Age-dependent divergent interactions between CX3CR1 absence and MK- 801 neonatal administration in a novel “dual hit” schizophrenia model

Abstract

The diathesis–stress model of schizophrenia posits that a constitutive factor increases the vulnerability to secondary stressors. Alterations in neuron–microglia communication through the fractalkine pathway is a potential predisposing factor. Wild-type (WT) and Cx3cr1−/− (KO) mice of both sexes randomly received either a low (0.5 mg/kg) or high dose (1 mg/kg) of MK-801 or saline during early postnatal development. Neuronal apoptosis was assessed at a midpoint of the pharmacological protocol. Survival and growth rates were determined up to adulthood when innate behaviors, unconditioned anxiety, contextual memory and seizure susceptibility were evaluated, as well as hippocampal local field potential and sensory gating. Fractalkine receptor (CX3CR1) depletion and MK-801 treatment had a synergistic effect, increasing neuronal apoptosis and overall mortality. Both factors independently induced long-lasting cognitive impairments in the wide array of tasks assessed. Low MK-801 dose treatment greatly augmented the mortality of pentylenetetrazol-induced seizures in WT mice, an effect prevented by CX3CR1 depletion. MK-801 treatment induced a shift in the power spectrum of the hippocampal local field potential towards higher frequencies that was averted in Cx3cr1−/− mice by an opposite shift. CX3CR1 depletion severely increases the vulnerability to neonatal NMDA antagonism with additional complex interactions regarding cognitive and neurophysiological effects.