MK-801-induced cognitive dysfunction in a schizophrenia model: mechanistic links between interstitial fluid drainage impairment and neural metabolic disturbances

Abstract

Aim: To investigate the mechanisms underlying MK-801-induced schizophrenia-like cognitive dysfunction by examining the interplay between brain interstitial fluid (ISF) drainage impairment, myelin structural integrity, and regional neurometabolic disturbances.

Methods: Mice received chronic administration of MK-801 (2 mg/kg/day) for two weeks to induce schizophrenia-like phenotypes. Cognitive function and sensorimotor gating were evaluated using the novel object recognition test and pre-pulse inhibition (PPI) assessment. ISF drainage patterns were visualized via fluorescent tracing with Lucifer Yellow. Myelin integrity in the internal capsule was quantified using Luxol Fast Blue (LFB) staining and transmission electron microscopy (TEM). Regional metabolic profiles in the caudate nucleus and thalamus were analyzed using untargeted metabolomics.

Results: MK-801 treatment resulted in significant recognition memory impairment and sensorimotor gating deficits. Fluorescent tracing revealed pathological ISF reflux from the caudate nucleus toward the thalamus, which was restricted in control mice. This drainage failure corresponded to severe demyelination and ultrastructural damage in the internal capsule, characterized by increased myelin thickness and a significantly decreased G-ratio. Furthermore, regional metabolomic analysis identified distinct dysregulation of tryptophan metabolism in the caudate nucleus and tyrosine metabolism in the thalamus.

Conclusions: Myelin degradation in the internal capsule disrupts the structural barrier required for compartmentalized ISF drainage. The resulting ISF reflux facilitates regional metabolic imbalances, particularly within tryptophan and tyrosine pathways, suggesting that fluidic dynamics failure is a critical contributor to the neurochemical pathology of schizophrenia.

Keywords

MK-801 / cognition / neurometabolite / interstitial fluid

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