Cerebellar Plasticity and Wiring Defects in a Rodent Model of Non-Syndromic Autism

Background: Human genetic studies have let to the identification of a significant number of autism risk genes, reflecting a significant genetic heterogeneity of the disorder. Monogenic syndromes, such as Fragile X, include autism as one of their multi-facetted symptoms and have revealed specific defects in synaptic plasticity. However, it remains unclear whether non-syndromic forms of autism share common neuronal alterations. In this study we performed a detailed analysis of a mouse model for a non-syndromic form of autism associated with a loss-of-function in neuroligin-3, a gene that encodes a synaptic adhesion molecule.

Objectives: We analyzed functional and structural consequences of neuroligin-3 ablation in cerebellar circuits. The potential reversibility of developmental phenotypes was tested by re-expression of neuroligin-3 in the adult nervous system.

Methods: We examined subcellular and ultrastructural consequences of neuroligin-3 ablation. The function of cerebellar circuits was further assessed using electrophysiological recordings and behavioral assays.

Results: Neuroligin-3 knock-out mice exhibited disrupted hetero-synaptic competition, ectopic climbing fiber synapse formation, and perturbed metabotropic glutamate receptor-dependent synaptic plasticity (mGluR-LTD). Disruption of mGluR-LTD is also a hallmark of Fragile X, a syndromic form of autism. These phenotypes could be rescued by re-expression of neuroligin-3 in juvenile mice.

Conclusions: We discovered an unexpected convergence of synaptic pathophysiology in a non-syndromic form of autism with those in Fragile X syndrome. Our rescue experiments highlight the possibility for reverting neuronal circuit alterations in autism after completion of development. Finally, our study highlights specific wiring defects in cerebellar circuits caused by an autism-associated mutation.