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.

A computational perspective on autism

“…2). Decreases in ν or c may reflect decreases in GABArelated inhibition that are also consistent with physiological data on autism (7,23,31,32). Changes in the extent of neuronal pooling in the suppressive field SðX, θÞ (e.g., altered lateral connectivity) could also alter the amount of inhibition acting on a neuron.…”

“…5D). Supporting this idea, the GABAergic pathways likely contribute to autism (7,8,31,32), and GABA A and GABA B can contribute differently to divisive normalization. In V1, GABA A modulates response gain but not contrast sensitivity (77), suggesting it contributes to the suppressive field gain term (c) but not the semisaturation constant (ν).…”

“…For example, decreased GABA receptor protein subunits are reported in autism (29,30). Histological analysis further shows decreased mRNA levels of the enzyme GAD in autism (31,32), and mice lacking GAD have decreased GABA levels (23). In a mouse model of autism with increased translation of neuroligins, both an increased E/I ratio and autistic-like behaviors are observed (33).…”

Measuring neural excitation and inhibition in autism: Different approaches, different findings and different interpretations

“…Glutamic acid decarboxylase (GAD) is an enzyme responsible for catalysing the decarboxylation of glutamic acid to form GABA and exists in two isoforms: 65 and 67 (GAD65; GAD67). Post mortem studies have revealed that both GAD65 and GAD 67 are decreased in the cerebellum and parietal cortex of individuals with ASD (Fatemi et al, 2002;Yip, glutamate-glutamine cycle are decreased in post mortem brain tissue of individuals with ASD, thus also suggesting a dysfunction in excitatory neurotransmission in ASD.…”

A single low dose of valproic acid in late prenatal life alters postnatal behavior and glutamic acid decarboxylase levels in the mouse

“…Differences in the expression of GAD isoforms have been reported in people with ASD: GAD65 and GAD67 has been reported to be lower in parietal and cerebellar cortices [39]; GAD67 mRNA levels have been observed as lower in cerebellar Purkinje cells; GAD65 mRNA is lower in select subpopulations of neurons in the cerebellar dentate nuclei [76,77]; and GAD67 mRNA expression is greater in cerebellar interneurons [78]. In the current study, animals exposed had lower GAD65 in all 6 brain regions examined; GAD67 was lower in MB, OB and PFC, but increased in CB, HP and STR.…”