The PFC-LH-VTA pathway contributes to social deficits in IRSp53-mutant mice

초록

Dopamine (DA) neurons in the ventral tegmental area (VTA) promote social brain functions by releasing DA onto nucleus accumbens neurons, but it remains unclear how VTA neurons communicate with cortical neurons. Here, we report that the medial prefrontal cortex (mPFC)-lateral hypothalamus (LH)-VTA pathway contributes to social deficits in mice with IRSp53 deletion restricted to cortical excitatory neurons (Emx1-Cre;Irsp53(fl/fl) mice). LH-projecting mutant mPFC neurons display abnormally increased excitability involving decreased potassium channel gene expression, leading to excessive excitatory synaptic input to LHGABA neurons. A circuit-specific IRSp53 deletion in LH-projecting mPFC neurons also increases neuronal excitability and induces social deficits. LH-GABA neurons with excessive mPFC excitatory synaptic input show a compensatory decrease in excitability, weakening the inhibitory LHGABA-VTA(GABA) pathway and subsequently over-activating VTA-GABA neurons and over-inhibiting VTADA neurons. Accordingly, optogenetic activation of the LHGABA-VTA(GABA) pathway improves social deficits in Emx1-Cre;Irsp53fl/ fl mice. Therefore, the mPFC-LHGABA-VTA(GABA)-VTA(DA) pathway contributes to the social deficits in Emx1-Cre;Irsp53fl/ fl mice.

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