From Drug-Induced Network Hyperexcitability to Neuronal ATP Failure and Mitochondrial Dysfunction: A Cross-Tier Framework and Experimental Roadmap

A growing body of experimental evidence indicates that brief or sustained network hyperexcitability can precipitate and amplify mitochondrial pathology by converting transient metabolic stress into enduring neuronal and circuit dysfunction. We synthesize this evidence into an operational integrative model: (1) elevated firing increases Na⁺/K⁺-ATPase and other pump workload, sharply elevating local ATP demand; (2) mitochondrial Ca²⁺ uptake via the MCU initially stimulates metabolism but, when excessive, triggers ΔΨm collapse, mPTP opening, ROS production and mtDNA/ETC damage—all reducing ATP supply (Kovács et al., 2012; Bernardi et al., 2015; Meyer et al., 2022); (3) ATP shortage impairs ion homeostasis, producing membrane instability and a feed-forward loop that sustains bioenergetic failure and structural synaptic changes. Energy deficits also impair astrocytic glutamate clearance and lactate support and shift microglia toward pro-inflammatory glycolytic phenotypes, thereby amplifying excitotoxic and demyelinating pathways (Pellerin & Magistretti, 1994; Danbolt, 2001). We stratify existing evidence into three tiers (from human electrophysiology/cohorts to in-vivo animal manipulations and molecular/cellular experiments) and propose concrete experimental and translational approaches (co-measurements of ATP and electrical activity in animals, high-field ^31P-MRS and EEG correlations in humans) to test causal links. The framework highlights how pharmacological exposures (polypharmacy, withdrawal/kindling) can increase network energy vulnerability via both demand-side (hyperexcitability) and supply-side (mitochondrial toxicity) routes, and outlines priorities for biomarker development and interventional research.