Elucidating mechanisms and finding a novel source of GABA signaling in the neurogenic subventricular zone

The generation of new neurons in the brain after birth occurs in two privileged regions of the brain, the largest one being the subventricular zone (SVZ) that lines the lateral ventricles of human and murine brains. Many signals have been shown to play a role in the regulation of the SVZ stem cells and their progeny. One such signal is the neurotransmitter gamma-amino butyric acid (GABA). GABA is the main inhibitory transmitter in mature neurons, but has significant roles in regulating various phases of development in immature and developing brain regions. GABA will typically "inhibit" a neuron, but in immature cells, GABA appears to do the opposite by acting as a depolarizing signal. Here, I explored three unique aspects of GABA signaling that provide a broader view of GABA as a signaling molecule. First, I looked at the mechanism by which GABA depolarizes the putative astrocyte-like stem cells of the SVZ. It appears that GABA signaling in SVZ astrocytes is dependent on L- and T- type voltage gated channels for intracellular calcium increases. Second, I examined what the in vivo role of GABA is in the generation of new neurons by altering its ability to depolarize SVZ cells. I found that by shifting GABA hyperpolarization earlier in the development of SVZ cells, calcium dynamics and newborn cell morphology is altered, which confirms similar findings in other immature regions. In addition, with the lack of depolarization from GABA the number of neurons generated from the astrocyte-like stem cells in the SVZ is reduced. Third, I found a novel source of GABA from striatal neurons that contact SVZ cells. Together, these data provide a better idea about how GABA may differentially affect SVZ astrocytes versus the immature neurons that are born from that region. In addition, by potentially incorporating signaling from surrounding mature neuronal networks, it points to a broader definition of the SVZ as a neurogenic niche. By elucidating the signals and mechanisms that can regulate and alter the behaviors of these cells, we can begin to understand the characteristics that make SVZ cells uniquely capable of generating new neurons in the adult brain.