Perineuronal nets in cerebellar nuclei neurons orchestrate social behaviour via regulation of neuronal activity in circuits innervated by the cerebellum.

Abstract

Certain types of neurons in the central nervous system are wrapped in extracellular matrix protein complexes named perineuronal nets (PNNs). While it is known that PNNs regulate neuronal activity by modulating synaptic plasticity, their pathophysiological role in psychiatric disorders has not been sufficiently clarified. Here, we demonstrate that the expression of PNNs in autism-spectrum-disorder (ASD)-associated mice, valproic acid-injected mice and chromodomain helicase DNA-binding protein 8 (Chd8) gene haploinsufficient mice was decreased in cerebellar nuclei neurons. The pharmacological disruption of PNNs by the enzyme chondroitinase ABC (ChABC) injection into the deep cerebellar nuclei was associated with an impairment of social interaction compared with sham-operated mice. In the large glutamatergic neurons, neuronal activity was increased during social behavior which was revealed by intracellular calcium dynamics and phosphorylation of cAMP responsive element-binding protein 1 (CREB1). The transcriptional factor aryl hydrocarbon receptor nuclear translocator 2 (ARNT2), which regulates neuronal activity, was increased in ChABC-injected mice and ASD-associated mice under the basal condition without any neuronal activity-dependent stimulation of gene expression. Moreover, the evaluation of neuronal activity by the increase of c-Fos in distal regions, including the red nucleus and ventromedial thalamic nuclei, revealed that ChABC injection into the deep cerebellar nuclei negatively affected the c-Fos induction after the social interaction test. The reduction of ARNT2 by injection of adeno-associated virus (AAV) carried shRNA-ARNT2 into the deep cerebellar nuclei, together with ChABC, rescued the impairment of social interaction and restored the induction of c-Fos expression in distal regions compared with scrambled-shRNA-injected mice. Therefore, the present results may imply a functional role of PNNs in the regulation of neuronal activity in the circuits innervated by the cerebellum that orchestrate social behaviour.