Impaired synaptic plasticity in an animal model of autism exhibiting early hippocampal GABAergic-BDNF/TrkB signaling alterations

In Neurodevelopmental Disorders, alterations of synaptic plasticity may trigger structural changes in neuronal circuits involved in cognitive functions. This hypothesis was tested in mice carrying the human R451C mutation of Nlgn3 gene (NLG3R451C KI), found in some families with autistic children. To this aim, the spike time dependent plasticity (STDP) protocol was applied to immature GABAergic Mossy Fibers (MF)-CA3 connections in hippocampal slices from NLG3R451C KI mice. These animals failed to exhibit STD-LTP, an effect that persisted in adulthood when these synapses became glutamatergic. Similar results were obtained in mice lacking the Nlgn3 gene (NLG3 KO mice), suggesting a loss of function. The loss of STD-LTP was associated with a premature shift of GABA from the depolarizing to the hyperpolarizing direction, a reduced BDNF availability and TrkB phosphorylation at potentiated synapses. These effects may constitute a general mechanism underlying cognitive deficits in those forms of Autism caused by synaptic dysfunctions.

Automated summary

In Neurodevelopmental Disorders, changes in synaptic plasticity can lead to structural alterations in neuronal circuits involved in cognitive functions. This study tested this hypothesis in mice with the human R451C mutation of the Nlgn3 gene, which is found in some families with autistic children. The results showed that these mice failed to exhibit STD-LTP and this effect persisted into adulthood. Similar results were found in mice lacking the Nlgn3 gene. The loss of STD-LTP was associated with a premature shift of GABA and reduced BDNF availability, suggesting a potential mechanism underlying cognitive deficits in forms of Autism caused by synaptic dysfunctions.