Dysregulation of the Synaptic Cytoskeleton in the PFC Drives Neural Circuit Pathology, Leading to Social Dysfunction
Il Hwan Kim,
Namsoo Kim,
Sunwhi Kim,
Koji Toda,
Christina M. Catavero,
Jamie L. Courtland,
Henry H. Yin,
Scott H. Soderling
Affiliations
Il Hwan Kim
Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN, USA; Department of Psychiatry and Behavioral Sciences, Duke University Medical School, Durham, NC, USA
Namsoo Kim
Department of Psychology and Neuroscience, Duke University, Durham, NC, USA
Sunwhi Kim
Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN, USA
Koji Toda
Department of Psychology and Neuroscience, Duke University, Durham, NC, USA
Christina M. Catavero
Department of Cell Biology, Duke University Medical School, Durham, NC, USA
Jamie L. Courtland
Department of Cell Biology, Duke University Medical School, Durham, NC, USA; Department of Neurobiology, Duke University Medical School, Durham, NC, USA
Henry H. Yin
Department of Psychology and Neuroscience, Duke University, Durham, NC, USA; Department of Neurobiology, Duke University Medical School, Durham, NC, USA
Scott H. Soderling
Department of Cell Biology, Duke University Medical School, Durham, NC, USA; Department of Neurobiology, Duke University Medical School, Durham, NC, USA; Corresponding author
Summary: Psychiatric disorders are highly heritable pathologies of altered neural circuit functioning. How genetic mutations lead to specific neural circuit abnormalities underlying behavioral disruptions, however, remains unclear. Using circuit-selective transgenic tools and a mouse model of maladaptive social behavior (ArpC3 mutant), we identify a neural circuit mechanism driving dysfunctional social behavior. We demonstrate that circuit-selective knockout (ctKO) of the ArpC3 gene within prefrontal cortical neurons that project to the basolateral amygdala elevates the excitability of the circuit neurons, leading to disruption of socially evoked neural activity and resulting in abnormal social behavior. Optogenetic activation of this circuit in wild-type mice recapitulates the social dysfunction observed in ArpC3 mutant mice. Finally, the maladaptive sociability of ctKO mice is rescued by optogenetically silencing neurons within this circuit. These results highlight a mechanism of how a gene-to-neural circuit interaction drives altered social behavior, a common phenotype of several psychiatric disorders.
