The dentate gyrus of the hippocampal formation is a region in the adult brain where new neurons continue to be generated throughout life. Despite increasing evidence that altered adult neurogenesis is associated with the symptoms of depression, traumatic brain injury, epilepsy, and Alzheimer's Disease, the function and regulation of adult neurogenesis is not fully understood. While most adult-generated granule cells (GCs) undergo apoptosis within the first few weeks of maturation, a fraction survives and becomes integrated into the circuit. GABA, the major inhibitory neurotransmitter in the brain, provides the initial depolarizing input and promotes the survival, maturation, and integration of newborn GCs. Previous work from our lab has shown that newborn GCs receive GABAergic signaling from a family of interneurons called Ivy/Neurogliaform cells (NGFCs), yet recently a well-known interneuron subtype called parvalbumin (PV)-expressing interneurons has also been implicated in regulation of neurogenesis. These two types of interneurons have dissimilar functions within neural circuits due to their distinct physiological properties and mechanisms of GABAergic transmission. PV interneurons innervate postsynaptic target cells with temporal and spatial precision, providing rapid GABAA receptor-mediated postsynaptic currents (PSCs) on the soma and axon initial segment, whereas Ivy/NGFC transmission is mediated by a slower synaptic signaling with characteristics of spillover, a form of volume transmission that lacks spatial and temporal specificity. Our preliminary data shows that optogenetic activation of PV+ interneurons in adult brain slices results in slow PSCs in newborn GCs that have characteristics of spillover rather than the fast PSCs generated in neighboring mature GCs. Thus our goal is to determine how a diverse interneuron population signals to newborn GCs and to understand the molecular mechanisms that control the timing and sequence of GABAergic innervation. To address this hypothesis, we will 1) determine mechanisms of GABAergic signaling to newborn GCs, and 2) identify extracellular matrix molecules that regulate GABAergic signaling to newborn GCs. This research will provide a better understanding of activity- dependent regulation of adult neurogenesis as well as reveal novel information about specific functions of these interneuron classes within the DG network. These goals will be achieved using electrophysiology paired with optogenetics and a variety of other diverse techniques under the expert guidance of the sponsor. The proposed work will provide detailed understanding of mechanisms underlying GABAergic signaling to newborn GCs and could provide insight to better interpret the association between disrupted adult neurogenesis and the symptoms of several diseases. The PI's training plan includes participation in formal lab meetings, journal clubs, annual department seminars, presentations at national meetings, training in ethical scientific practices, and regular meetings with the mentor.
The dentate gyrus is one of few brain regions known to produce neurons throughout life. The experiments proposed here will investigate GABAergic synaptic transmission underlying the survival, maturation, and synaptic integration of adult-generated neurons. This project will expand understanding of how a diverse interneuron population works to provide GABAergic signaling to adult-generated neurons and will provide training in fundamental knowledge of synaptic transmission, adult neurogenesis and inhibitory interneuron function.
| Adlaf, Elena W; Vaden, Ryan J; Niver, Anastasia J et al. (2017) Adult-born neurons modify excitatory synaptic transmission to existing neurons. Elife 6: |
