Ventral CA1 excitability-margin collapse as a unifying trigger of emotional replay in schizophrenia, depression, and PTSD

  1. Patryk Rosa

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Abstract

We introduce the Excitability-Margin Model (EMM), a falsifiable framework centred on the excitability margin (ΔVmargin = spike threshold − resting potential) that predicts when hippocampal events trigger emotional replay. Re-analysis of ventral CA1 (vCA1) data indicates that chronic restraint stress narrows ΔVmargin by ~11 mV via convergent shifts in chloride transport (KCC2↓, IL-6/NKCC1), leak K⁺ currents (GIRK/TASK) and Na⁺/K⁺-ATPase α1. When this stressed baseline combines with transient “hot-spot’’ plasticity in CREB-high pyramidal neurons and a single common risk variant (e.g. CACNA1C rs1006737 A or SCN2A R1882Q), the static vCA1 buffer after accounting for rheobase reductions shrinks to the ~1–3 mV range. In this near-threshold regime, ordinary transients—θ peaks, θ–γ packets, sharp-wave ripples, dendritic plateaus, brief [K⁺]o elevations, and crosstalk from neighbouring engrams— repeatedly cross threshold and drive involuntary replay of emotional assemblies. Within EMM, the valence of the recruited engram steers the clinical trajectory: fear-biased replays amplify dopamine–cortisol cascades with γ-band desynchronisation (schizophrenialike); sadness-biased replays reinforce δ–θ rumination loops with monoaminergic suppression (depression-like); and trauma-biased replays evoke locus-coeruleus noradrenergic bursts with β–γ “alarm’’ dynamics (PTSD-like). In each case, replay both expresses and further erodes a critically low ΔVmargin via activity-dependent Na⁺/Ca²⁺ influx and IL-6-mediated KCC2 downregulation, creating a self-reinforcing loop. EMM maps diverse risk factors onto four axes of excitability control (A–D) and motivates a multi-vector intervention blueprint (Four-Axis Reset, FAR) to widen ΔVmargin. It yields clear stability thresholds and testable biomarkers, including MEG γ-burst reduction and HRV rMSSD increase. As an optional falsifiable extension, EMM posits that—only when ΔVmargin is critically narrowed—weak environmental extremely low-frequency (7–30 Hz) fields could modestly bias the timing of intrinsic θ/SWR and other replay-relevant transients via phase synchronisation, without direct depolarising drive. This ELF branch is adjudicated solely by a preregistered environment-to-clinic β-loop; a null result removes it without affecting the core ΔVmargin hypothesis. Together, these elements propose a quantitative link between stress, risk variants, replay load and phenotype across schizophrenia, major depression and PTSD, and generate testable predictions for translational studies.

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  1. Version published to 10.31219/osf.io/e4cwb_v4 on OSF Preprints
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  3. Version published to 10.31219/osf.io/e4cwb_v3 on OSF Preprints
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