Social subordination induced by early life adversity rewires inhibitory control of the prefrontal cortex via enhanced Npy1r signaling.

Social hierarchies are present in most mammalian species. In nature, hierarchies offer a tradeoff between reduction of in-group fighting between males, at the expense of an asymmetric sharing of resources. Early life experiences and stress are known to influence the rank an individual attains in adulthood, but the associated cellular and synaptic alterations are poorly understood. Using a maternal separation protocol, we show that care-deprived mice display a long-lasting submissive phenotype, increased social recognition, and enhanced explorative behavior. These alterations are consistent with an adaptation that favors exploration rather than confrontation within a group setting. At the neuronal level, these animals display dendritic atrophy and enhanced inhibitory synaptic inputs in medial prefrontal cortex (mPFC) neurons. To determine what could underlie this synaptic modification, we first assessed global gene expression changes via RNAseq, and next focused on a smaller subset of putatively altered synaptic receptors that could explain the changes in synaptic inhibition. Using different cohorts of maternally deprived mice, we validated a significant increase in the expression of Npy1r, a receptor known to play a role in maternal care, anxiety, foraging, and regulation of group behavior. Using electrophysiological recordings in adult mice while blocking NPY1R signaling, we determined that this receptor plays a key role in enhancing GABAergic currents in mice that experience maternal deprivation. Taken together, our work highlights the potential of regulating NPY1R in social anxiety disorders and the alterations induced in brain circuitry as a consequence of early life stress and adversity.

Abnormal mGluR-mediated synaptic plasticity and autism-like behaviours in Gprasp2 mutant mice.

Autism spectrum disorder (ASD) is characterized by dysfunction in social interactions, stereotypical behaviours and high co-morbidity with intellectual disability. A variety of syndromic and non-syndromic neurodevelopmental disorders have been connected to alterations in metabotropic glutamate receptor (mGluR) signalling. These receptors contribute to synaptic plasticity, spine maturation and circuit development. Here, we investigate the physiological role of Gprasp2, a gene linked to neurodevelopmental disabilities and involved in the postendocytic sorting of G-protein-coupled receptors. We show that Gprasp2 deletion leads to ASD-like behaviour in mice and alterations in synaptic communication. Manipulating the levels of Gprasp2 bidirectionally modulates the surface availability of mGluR5 and produces alterations in dendritic complexity, spine density and synaptic maturation. Loss of Gprasp2 leads to enhanced hippocampal long-term depression, consistent with facilitated mGluR-dependent activation. These findings demonstrate a role for Gprasp2 in glutamatergic synapses and suggest a possible mechanism by which this gene is linked to neurodevelopmental diseases.