Lateral Septal Circuits Govern Schizophrenia-Like Effects of Ketamine on Social Behavior

Social deficits in schizophrenia may stem from underactivity in a specific brain region called the lateral septum (LS). In mice given chronic ketamine to model schizophrenia-like symptoms, the LS showed reduced activation during social encounters. Artificially stimulating the LS restored normal social behavior, while silencing it in healthy mice caused social impairments. Genetic analysis of LS neurons revealed dysregulation of genes linked to neuronal excitability and cell death, with 38 genes overlapping those implicated in human schizophrenia. Activating LS neurons triggered activity in brain areas involved in reward, fear, and sensory processing. The findings suggest the LS acts as a central hub for social behavior, and its dysfunction may underlie social challenges in schizophrenia, pointing to potential targets for new therapies.

Study at a glance

Abstract

Schizophrenia is marked by poor social functioning that can have a severe impact on quality of life and independence, but the underlying neural circuity is not well understood. Here we used a translational model of subanesthetic ketamine in mice to delineate neural pathways in the brain linked to social deficits in schizophrenia. Mice treated with chronic ketamine (30 mg/kg/day for 10 days) exhibit profound social and sensorimotor deficits as previously reported. Using three- dimensional c-Fos immunolabeling and volume imaging (iDISCO), we show that ketamine treatment resulted in hypoactivation of the lateral septum (LS) in response to social stimuli. Chemogenetic activation of the LS rescued social deficits after ketamine treatment, while chemogenetic inhibition of previously active populations in the LS (i.e. social engram neurons) recapitulated social deficits in ketamine-naïve mice. We then examined the translatome of LS social engram neurons and found that ketamine treatment dysregulated genes implicated in neuronal excitability and apoptosis, which may contribute to LS hypoactivation. We also identified 38 differentially expressed genes (DEGs) in common with human schizophrenia, including those involved in mitochondrial function, apoptosis, and neuroinflammatory pathways. Chemogenetic activation of LS social engram neurons induced downstream activity in the ventral part of the basolateral amygdala, subparafascicular nucleus of the thalamus, intercalated amygdalar nucleus, olfactory areas, and dentate gyrus, and it also reduces connectivity of the LS with the piriform cortex and caudate-putamen. In sum, schizophrenia-like social deficits may emerge via changes in the intrinsic excitability of a discrete subpopulation of LS neurons that serve as a central hub to coordinate social behavior via downstream projections to reward, fear extinction, motor and sensory processing regions of the brain.