Maturation of Nucleus Accumbens Synaptic Transmission Signals a Critical Period for the Rescue of Social Deficits in a Mouse Model of Autism Spectrum Disorder

Abstract

Social behavior emerges early in development, a time marked by the onset of neurodevelopmental disorders featuring social deficits, including autism spectrum disorder (ASD). Although deficits in social interaction and communication are at the core of the clinical diagnosis of ASD, very little is known about their neural correlates at the time of clinical onset of the disorder. The nucleus accumbens (NAc), a brain region extensively implicated in social behavior, undergoes synaptic, cellular and molecular alterations in early life, and is particularly affected in ASD mouse models. To explore a link between the maturation of the NAc and neurodevelopmental deficits in social behavior, we compared age-dependent changes in spontaneous synaptic transmission in NAc shell medium spiny neurons (MSNs) between the highly social C57BL/6J mouse strain and the idiopathic ASD mouse model BTBR T+ Itpr3tf/J at postnatal day (P) 4, P6, P8, P12, P15, P21 and P30. We found that MSNs from both C57BL/6J and BTBR mice display age-dependent increases in spontaneous excitatory and inhibitory synaptic currents between P4 and P30. Comparison of NAc spontaneous transmission between strains showed that BTBR MSNs display increased excitatory transmission during the first postnatal week, and increased inhibition across the first, second and fourth postnatal weeks, suggesting accelerated maturation of excitatory and inhibitory synaptic inputs onto BTBR MSNs compared to C57BL/6J mice. These early life changes in synaptic transmission are consistent with a potential critical period in the maturation of the NAc, which could maximize the efficacy of interventions affecting social behavior. To test this possibility, we treated BTBR mice in either early life (P4-P8) or adulthood (P60-P64) with the mTORC1 antagonist rapamycin, a well-established rescue intervention for ASD-like behavior. We found that rapamycin treatment rescued social interaction deficits in BTBR mice when injected in infancy, but not in adulthood. These data emphasize the importance of studying brain regions involved in the pathophysiology of neurodevelopmental disorders at clinically-relevant time points, which may offer novel insight into the timing and targets of therapeutic interventions to maximize positive outcomes.

Synaptic pruning during adolescence shapes adult social behavior in both males and females

“…Taken together, these findings suggest that interfering with complement‐mediated microglial pruning might delay symptoms and the onset of schizophrenia. Furthermore, studies in mouse models of autism, which show deficit in both pruning and social behavior, report a sensitive period in the NAc for effective treatment of social deficit (Matthiesen et al., 2023). These data suggest that understanding the healthy and abnormal regulation of temporally bound C3‐mediated pruning at the synaptic level may be important to understand complex neurodevelopmental disorders.…”

The lateral habenula integrates age and experience to promote social transitions in developing rats

“…To identify a potential neural substrate for this change, we adapted a viral activity-dependent tagging strategy for developing rats, which showed that distinct neural ensembles are activated by the social-threat test in infants versus juveniles. Future work will be necessary to more fully characterize the neural mechanisms supporting this change across weaning, although targeting downstream, functionally-dissociated projections, such as LHb-VTA-NAc and LHb-VTA-mPFC, is a promising approach 120,121 .…”