Summary Objective Blood–brain barrier (BBB) impairment, redistribution of pericytes, and disturbances in cerebral blood flow may contribute to the increased seizure propensity and neurological comorbidities associated with epilepsy. However, despite the growing evidence of postictal disturbances in microcirculation, it is not known how recurrent seizures influence pericytic membrane currents and subsequent vasodilation. Methods Here, we investigated successive changes in capillary neurovascular coupling and BBB integrity during recurrent seizures induced by 4‐aminopyridine or low‐Mg2+ conditions. To avoid the influence of arteriolar dilation and cerebral blood flow changes on the capillary response, we measured seizure‐associated pericytic membrane currents, capillary motility, and permeability changes in a brain slice preparation. Arteriolar responses to 4‐aminopyridine–induced seizures were further studied in anesthetized Sprague Dawley rats by using electrocorticography and tissue oxygen recordings simultaneously with intravital imaging of arteriolar diameter, BBB permeability, and cellular damage. Results Within the preserved vascular network in hippocampal slice cultures, pericytes regulated capillary diameter in response to vasoactive agents and neuronal activity. Seizures induced distinct patterns of membrane currents that contributed to the regulation of pericytic length. During the course of recurrent seizures, individual vasodilation responses eroded and BBB permeability increased, despite unaltered neurometabolic coupling. Reduced vascular responsiveness was associated with mitochondrial depolarization in pericytes. Subsequent capillary constriction preceded BBB opening, suggesting that pericyte injury mediates the breach in capillary integrity. In vivo findings were consistent with slice experiments, showing seizure‐related neurovascular decoupling and BBB dysfunction in small cortical arterioles, accompanied by perivascular cellular injury despite normoxic conditions. Significance Our study presents a direct observation of gradually developing neurovascular decoupling during recurrent seizures and suggests pericytic injury as an inducer of vascular dysfunction in epilepsy.

Dysfunction of parvalbumin (PV)-expressing interneurons is thought to underlie the alterations of gamma-band oscillations observed in schizophrenia. Although the pathomechanisms of this disease remain unclear, oxidative stress induced by NMDA receptor (NMDAR) hypofunction and decreased glutathione (GSH) synthesizing capacity have been shown to lead to PV-loss and aberrant oscillatory activity. However, the individual contributions of NMDAR-inhibition and GSH-depletion to the developmental alterations observed in schizophrenia are largely unknown. We therefore investigated each condition in isolation using hippocampal slice cultures wherein interneuron maturation occurs entirely in vitro. Although both treatments caused oxidative stress, NMDAR-inhibition led to an immediate reduction in gamma oscillation frequency and a delayed loss of PV. In contrast, GSH-depletion immediately decreased PV expression and increased power, without affecting frequency. Hence, although disturbances of PV-expression and gamma oscillations coexist in schizophrenia, they can arise from separate pathological processes.

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Myelination enhances the conduction velocity of action potentials (AP) and increases energy efficiency. Thick myelin sheaths are typically found on large-distance axonal connections or in fast-spiking interneurons, which are critical for synchronizing neuronal networks during gamma-band oscillations. Loss of myelin sheath is associated with multiple alterations in axonal architecture leading to impaired AP propagation. While numerous studies are devoted to the effects of demyelination on conduction velocity, the metabolic effects and the consequences for network synchronization have not been investigated. Here we present a unifying computational model for electrophysiology and metabolism of the myelinated axon. The computational model suggested that demyelination not only decreases the AP speed but AP propagation in demyelinated axons requires compensatory processes like mitochondrial mass increase and a switch from saltatory to continuous propagation to rescue axon functionality at the cost of reduced AP propagation speed and increased energy expenditure. Indeed, these predictions were proven to be true in a culture model of demyelination where the pharmacologically-induced loss of myelin was associated with increased oxygen consumption rates, and a significant broadening of bandwidth as well as a decrease in the power of gamma oscillations.

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