Circuit-based mechanisms of neuronal vulnerability in the adult EC

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Project summary/abstract. Entorhinal cortex layer II (ECII) neurons are some of the first cells to degenerate in Alzheimer’s Disease (AD). ECII axons form the perforant pathway and are the major cortical input into the hippocampus. The perforant pathway supports memory formation and spatial navigation throughout life, and loss of this input is consistent with the cognitive deficits that present early in AD. To mimic the loss of this input in AD, the Jankowsky lab created a chemogenetic mouse model of perforant pathway disruption in which a subset of ECII neurons express an engineered chloride channel (GlyCl) to prevent the generation of action potentials. We unexpectedly discovered that entorhinal neurons were highly vulnerable to silencing. Shortly after being inactivated, many ECII neurons retract their axons from the dentate gyrus, express pro- apoptotic proteins, and then are eliminated from the circuit. We observed similar neurodegeneration after eliminating neurotransmitter release with tetanus toxin (TeTX), confirming that neuronal loss is not an artifact of GlyCl activation. Further, this silencing-induced degeneration is not shared by other brain regions, as neither the pre/parasubiculum nor retrosplenial cortex exhibit cell loss after neuronal inactivation. This suggests that specific features of the entorhinal cortex may confer neuronal vulnerability to inactivity. One possible vulnerability could be related to the formation of entorhinal-hippocampal circuit. We noted that the pattern of ECII degeneration after silencing was strikingly similar to the processes that guide to refinement of the perforant pathway during development. In early post-natal periods, inactive ECII neurons are pruned from the circuit in a process that is mediated by local differences in activity, referred to as activity- dependent competition. Projections are only pruned when neurons are sparsely inactive - when all cells are equally inactive, none are removed. This proposal will test two hypotheses about the cellular mechanism driving neuronal death in the mature entorhinal cortex. Aim 1 will determine whether activity-dependent competition persists in the adult ECII. Pharmacological and genetic approaches will be used to modulate relative activity levels to determine how cell death is influenced by activity differences between neighboring cells. Aim 2 will determine whether post-synaptic partners promote the survival of ECII neurons. Our preliminary data suggests that eliminating neurotransmitter release from ECII neurons – without blocking action potentials - is sufficient to induce degeneration. I will therefore use pharmacological and genetic approaches to both reduce neurotransmitter binding in dentate granule cells and eliminate their ability to fire action potentials in response to ECII input. This will test whether neurotransmitter-mediate signaling, or post-synaptic activity itself, is required for ECII neuron survival. Data from these aims will determine how activity disruption may mediate cell death in the adult brain. Further, these data may suggest that mechanisms which drive cell death during postnatal development are not necessarily limited to critical periods but may persist into adulthood within certain pathways. Understanding these mechanisms may inform future studies on neurodegenerative disease and how circuit disruption may contribute to neuronal loss.