Acute and Long-Term Consequences of Neonatal NMDA Blockade in the Cx3cr1 Knock-Out Mouse.

Abstract

Neuron-microglia communication through the fractalkine pathway is a critical factor mediating microglial proliferation, migration, release of mediators, and clearance of cellular debris, as well as the function of neuronal NMDA receptors. Disruption of the fractalkine-mediated microglia-neuron communication is associated with divergent outcomes, from damaging to protective, in different neurological conditions (including schizophrenia and epilepsy). In the present work we explore the impact of the absence of the fractalkine receptor (CX3CR1) after neonatal blockade of NMDA receptors, which induces acute and long-term alterations in behavior, neuronal integrity and excitability. 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 (NMDA receptor antagonist) or saline, for five consecutive days, 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. CX3CR1 depletion and neonatal MK-801 treatment had a synergistic acute effect, increasing neuronal apoptosis and overall mortality. Both factors independently induced long-lasting impairments in the wide array of behavioral tasks assessed during adulthood. However, 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. Our results reveal that CX3CR1 depletion severely increases the vulnerability to neonatal NMDA antagonism with additional complex interactions regarding cognitive and neurophysiological effects, which should be considered in the context of neuron-microglia miscommunication in many neurological disorders including schizophrenia and epilepsy.