Abstract
IRSp53, an abundant excitatory postsynaptic scaffolding protein that regulates dendritic spines and synaptic function through Rac/Cdc42- dependent modulation of actin, has been implicated in psychiatric disorders, including autism spectrum disorders. Deletion of Irsp53 in mice leads to strong social deficits, but which brain circuits are associated with this phenotype remains unclear. Here, we report that conditional Irsp53 deletion restricted to glutamatergic, but not GABAergic, neurons leads to strong social deficits. Virus-mediated local Irsp53 deletion revealed that the lateral hypothalamus (LH) is a unique brain region associated with similar social deficits. These two different types of Irsp53 deletions lead to similar weakening of the inhibitory LH-to-VTA (ventral tegmental area) pathway. Notably, chemogenetic modulation of this pathway improved social deficits in Irsp53-knockout mice. These results suggest that the inhibitory LH-VTA pathway contributes to social deficits in Irsp53-knockout mice.
Published Version
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