Adult hippocampal neurogenesis and social behavioural deficits in the R451C Neuroligin3 mouse model of autism are reverted by the antidepressant fluoxetine. Issue 3 (9th January 2023)

• Record Type: Journal Article
• Authors: Gioia, Roberta; Seri, Tommaso; Diamanti, Tamara; Fimmanò, Stefania; Vitale, Marina; Ahlenius, Henrik; Kokaia, Zaal; Tirone, Felice; Micheli, Laura; Biagioni, Stefano; Lupo, Giuseppe; Rinaldi, Arianna; De Jaco, Antonella; Cacci, Emanuele
• Is Part Of: Journal of neurochemistry. Volume 165:Issue 3(2023)
• Page Start: 318
• Page End: 333
• Publication Date: 2023-01-09
• Subjects: Neurochemistry -- Periodicals; 616.8042
• DOI: 10.1111/jnc.15753
• Languages: English
• ISSNs: 0022-3042

Abstract

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. Abstract : Alterations in hippocampal adult neurogenesis (AHN) have been associated with autism spectrum disorders (ASDs). We show a reduced number of NeuN (green) and Brdu (red) adult‐born neurons and impairment in social behavioural in R451C Neuroligin3 knock‐in mice, a model of monogenic form of autism. Fluoxetine injection reversed both deficits. Our data support the hypothesis that neurogenic dysfunction could play a role in the autistic phenotype, opening new avenues towards pharmacological treatments for ASDs.