Cortical Brain Injury Causes Retrograde Degeneration of Afferent Basal Forebrain Cholinergic Neurons via the p75NTR

DASGUPTA, SRESTHA; MONTROULL, LAURA; FRIEDMAN, WILMA J.

Congreso; 52nd Annual American Society for Neurochemistry Meeting; 2022

Basal forebrain cholinergic neurons (BFCNs) extend long projections to multiple targets in the brain to regulate cognitive functions and are compromised in numerous neurodegenerative disorders. To assess how injury to the target region of these neurons affects their viability in vivo, we are using the Fluid Percussion Injury (FPI) model to test the effects of injury at the cortex on the afferent BFCNs. Our studies show significantly fewer BFCNs ipsilateral to the injury compared to the contralateral side of the brain 7 and 14 days after the injury, an effect which is absent in p75 knockout mice. These results suggest a retrograde degenerative effect of the cortical injury on the projecting BFCNs through p75NTR. Basal forebrain survival, growth, synaptic maintenance, and apoptosis is governed primarily by neurotrophins (NT). Treatment of BFCN neurons with mature NTs promote survival via the Trk family of receptors, while pro-neurotrophins (pro-NT) trigger apoptosis via p75NTR. Interestingly BFCNs express all the neurotrophin receptors throughout life and may access NTs locally or from their targets such as cortex, hippocampus and amygdala. We have observed an induction of proBDNF and proNGF in the cortex and hippocampus after cortical FPI, both in WT and p75KO mice, suggesting that the induction of these factors my contribute to BFCN degeneration. To determine the effects of NT and proNT signaling directly on BFCN viability and function, we are using microfluidic and filter chamber cultures to segregate BFCN soma and axons in vitro allowing for compartmentalized treatment with pro/mature NTs. Our studies show that stimulation of BFCN axon terminals with proNGF which is a ligand for p75NTR, elicits retrograde degeneration of the axons and cell death of these neurons in vitro. Moreover, exposure of these neurons to mature or proNTs in the axonal or soma compartments may activate specific signaling mechanisms with different functional consequences. The knowledge of how pro or mature NTs affect axonal integrity and BFCN survival will shape our understanding of the role of NTs in BFCN development and in conditions of neurodegeneration.