Adult hippocampal neurogenesis and social behavioural deficits in the R451C Neuroligin3 mouse model of autism are reverted by the antidepressant fluoxetine

Abstract

Neuron generation persists throughout life in the hippocampus but is altered in animal models of neurological and neuropsychiatric diseases, suggesting that disease‐associated decline in cognitive and emotional hippocampal‐dependent behaviours might be functionally linked with dysregulation of postnatal neurogenesis. Depletion of the adult neural stem/progenitor cell (NSPCs) pool and neurogenic decline have been recently described in mice expressing synaptic susceptibility genes associated with autism spectrum disorder (ASDs). To gain further insight into mechanisms regulating neurogenesis in mice carrying mutations in synaptic genes related to monogenic ASDs, we used the R451C Neuroligin3 knock‐in (Nlgn3 KI) mouse, which is characterized by structural brain abnormalities, deficits in synaptic functions and reduced sociability. We show that the number of adult‐born neurons, but not the size of the NSPC pool, was reduced in the ventral dentate gyrus in knock‐in mice. Notably, this neurogenic decline was rescued by daily injecting mice with 10 mg/Kg of the antidepressant fluoxetine for 20 consecutive days. Sustained treatment also improved KI mice's sociability and increased the number of c‐Fos active adult‐born neurons, compared with vehicle‐injected KI mice. Our study uncovers neurogenesis‐mediated alterations in the brain of R451C KI mouse, showing that the R451C Nlgn3 mutation leads to lasting, albeit pharmacologically reversible, changes in the brain, affecting neuron formation in the adult hippocampus. Our results suggest that fluoxetine can ameliorate social behaviour in KI mice, at least in part, by rescuing adult hippocampal neurogenesis, which may be relevant for the pharmacological treatment of ASDs.

Glucocorticoids rescue cell surface trafficking of R451C Neuroligin3 and enhance synapse formation

“…Consequently, NLGN3 protein levels in the brain are reduced to around 10% compared with its levels in the parental mice strain. 19,20 Consistent to the in vitro findings, the mutant protein is retained in the ER and degraded by the proteasome also in vivo. 21 The accumulation of misfolded proteins in the ER can lead to a cellular stress condition and to the activation of the unfolded protein response (UPR), a signaling pathway that aims at reducing the stress in the organelle by enhancing protein folding capacity and proteasome-mediated degradation, while attenuating protein synthesis.…”

“…In the knock‐in mouse strain expressing the R451C mutation, mutant endogenous NLGN3 is highly unstable and is promptly degraded by the proteasome. Consequently, NLGN3 protein levels in the brain are reduced to around 10% compared with its levels in the parental mice strain 19,20 . Consistent to the in vitro findings, the mutant protein is retained in the ER and degraded by the proteasome also in vivo 21 .…”

Insights into the structure and function of the hippocampus: implications for the pathophysiology and treatment of autism spectrum disorder

“…This positive behavioral effect was associated with restored neuronal survival, dendritic development, and synaptic connectivity in the dentate gyrus and CA1 pyramidal neurons ( 256 ). Recent evidence suggests that fluoxetine can ameliorate social behavior in Nlgn3 -KO mice, at least in part, by promoting adult hippocampal neurogenesis ( 257 ). More typically, long-term fluoxetine treatment normalizes hippocampal parvalbumin-positive interneurons number and glucocorticoid signaling of Angelman syndrome model mice, which is important for the restoration of anxiety-like behaviors ( 129 ).…”

Social withdrawal and anxiety-like behavior have an impact on zebrafish adult neurogenesis

“…A high rate of comorbidity between impairment in social functioning and anxiety characterizes many neuropsychiatric and neurological disorders ( Allsop et al, 2014 ). Although, the etiology for the above comorbidity remains largely unknown, defects in adult hippocampal neurogenesis, including alterations in both progenitors’ proliferation as well as on the density of newly born neurons, have gained more attention as possible contributors to the co-existence of above pathologies ( Malberg and Duman, 2003 ; Zhao et al, 2019 ; Gioia et al, 2022 ). More specifically, reduced number of hippocampal newly born neurons, attributed to decreased neuroblast proliferation, was observed in the R451C Neuroligin 3 knock-in mouse model of autism spectrum disorder (ASD) also characterized by reduced sociability ( Gioia et al, 2022 ).…”

“…Although, the etiology for the above comorbidity remains largely unknown, defects in adult hippocampal neurogenesis, including alterations in both progenitors’ proliferation as well as on the density of newly born neurons, have gained more attention as possible contributors to the co-existence of above pathologies ( Malberg and Duman, 2003 ; Zhao et al, 2019 ; Gioia et al, 2022 ). More specifically, reduced number of hippocampal newly born neurons, attributed to decreased neuroblast proliferation, was observed in the R451C Neuroligin 3 knock-in mouse model of autism spectrum disorder (ASD) also characterized by reduced sociability ( Gioia et al, 2022 ). Interestingly, prominent neurogenesis defects were observed in the prefrontal cortex and cerebellum of valproic acid-treated, non-human primates accompanied also by aberrant social interactions ( Zhao et al, 2019 ).…”