From Hyposociability to Hypersociability—The Effects of PSD-95 Deficiency on the Dysfunctional Development of Social Behavior

Abstract

Abnormal social behavior, including both hypo- and hypersociability, is often observed in neurodevelopmental disorders such as autism spectrum disorders. However, the mechanisms associated with these two distinct social behavior abnormalities remain unknown. Postsynaptic density protein-95 (PSD-95) is a highly abundant scaffolding protein in the excitatory synapses and an essential regulator of synaptic maturation by binding to NMDA and AMPA receptors. The DLG4 gene encodes PSD-95, and it is a risk gene for hypersocial behavior. Interestingly, PSD-95 knockout mice exhibit hyposociability during adolescence but hypersociability in adulthood. The adolescent hyposociability is accompanied with an NMDAR hyperfunction in the medial prefrontal cortex (mPFC), an essential part of the social brain for control of sociability. The maturation of mPFC development is delayed until young adults. However, how PSD-95 deficiency affects the functional maturation of mPFC and its connection with other social brain regions remains uncharacterized. It is especially unknown how PSD-95 knockout drives the switch of social behavior from hypo- to hyper-sociability during adolescent-to-adult development. We propose an NMDAR-dependent developmental switch of hypo- to hyper-sociability. PSD-95 deficiency disrupts NMDAR-mediated synaptic connectivity of mPFC and social brain during development in an age- and pathway-specific manner. By utilizing the PSD-95 deficiency mouse, the mechanisms contributing to both hypo- and hyper-sociability can be studied in the same model. This will allow us to assess both local and long-range connectivity of mPFC and examine how they are involved in the distinct impairments in social behavior and how changes in these connections may mature over time.

Integrating unsupervised and reinforcement learning in human categorical perception: A computational model

“…However, the ‘extreme reinforcement learning’ model, reaching sub-optimal performances and potentially low generalisation skills, corroborates an alternative theoretical proposal for which autism could be supported by an extreme and inefficient reward-dependent representation learning [ 15 ]. Considering that autism spectrum condition shows many phenotypes in the social domain (e.g., iper-social and ipo-social profiles; [ 101 ]), our model reconciles the two opposing views suggesting that both the extreme UL/RL models corroborate the existence of different categorisation profiles in autism spectrum condition.…”

Granulocyte colony‐stimulating factor has a sex‐dependent positive effect in the maternal immune activation‐induced autism model

“…Concurring evidence shows that ASD may be significantly associated with a disorder in glial cells (Coley & Gao, 2019; Feyder et al, 2010). In particular, GFAP was demonstrated to be expressed at higher levels in the ASD brain than in healthy controls (Gao & Mack, 2021). Our results indicate that G‐CSF has beneficial effects on the hippocampus depending on sex.…”

Physical Activity, Gut Microbiota, and Genetic Background for Children and Adolescents with Autism Spectrum Disorder

“…The deletion of the DLG4 gene, which encodes PSD-95, leads to behavioral abnormalities that are similar to those found in ASD patients [ 202 ]. PSD-95 knockouts are predicted to result in an increase in silent synapses in prefrontal neurons, resulting in long-range disconnection from other areas of the brain [ 208 ]. According to Coley and Gao, 2019, PSD-95 KO mice displayed impaired memory and learning novelty and hyposociability during adolescence [ 202 , 208 , 209 ].…”

“…PSD-95 knockouts are predicted to result in an increase in silent synapses in prefrontal neurons, resulting in long-range disconnection from other areas of the brain [ 208 ]. According to Coley and Gao, 2019, PSD-95 KO mice displayed impaired memory and learning novelty and hyposociability during adolescence [ 202 , 208 , 209 ]. During development, a PSD-95 deficiency disrupts social brain and synaptic connectivity development, resulting in hyper/hyposociability [ 208 ].…”

“…According to Coley and Gao, 2019, PSD-95 KO mice displayed impaired memory and learning novelty and hyposociability during adolescence [ 202 , 208 , 209 ]. During development, a PSD-95 deficiency disrupts social brain and synaptic connectivity development, resulting in hyper/hyposociability [ 208 ].…”