Neural activity alterations and functional connectivity deficits in a developmental mouse model of schizophrenia

ALVAREZ, RODRIGO; ZOLD, CL; BELFORTE, JE

Congreso; Congreso Anual de la Sociedad Argentina de Investigación en Neurociencia; 2015

The glutamatergic hypofunction theory postulates that a dysfunction in NMDA receptors (NMDAr) in cortical interneurons is central in the pathophysiology of schizophrenia. In our previous work, restricted ablation of NMDAr in corticolimbic parvalbumin interneurons during early postnatal development resulted in schizophrenia-like phenotypes in adulthood. To elucidate the pathophysiological changes leading to this phenotype, we placed tetrodes in the mPFC in anesthetized control and mutant, juvenile and adult mice. We found a significant increase in spontaneous firing rate and altered entrainment tocortical local and distant rhythms in mutant juvenile and adult mice. Since juvenile mutant mice lack NMDAr but show no schizophrenia-like phenotype, the above mentioned changes could not explain the behavioral abnormalities of adults. Normal synaptic pruning of local and distant inputs to mPFC occurs during adolescence. We analyzed functional connectivity of the vHP-mPFC pathway before and after adolescence. Mutant adult mice present diminished amplitude of the evoked response in mPFC. We also measured the status of circuit plasticity and found that adult but not juvenile mutant mice are more susceptible to undergo LTD. We propose that early ablation of NMDAr in interneuronsleads to an overexcited/uncoordinated cortical circuit that propitiates LTD during adolescence. This results in a decreased functional connectivity in adults that may underlie the schizophrenia-like phenotype.