Adult neurogenesis is a process that occurs in physiological conditions, and its alteration has been associated with neuropsychiatric disorders. Adult neural stem cells (NSC) pool and formation of new neurons in the hippocampus were found altered in mice expressing susceptibility genes associated with autism spectrum disorders (ASDs), suggesting that some of the behavioural deficits in these mice may be linked with deregulated neurogenesis. Neuroligin genes are involved in several forms of monogenic ASDs and they are implicated in maturation, specification and plasticity of neural network, acting as ligands for presynaptic Neurexins. Neuroligin 3 knock-in mice carrying the R451C substitution displayed deficits in synaptic functions, structural brain abnormalities and behavioural alteration resembling some of the ASDs features. The present project is aimed at investigating NSC properties and adult neurogenesis in the knock-in mice carrying the R451C substitution in NLGN3. We will study the impact of this specific mutation in the NLG3 gene focusing on the subventricular zone (SVZ) and subgranular zone (SGZ) of the hippocampal dentate gyrus (DG), the main neurogenic niche of the adult brain. Specifically, we will compare proliferation, maturation and differentiation of new neurons between knock-in and wild-type mice, both in vivo and in vitro. Adult neurogenesis might have a role in this monogenic form of autism, and we will study in deep how neurogenesis perturbation could be related with autism features.
The reciprocal link between hippocampal neurogenesis regulation and functions is further corroborated by studies showing that adult neuron formation is impaired in neurological disorders marked by dysfunctional DG [1] and that it is feasible to correct part of these deficits by targeting adult born neurons.
In light with these studies there has been growing interest in understanding the contribution of adult hippocampal neurogenesis in cognition and to explore whether defects in this process may be involved in the onset of specific neuropsychiatric disorders, or at least in the appearance of a subset of behavioural deficit associated with such disorders.
In our case the perturbation of hippocampal neurogenesis might be related to the autism associated features. Notably, mice with conditional ablation of Pten (a gene found mutated in autistic patients) in adult neural stem cells showed alteration of adult neurogenesis and impairment in social interactions, suggesting a role of adult neurogenesis in the pathogenesis of abnormal social behaviours [2]. Furthermore, neurogenesis was found altered in other mice model expressing susceptibility genes associated with autism. For example Cntnap2 knock-out mice, Shank3 mutated mice and BTBR mice showed a decrease in neuron formation in the adult hippocampus although the underpinning mechanisms have not been extensively elucidated yet [3; 4].
To determine whether an alteration in number of immature neurons are a general phenomenon of autism, and to asses how perturbation of this process might be related with at least a subset of autism associated features, it will be necessary to extend these analyses to other mice models, such as our R451C Neuroligin3 mice model that expresses a mutation found in autistic patients. The present project could be very promising because it is aimed at investigating adult hippocampal neural stem cell properties for the first time in this NLGN3 mice model.
[1] Sacco, R., et al. (Feb 2018): 131-38 Curr Opin Neurobiol 48.
[2] Amiri, A., et al. (Apr 25 2012):5880-90 J Neurosci 32, no.17.
[3] Cope, E. C., et al. ( sep.-Oct. 2016) eNeuro 3, no.5.
[4] Stephenson, D.T. (May 16 2011) Mol Autism 2, no.1.