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.
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