍，常伴有精神疾病，包括自闭症谱系障碍（ASD）。ASD 的特征是受限、重复和不灵活的行为，这可能是由于调节运动学习和动作选择的纹状体回路异常活动所致。为了测试 TSC 背景下纹状体活动的改变是否导致异常运动行为，我们条件性地从直接或间接通路纹状体投射神经元（dSPN 或 iSPN）中缺失 Tsc1。我们发现，dSPN 特异性缺失 Tsc1 会损害皮质- dSPN 突触处的内源性大麻素介导的长时程抑制（eCB-LTD），并强烈增强皮质纹状体的突触驱动，而 iSPN 中则没有观察到这种现象。dSPN-Tsc1 KO，但不是 iSPN-Tsc1 KO，小鼠表现出增强的运动学习，这是几种 ASD 小鼠模型中观察到的表型。这些发现表明 dSPN 对 Tsc1 缺失特别敏感，并提示增强的皮质纹状体激活可能导致 TSC 中运动行为的改变。
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