Excitability-margin narrowing as a candidate gating mechanism for maladaptive circuit reactivation: a ventral...

We propose that the excitability margin (ΔV _margin ), defined as the difference between spike threshold and resting membrane potential, may function as a quantitative gating variable linking chronic stress, inflammatory load, and transient increases in excitability associated with reactivation to emotionally polarized replay or other maladaptive forms of circuit reactivation. 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 model-derived effective margin decreased from 18.4 mV to approximately 6.0 mV, corresponding to a 67.5% reduction. Additional illustrative pro-excitatory scenarios 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 in circuits where analogous transient depolarizing events occur, narrowing of ΔV _margin may increase the likelihood that otherwise subthreshold network activity contributes to threshold crossing and maladaptive reactivation. We therefore hypothesize that progressive narrowing of ΔV _margin may act as a gating mechanism for preferential reactivation of vulnerable neuronal ensembles, increasing the probability of repetitive, emotionally polarized replay or other maladaptive forms of circuit reactivation and secondary circuit destabilization. This framework may provide a unifying excitability-based mechanistic hypothesis and a hypothesis-generating transdiagnostic framework relevant to schizophrenia-, depression-, and trauma-related phenotypes, while remaining potentially informative for other conditions characterized by excitability instability. The model generates clear, falsifiable predictions: interventions that widen ΔV _margin or reduce trigger efficacy should attenuate hyperreactivity in the vCA1/vHipp system analyzed here and limit secondary markers of network dysregulation, while also providing a transferable framework for testing analogous low-margin dynamics in other phenotype-relevant circuit nodes.