Presynaptic But Not Postsynaptic GABA Signaling at Unitary Mossy Fiber Synapses

Abstract

Dentate gyrus granule cells have been suggested to corelease GABA and glutamate both in juvenile animals and under pathological conditions in adults. Although mossy fiber terminals (MFTs) are known to express glutamic acid decarboxylase (GAD) in early postnatal development, the functional role of GABA synthesis in MFTs remains controversial, and direct evidence for synaptic GABA release from MFTs is missing. Here, using GAD67-GFP transgenic mice, we show that GAD67 is expressed only in a population of immature granule cells in juvenile animals. We demonstrate that GABA can be released from these cells and modulate mossy fiber excitability through activation of GABAB autoreceptors. However, unitary postsynaptic currents generated by individual, GAD67-expressing granule cells are purely glutamatergic in all postsynaptic cell types tested. Thus GAD67 expression does not endow dentate gyrus granule cells with a full GABAergic phenotype and GABA primarily instructs the pre-rather than the postsynaptic element.

GABABreceptors

“…39 Immature granule neurons in the postnatal DG express functional GABA B receptors that modulate presynaptic excitability and could potentially influence differentiation of these cells. 16 Interestingly, even though dendritic length and morphology of newborn neurons were not analyzed, a decrease in Doublecortin expression and an increase in NeuN expression were detected in the DG of adult GABA B1deficient mice, suggesting that accelerated neuronal maturation, in addition to increased cell proliferation, contributes to enhanced hippocampal neurogenesis in the absence of functional GABA B receptors. 40 However, and in apparent contrast to these findings, treatment with a GABA B receptor antagonist had no significant effects on dendritic initiation in postnatally generated olfactory bulb interneurons.…”

“…16,40 Expression of GABA B receptors in the adult SVZ has not been addressed in great detail. However, mRNA of several G-protein-coupled receptors, including the GABA B1 receptor subunit, has been detected in SVZ NSCs.…”

“…39 Mechanistically, it is not known how GABA B receptors regulate adult neurogenesis and the downstream molecular pathways involved. Presynaptic GABA B receptors seem to be coupled to GIRK channels in immature granule neurons of the hippocampus 16 and activation of GIRKs can induce changes in membrane excitability and in turn affect several cellular processes. GABA B receptors are also able to modulate opening of calcium channels at the cell membrane as well as intracellular calcium mobilization by regulating phospholipase C, thereby influencing calcium-sensitive signaling cascades that could affect adult neurogenesis.…”

“…[12][13][14] In addition to interneurons, new glutamatergic granule cells can transiently release GABA during their differentiation. 15,16 Genetic loss of function experiments demonstrated that GABA A receptor activity inhibits cell proliferation in the adult hippocampus. 12,17 In the same line, GABA A neural stem cells (nSCs) continually produce differentiated progeny within restricted areas of the adult mammalian brain.…”

Viral and Transgenic Reporters and Genetic Analysis of Adult Neurogenesis

“…The intrinsic and synaptic properties of immature GCs in another line of GAD67-GFP mice have also been well characterized (Cabezas et al 2013). Although the functional role of GABA synthesis in immature GCs remains controversial (Uchigashima et al 2007), recent work using GAD67-GFP transgenic mice showed that GABA release from immature mossy fibers can modulate mossy fiber excitability via GABA B autoreceptors (Cabezas et al 2012). …”