Abstract
Dentate gyrus granule cells (GCs) have been suggested to synthesize both GABA and glutamate immediately after birth and under pathological conditions in the adult. Expression of the GABA synthesizing enzyme GAD67 by GCs during the first few weeks of postnatal development may then allow for transient GABA synthesis and synaptic release from these cells. Here, using the GAD67-EGFP transgenic strain G42, we explored the phenotype of GAD67-expressing GCs in the mouse dentate gyrus. We report a transient, GAD67-driven EGFP expression in differentiating GCs throughout ontogenesis. EGFP expression correlates with the expression of GAD and molecular markers of GABA release and uptake in 2–4 weeks post-mitotic GCs. These rather immature cells are able to fire action potentials (APs) and are synaptically integrated in the hippocampal network. Yet they show physiological properties that differentiate them from mature GCs. Finally, GAD67-expressing GCs express a specific complement of GABAA receptor subunits as well as distinctive features of synaptic and tonic GABA signaling. Our results reveal that GAD67 expression in dentate gyrus GCs is a transient marker of late differentiation that persists throughout life and the G42 strain may be used to visualize newborn GCs at a specific, well-defined differentiation stage.
Highlights
Dentate gyrus granule cells (GCs) convey synaptic signals from entorhinal cortex to the hilus and Ammon’s horn through a complex axonal arborization, the mossy fibers (MFs)
GCs appear to contain two, fast-acting neurotransmitters with opposing post-synaptic effects and may switch neurotransmitter modality during postnatal developmental and in pathological conditions (Gutierrez, 2005). Consistent with this hypothesis, putative monosynaptic IPSCs were recorded in CA3 principal cells upon minimal MF stimulation (Walker et al, 2001; Gutierrez et al, 2003; Safiulina et al, 2006), suggestive of synaptic GABA release from mossy fiber terminals (MFTs) and activation of post-synaptic GABAA receptors. This conclusion was recently challenged by experimental evidence showing that (1) the vesicular transporter of GABA (VIAAT) is not detected in MFTs (Sperk et al, 2003; Uchigashima et al, 2007), (2) monosynaptic IPSCs evoked by extracellular stimulation in the granule cell layer do not show typical properties of synaptic transmission from MFTs (Uchigashima et al, 2007), (3) stimulation of individual GCs does not induce monosynaptic IPSCs in CA3 pyramidal cells (Mori et al, 2004; Cabezas et al, 2012)
In the hippocampus, EGFP expression was largely confined to the dentate gyrus (Cabezas et al, 2012) where it did not colocalize with parvalbumin (Figure 1A)
Summary
Dentate gyrus granule cells (GCs) convey synaptic signals from entorhinal cortex to the hilus and Ammon’s horn through a complex axonal arborization, the mossy fibers (MFs). GCs appear to contain two, fast-acting neurotransmitters with opposing post-synaptic effects and may switch neurotransmitter modality during postnatal developmental and in pathological conditions (Gutierrez, 2005). Consistent with this hypothesis, putative monosynaptic IPSCs were recorded in CA3 principal cells upon minimal MF stimulation (Walker et al, 2001; Gutierrez et al, 2003; Safiulina et al, 2006), suggestive of synaptic GABA release from MFTs and activation of post-synaptic GABAA receptors. This conclusion was recently challenged by experimental evidence showing that (1) the vesicular transporter of GABA (VIAAT) is not detected in MFTs (Sperk et al, 2003; Uchigashima et al, 2007), (2) monosynaptic IPSCs evoked by extracellular stimulation in the granule cell layer do not show typical properties of synaptic transmission from MFTs (Uchigashima et al, 2007), (3) stimulation of individual GCs does not induce monosynaptic IPSCs in CA3 pyramidal cells (Mori et al, 2004; Cabezas et al, 2012)
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