Inositolphospholipid-linked glutamate receptors mediate cerebellar parallel-fiber-Purkinje-cell synaptic transmission.

Abstract

In slices of adult rat cerebellum inositolphospholipid turnover is stimulated markedly by glutamate and its rigid analogues quisqualate and ibotenate. The drug and amino acid specificity of the response reflects a quisqualate-preferring excitatory amino acid receptor. The absence of glutamateenhanced inositolphospholipid turnover in mice with Purkinjecell degeneration indicates that the inositolphospholipid-linked quisqualate receptor mediates parallel fiber-Purkinije cell synaptic transmission. The quantitative prominence of this synapse accounts for the massive enrichment of elements of the inositolphospholipid system in cerebellar Purkinje cells.The inositolphospholipid ("phosphoinositide") (PI) cycle signal-transduction mechanism involves phospholipase Ccatalyzed hydrolysis of phosphatidylinositol 4,5-bisphosphate, forming inositol 1,4,5-trisphosphate (InsP3) and 1,2-diacylglycerol. InsP3 mobilizes calcium from intracellular stores, whereas diacylglycerol activates protein kinase C (1). NaCI/4.7 mM KCl/1.3 mM CaCl2/1.2 mM KH2PO4/1.2 mM MgSO4/25 mM NaHCO3/11.7 mM glucose) equilibrated to pH 7.4 with 5% C02/95% 02 (vol/vol). The slices were preincubated at 37°C in a shaking waterbath for 1 hr, during which the buffer was changed twice.Olivocerebellar projections of some male Sprague-Dawley rats (150-175 g) were lesioned by i.p. injection of 3-acetylpyridine (Sigma) (10). Age-matched controls, injected with saline, were maintained under identical conditions. Rats were sacrificed 14 days after injection, the cerebella were removed, and slices were prepared as described above.Male Purkinje cell degeneration mice (pcd/pcd, C57BR/6J strain) and phenotypically normal littermates (pcd/+) used as controls were purchased from The Jackson Laboratory. The mice were sacrificed by cervical dislocation 35-40 days after birth. Cerebella were removed, and slices were prepared as described. PI

Nitric oxide mediates glutamate-linked enhancement of cGMP levels in the cerebellum.

“…Glutamate is thought to be the neurotransmitter of these parallel fibers. Parallel fibers can influence Purkinje cells by opening ion channels (24) or stimulating phosphatidyl inositol turnover (25), but it has not been established whether they can regulate cGMP levels. Although a substantial body of evidence suggests Purkinje cells as a site where cGMP levels are regulated, other evidence implies an involvement of granule cells and glia (26).…”

Cloning and expression of human brain type I inositol 1,4,5‐trisphosphate 5‐phosphatase High levels of mRNA in cerebellar Purkinje cells

“…It is known that glutamate stimulates Pi turnover and InsP3 accumulation in Purkinje cells [9]. Purkinje neurons of the cerebellar cortex contain a particularly high density of InsP3 receptors [10].…”

Pairing of pre‐ and postsynaptic activities in cerebellar Purkinje cells induces long‐term changes in synaptic efficacy in vitro.

“…In the hippocampus, this molecule acts as a retrograde messenger released by the postsynaptic cell to increase Glu release by presynaptic terminals, and thus contributes to maintenance of LTP Williams, Errington, Lynch & Bliss, 1989). Since ionotropic and metabotropic QA receptors are well expressed in PCs, probably at PF-PC synapses (Crepel et al 1982;Kano & Kato, 1987;Blackstone, Supattapone & Snyder, 1989), we can make the assumption that a similar mechanism operates during pairing PF-mediated EPSPs with trains of sodium spikes. In this case, the retrograde signal would reinforce LTP induced at a presynaptic level (see above).…”