Young Woo Noh1,7, Yangsik Kim2,7, Soowon Lee3, Yeonghyeon Kim1, Jae Jin Shin4, Hyojin Kang5, Il Hwan Kim6 and Eunjoon Kim1,4
1Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea.
2Department of Psychiatry, Inha University Hospital, Incheon 22332, Korea.
3Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Korea.
4Center for Synaptic Brain Dysfunctions, Institute for Basic Science, Daejeon 34141, Korea.
5Division of National Supercomputing, Korea Institute of Science and Technology Information (KISTI), Daejeon 34141, Korea.
6Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
7These authors contributed equally: Young Woo Noh, Yangsik Kim.
Corresponding author : Correspondence to Eunjoon Kim.
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;Irsp53fl/fl mice). LH-projecting mutant mPFC neurons display abnormally increased excitability involving decreased potassium channel gene expression, leading to excessive excitatory synaptic input to LH-GABA 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-VTAGABA pathway and subsequently over-activating VTA-GABA neurons and over-inhibiting VTA-DA neurons. Accordingly, optogenetic activation of the LHGABA-VTAGABA pathway improves social deficits in Emx1-Cre;Irsp53fl/fl mice. Therefore, the mPFC-LHGABA-VTAGABA-VTADA pathway contributes to the social deficits in Emx1-Cre;Irsp53fl/fl mice.