DECREASED mGLUR1 RECEPTORS IN THE DENTATE NUCLEUS AND AMPA RECEPTORS IN THE POSTEROLATERAL CEREBELLAR CORTEX IN AUTISM

Background: Purkinje cells in the lateral hemisphere of the cerebellum send robust projections to the dentate nuclei that in turn project to the cerebral cortex. There is strong emerging evidence that this pathway modulates cognitive activity in the cortex and, that the lateral hemisphere sustains a significant decrease in Purkinje cells in many cases of autism.  Inputs to the cerebellar cortex are largely glutamatergic and the preservation of the balance of key GABA and glutamate receptor subtypes is critical to the normal functioning of the cerebellum.

Objectives: To determine the density and distribution of AMPAR, NMDAR, and mGluR1 receptors in the posterolateral cerebellar cortex and dentate nucleus in adult autistic and control cases.

Methods: Radioligand binding experiments were performed in the posterolateral cerebellar cortex (granule cell, Purkinje cell and molecular layers) and dentate nucleus using ³H-AMPA for AMPAR, ³H-MK-801 for NMDAR and ³H-quisqualate for mGluR1 in adult autistic and normal cases. Optical densities were measured and student t-tests were used to compare density by layer and group.

Results: In the autism group, ³H-AMPA binding was significantly decreased in the granule cell layer (p = 0.04), there was a trend for a decrease in the molecular layer (p = 0.07), and ³H-quisqualate binding was significantly reduced in the dentate (p = 0.03). All other measures were in the normal range including ³H-MK-801 in both areas.

Conclusions:   In autism cases, decreased binding of AMPA in the granule cell layer suggests an alteration in afferents from precerebellar nuclei and/or altered glutamate release from mossy fiber terminals at the glomeruli. The trend for a decrease in the molecular layer suggests that the parallel fiber input to the remaining Purkinje cells may also be affected. Decreased mGluR1 binding in the dentate in autism cases may reflect alterations in mossy fiber/climbing fiber collaterals.