Hippocampal Granule Cells Downregulate Their GABAergic Phenotype and Deactivate Its Activity‐Dependent Reinduction in Culture Conditions

Hippocampal granule cells express GABAergic and glutamatergic phenotype markers during development; hence, they corelease GABA and glutamate. In the adult, the GABAergic phenotype is switched off; however, increased excitability upregulates the GABAergic phenotype and thus, granule cells corelease glutamate and GABA. Previous work shows that short-term cultures (24 h) of dissociated granule cells prepared from adult rats, which do not express GAD or VGAT, can express these markers when exposed to kainic acid and BDNF. We here test whether the same manipulation enables granule cells to corelease glutamate and GABA in long-term cultures where cells are connected. Interestingly, we find that long-term cultured cells are not able to express the GABAergic phenotype despite presenting it during their development, and with paired recordings, we confirm that granule cells only release glutamate. The development of granule cells in long-term isolation likely deprives them of essential signaling that a normal cellular milieu provides to enable phenotypic change. The molecular mechanisms that could underlie this should be further explored by comparing their development in situ and in cultured conditions.