Molecular and functional characterization of GAD67-expressing, newborn granule cells in mouse dentate gyrus

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.

Ctip2-, Satb2-, Prox1-, and GAD65-Expressing Neurons in Rat Cultures: Preponderance of Single- and Double-Positive Cells, and Cell Type-Specific Expression of Neuron-Specific Gene Family Members, Nsg-1 (NEEP21) and Nsg-2 (P19)

“…Prox1/Ctip2 double-positive cells in the hippocampus have also recently been described in vivo during development [ 40 ]. We did not observe Prox1-positive cells co-expressing GAD65, even though Prox1-positive interneurons have been described in the cortex [ 20 ], transiently in the developing hippocampus [ 41 ], and in adult neurogenesis in the hippocampus [ 42 ]. The true complement of transcription factors in any given cell type is not yet known, but caution should be exercised for designating a cell type based on a single transcription factor.…”

The α7 nicotinic acetylcholine receptors regulate hippocampal adult-neurogenesis in a sexually dimorphic fashion

“…While the largest input onto these interneurons appears to be GABAergic, the MS/DBB also have cholinergic neurons both modulating GABAergic locally and projection neurons in intraseptal circuitry (Damborsky et al 2017), as well as directly activating interneurons in the hippocampus (Dannenberg et al 2015). It is also possible that immature neurons expressing GAD67 (Cabezas et al 2013) are contributing to the effect. In short, there are several possible sources of cholinergic input to the NSCs via interneurons as well.…”

Functions and Dysfunctions of Adult Hippocampal Neurogenesis

“…Optogenetic activation of newborn neurons confirmed functional glutamatergic synaptic outputs onto hilar mossy cells and interneurons and CA3 neurons (Gu et al 2012, Toni et al 2007). Two- to four-week-old adult-born neurons synthesize and corelease GABA, in addition to glutamate (Cabezas et al 2012, 2013). However, this GABA release appears to modulate presynaptic mossy fiber excitability only by activating GABA B autoreceptors and GABAergic postsynaptic responses have not been detected (Cabezas et al 2012).…”