Targeting Amygdala-Brainstem Synapses to Reverse Prepulse Inhibition Deficits

Abstract

Sensorimotor gating, a fundamental pre-attentive process, can be assessed using the acoustic prepulse inhibition (PPI) assay. PPI deficits are a hallmark endophenotype of schizophrenia and are observed across various neuropsychiatric disorders, often predicting symptoms such as attention impairments, psychosis, and other cognitive/motor dysfunctions. Reversal of PPI deficits is routinely tested in disease models as a preclinical trial for antipsychotic drug screening. However, the cellular and circuit-level mechanisms underlying PPI deficits remain unclear, limiting therapeutic progress. We recently identified an uncharted pathway in mice, by which glutamatergic neurons in the central nucleus of the amygdala (CeA) activate glycinergic neurons in the caudal pontine reticular nucleus (PnC), contributing to PPI regulation. Given the prevalence of amygdala dys-function in disorders associated with PPI deficits, CeA-PnC glutamatergic synapses represent a novel therapeutic target. Here, using "Cal-Light," an in vivo Ca2+-dependent photo-tagging approach, we precisely identified CeA and PnC neurons active during acoustic startle and PPI with high spatiotemporal resolution. Furthermore, we used mice carrying homozygous deficiency in PRODH, a schizophrenia-relevant gene encoding proline dehydrogenase and modulating PPI. While Prodh-/- mice showed aberrant CeA neuronal properties and reduced PPI levels, we restored PPI by photo-activating CeA-PnC glutamatergic synapses, underscoring their involvement in pathological states. These findings provide new mechanistic insights into the amygdala-brainstem circuitry that underlies PPI deficits, offering new potential for therapeutic interventions.