Ventral CA1 excitability-margin collapse as a candidate gating mechanism for emotional replay in schizophrenia, depression, and PTSD

Abstract We propose that the excitability margin (ΔVmargin), defined as the difference between spike threshold and resting membrane potential, may represent a common quantitative variable integrating the effects of chronic stress, inflammation, and maladaptive memory trace reactivation in schizophrenia, major depressive disorder, and post-traumatic stress disorder (PTSD). Based on a conceptually guided integration of published electrophysiological data, we modeled how chronic restraint stress, a conservatively parameterized stress-associated inflammatory component, and a transient state of increased engram reactivity may jointly reduce the excitability reserve of ventral CA1 (vCA1) pyramidal neurons. In the main scenario, the modeled margin decreased from 18.4 mV to approximately 6.0 mV, corresponding to a 67.5% reduction. Additional numerically parameterizable pro-excitatory modifiers further reduced the margin to approximately 4.3 mV, 3.7 mV, or 1.7 mV. These values fall within the range of physiologically reported amplitudes of transient depolarizing events, including local NMDA spikes, sharp wave–associated depolarizations, intracellular ripples, and larger subthreshold burst-related events. This suggests that network activity that remains subthreshold under normal excitability reserve conditions may become sufficient to trigger reactivation when ΔVmargin is narrowed. We therefore hypothesize that progressive narrowing of ΔVmargin may act as a gating mechanism for preferential reactivation of vulnerable neuronal ensembles, increasing the probability of repetitive, emotionally polarized replay and secondary circuit destabilization. The model generates clear, falsifiable predictions: interventions that widen ΔVmargin or reduce trigger efficacy should attenuate vCA1/vHipp hyperreactivity and limit secondary markers of network dysregulation.