Maturation of nucleus accumbens synaptic transmission signals a critical period for the rescue of social deficits in a mouse model of autism spectrum disorder

Molecular Brain

Research

Carl Frank David Steininger¹  Maryam Dadabhoy²  Melina Matthiesen²  Unza Mumtaz²  Abdessattar Khlaifia²  Maithe Arruda-Carvalho³ 

[1] Department of Cell and Systems Biology, University of Toronto, Toronto, ON, M5S3G5, Canada;Department of Psychology, University of Toronto Scarborough, M1C1A4, Toronto, ON, Canada;Department of Psychology, University of Toronto Scarborough, M1C1A4, Toronto, ON, Canada;Department of Cell and Systems Biology, University of Toronto, Toronto, ON, M5S3G5, Canada;

关键词: Development;    Social interaction;    Rapamycin;    BTBR;    Electrophysiology;   

DOI  :  10.1186/s13041-023-01028-8

 received in 2023-02-15, accepted in 2023-04-20,  发布年份 2023

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY   
© The Author(s) 2023

【 图 表 】

Fig. 2

Fig. 1

41116_2023_36_Article_IEq175.gif

41116_2023_36_Article_IEq173.gif

41116_2023_36_Article_IEq169.gif

41116_2023_36_Article_IEq158.gif