GABAergic cerebellar system in autism: A neuropathological and developmental perspective

Alterations in the GABAergic system in autism only recently became evident affecting specific receptors in die hippocampus, GAD protein levels in parietal cortex and cerebellum and a decreased number of GABAergic Purkinje cells evident in a subset of autistic cases. A candidate gene for the GABA-A beta 3 subunit has remained attractive on the chromosome 15q11-q13 region in a subset of individuals. Current Studies are revealing valuable data toward understanding how cerebellar circuitry may be altered in autism as better markers and techniques become available. In particular, immunostaining of Purkinje cells demonstrated that previous Nissl studies may have overlooked agonal effects on the efficacy of tissue sections bringing into question results of previous Studies, sonic of which also did not control for age. It appears that: the cerebellum in autism shows variability in neuropathology similar to that described for other affected brain areas in autism. Decreased Purkinje cells arc present in about half of cases in the posterior lateral cerebellar cortex yet normal cytoarchitecture persists throughout the cerebellum indicating completion of migration of both Purkinje cell and granule cell populations. Despite the Purkinje cell decrease, normal density of GABAergic interneurons, basket and stellate cells, are present in the molecular layer and neurons are also preserved in the principal olive that projects to the posterior lobe in the lateral hemisphere. This suggests that the Purkinje cell loss probably occurs at about 32 weeks of gestation or later but most likely no later that early postnatal development. Current Studies have demonstrated that Purkinje cells are deficient in GAD67 possibly affecting GABA synthesis.