Decreased GAD67 mRNA levels in cerebellar Purkinje cells in autism: pathophysiological implications

Abstract

The recent identification of decreased protein levels of glutamate decarboxylase (GAD) 65 and 67 isoforms in the autistic cerebellar tissue raises the possibility that abnormal regulation of GABA production in individual neurons may contribute to the clinical features of autism. Reductions in Purkinje cell number have been widely reported in autism. It is not known whether the GAD changes also occur in Purkinje cells at the level of transcription. Using a novel approach, the present study quantified GAD67 mRNA, the most abundant isoform in Purkinje cells, using in situ hybridization in adult autistic and control cases. The results indicate that GAD67 mRNA level was reduced by 40% in the autistic group (P < 0.0001; two-tailed t test), suggesting that reduced Purkinje cell GABA input to the cerebellar nuclei potentially disrupts cerebellar output to higher association cortices affecting motor and/or cognitive function. These findings may also contribute to the understanding of previous reports of alterations in the GABAergic system in limbic and cerebro-cortical areas contributing to a more widespread pathophysiology in autistic brains.