Title

Distribution and source of nerve terminals containing glutamic acid decarboxylase in the inferior olivary complex

Date of Completion

January 1988

Keywords

Biology, Neuroscience

Degree

Ph.D.

Abstract

The inferior olive is the source of the climbing fiber projection to the cerebellar cortex, and receives afferents from about 20 different sources. Glutamate decarboxylase (GAD) is a marker for neurons that release the putative inhibitory neurotransmitter $\gamma$-aminobutyric acid (GABA). These neurons are referred to as GABAergic neurons. An antibody raised against rat GAD was used to immunocyochemically detect a high density of GABAergic nerve terminals in all regions of the mammalian inferior olive, but variations of GAD immunostaining intensity were observed. The heterogenous staining pattern was described in detail for the rat inferior olive, and was found to be due, in part, to regional differences in the sizes of GABAergic boutons. Similar GAD immunostaining patterns and bouton size variations were also observed in rabbit, cat, rhesus monkey and human inferior olives. Local circuit neurons were considered as a possible source of the GABAergic innervation, but GAD immunocytochemistry revealed only a few GABAergic nerve cell bodies in the inferior olives of rat, cat, rhesus monkey and human. Extraolivary sources of the GABAergic boutons in most of the rat inferior olive were determined by retrograde tract-tracing in combination with GAD immunocytochemistry. The vast majority of GABAergic neurons in the cerebellar and lateral vestibular nuclei were retrogradely labelled by injections of peroxidase-conjugated wheat germ agglutinin into the inferior olive. A GABAergic projection from the spinal vestibular nucleus to the caudal inferior olive was also observed by this method. Localized lesions of these nuclei, or transections of their axons, resulted in a severe depletion of GAD-positive boutons in discrete regions of the inferior olive, demonstrating that these sources account for most of the GABAergic innervation in the inferior olive, and that the projections from each source is not overlapping. Preliminary evidence for GABAergic projections from the parasolitary and cuneate nuclei is also presented. This study has demonstrated that many projections once thought to be excitatory are, instead, GABAergic and, presumably, inhibitory. Thus, modulation of climbing fiber activity by GABAergic innervation seems to be an important feature of cerebellar function. ^