Social behavior emerges early in development, a time marked by the onset of neurodevelopmental disorders featuring social deficits, including autism spectrum disorder (ASD). Although social deficits are at the core of the clinical diagnosis of ASD, very little is known about their neural correlates at the time of clinical onset. 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 spontaneous synaptic transmission in NAc shell medium spiny neurons (MSNs) between the highly social C57BL/6J and the idiopathic ASD mouse model BTBR T+Itpr3tf/J at postnatal day (P) 4, P6, P8, P12, P15, P21 and P30. BTBR NAc MSNs display increased spontaneous 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 compared to C57BL/6J mice. BTBR mice also show increased optically evoked medial prefrontal cortex-NAc paired pulse ratios at P15 and P30. These early changes in synaptic transmission are consistent with a potential critical period, which could maximize the efficacy of rescue interventions. To test this, we treated BTBR mice in either early life (P4-P8) or adulthood (P60-P64) with the mTORC1 antagonist rapamycin, a well-established intervention for ASD-like behavior. Rapamycin treatment rescued social interaction deficits in BTBR mice when injected in infancy, but did not affect social interaction in adulthood.

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.

Social behavior emerges early in development, a time marked by the onset of neurodevelopmental disorders featuring social deficits, including autism spectrum disorder (ASD). Although social deficits are at the core of the clinical diagnosis of ASD, very little is known about their neural correlates at the time of clinical onset. 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 spontaneous synaptic transmission in NAc shell medium spiny neurons (MSNs) between the highly social C57BL/6J and the idiopathic ASD mouse model BTBR T+Itpr3tf/J at postnatal day (P) 4, P6, P8, P12, P15, P21 and P30. BTBR NAc MSNs display increased spontaneous 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 compared to C57BL/6J mice. BTBR mice also show decreased optically evoked medial prefrontal cortex-NAc synaptic transmission at P15 and P30. These early changes in synaptic transmission are consistent with a potential critical period, which could maximize the efficacy of rescue interventions. To test this, we treated BTBR mice in either early life (P4-P8) or adulthood (P60-P64) with the mTORC1 antagonist rapamycin, a well-established intervention for ASD-like behavior. Rapamycin treatment rescued social interaction deficits in BTBR mice when injected in infancy, but not in adulthood.