NMDA receptor ablation in cortical interneurons before adolescence results in a deficit in the hippocampal-medial prefrontal cortex functional connectivity

ÁLVAREZ RJ, ZOLD C, BELFORTE JE

Congreso; 2014 South American Regional Meeting de la Schizophrenia International Research Society; 2014

Background: Restricted genetic ablation of NMDA receptors in cortical parvalbumin (PV+) interneurons, during early postnatal development, resulted in impaired maturation of GABAergic cell function, which was sufficient to trigger the development of schizophrenia-like phenotypes in adulthood. The medial prefrontal cortex (mPFC) has been involved in the development of schizophrenic symptoms. Normal refinement of mPFC connectivity continues up to young adulthood and includes synaptic pruning of local and distant inputs, including hippocampal ones. To elucidate the pathophysiological changes leading to schizophrenia-like phenotype in our model we focused in the status of neuronal activity and functional connectivity of mPFC. Methods: We used the cre-loxP system to remove the NR1 subunit from the NMDA receptor in PV+ interneurons of the corticolimbic system during early postnatal development (Belforte, Nat. Neurosci. 2010). We recorded electrophysiological activity in urethane anesthetized, control and mutant mice. In a first set of experiments, we placed a stimulation electrode in the hippocampus and a recording electrode in mPFC to measure evoked response. In a second set, we used an array of tetrodes placed in the mPFC to record single unit activity. Local field potentials were acquired from mPFC and ventral hippocampus (vHP) to characterize global brain states and to analyze neuronal entrainment with cortical rhythms. Results: We found that responses evoked in the mPFC by electrical stimulation of the vHP are smaller in adults, but not in juvenile, mutant mice when compared with age matched controls. To gain insight into the physiological impact of this finding we recorded single unitary neuronal activity in mPFC. Global analysis of all recorded units shows a significant increase in the mean firing rate of electrophysiological-identified pyramidal cells in mutant mice during desynchronized state (2.4±0.2 vs 1.7±0.1Hz p