GABA increases Ca²⁺ in cerebellar granule cell precursors via depolarization: Implications for proliferation

Abstract

SummaryThe amino acids glutamate and gamma-aminobutyric acid (GABA) have primarily been characterized as the most prevalent excitatory and inhibitory, respectively, neurotransmitters in the vertebrate central nervous system. However, the role of these signaling molecules extends far beyond the synapse. GABA, glutamate, and their complement of receptors are essential signaling molecules that regulate developmental processes in both embryonic and young adult mammals. In this review, we describe the current knowledge on the role of GABA and glutamate in development, focusing on the perinatal cerebellum. We will then present novel data suggesting that GABA depolarizes granule cell precursors via GABA A receptors, which leads to calcium increases in these cells. Finally, we will consider the role of GABA and glutamate signaling on cell proliferation and perhaps neural cancers. From our review of the literature and these data, we hypothesize that GABA A receptors and metabotropic glutamate receptors may be a novel target for the pharmacological regulation of the cerebellar tumors, medulloblastomas.2009 IUBMB IUBMB Life, 61(5): [496][497][498][499][500][501][502][503] 2009

Repeated intermittent alcohol exposure during the third trimester-equivalent increases expression of the GABAA receptor δ subunit in cerebellar granule neurons and delays motor development in rats

“…The mechanism responsible for this effect is presently unknown. Expression of the GABA A R δ-subunit in developing CGNs has been shown to be induced and maintained by membrane potential depolarization, elevation of intracellular Ca 2+ levels, and activation of Ca 2+ /calmodulin-dependent kinase (Gault and Siegel, 1997), possibly driven by mossy fiber inputs (Dave and Bordey, 2009; Engblom et al, 2003; Gault and Siegel, 1998; Payne et al, 2008; Takayama and Inoue, 2004). PAE could increase expression levels of the δ subunit by enhancing any of these mechanisms.…”

GABAA Receptor and Glycine Receptor Activation by Paracrine/Autocrine Release of Endogenous Agonists: More Than a Simple Communication Pathway

“…Most studies point to a negative regulation of proliferation by GABA: in embryonic stem cells and peripheral neural crest cells [237,238], in neocortical neuroblasts in vitro [239] and in vivo [59], in cerebellar granule cells [240], in postnatal striatal progenitors [6]. Some other studies indicate a positive effect on NPC proliferation: in cerebellar granule cells [241] and in prominin-positive stem cells of the ependymal zone [242]. Nevertheless, when GABA negatively influences NPC proliferation, it seems to follow a similar sequence during development and in adult-born NPCs [234].…”

Neuronal Activity in Ontogeny and Oncology

“…Like the neurogenic precursor cells of the cerebrum, cerebellar GCPs are also depolarized by glutamate and by GABA via kainate and GABA A receptors, respectively [46]. The effect of depolarization on GCPs is not yet entirely clear [47].…”