Glutamic acid decarboxylase (GAD) as a biomarker of gabaergic activity in autism: Impact on cerebellar circuitry and function

Abstract

Basic circuits in the brain involve excitatory and inhibitory mechanisms. Inhibition in the brain is primarily sustained by the inhibitory neurotransmitter, gamma-amino-butyric acid (GABA). Neurons that use GABA as their neurotransmitter selectively express the GABA-synthesizing enzyme glutamic acid decarboxylase (GAD). This review focuses on recent studies showing abnormalities in the expression of two GAD isoforms, GAD65 and GAD67, by cerebellar GABAergic neurons in postmortem brain tissue sections from individuals with autism. The region of the cerebellum involved in these studies is in the lateral hemisphere, a part of the neocerebellum, in the Crus II region. This region of interest was chosen because of its abundant inputs from the frontal lobe, a region that is important for motor and cognitive processing including high-order executive function and set-shifting behavior tasks. These studies suggest that inhibitory mechanisms may be deeply altered in autism. Specifically, Purkinje cells that are decreased in some autism brains have a large decrease in GAD67 mRNA levels; basket cells, a type of inhibitory interneuron in the molecular layer of the cerebellum contains increased GAD67 mRNA levels; dentate neurons, from the dentate nucleus, a type of deep cerebellar nuclei, contain decreased GAD65 mRNA levels; whereas a large inhibitory neuron type in the granular layer of the cerebellum, Golgi type II cells have normal GAD67 mRNA levels. The chapter describes possible alterations of the normal functioning of cerebellar circuitry which may impact motor and/or cognitive behaviors related to the autistic phenotype. The possibility that these changes could also be a causal role in the disease process is presented.