Modulation of glutamatergic functional connectivity by a prototypical antipsychotic: translational inference from a postsynaptic density Immediate-Early Gene-based network analysis

BACKGROUND: Although extensively studied, the effect of antipsychotics is not completely understood at a network level. We tested the hypothesis that acute administration of haloperidol would modulate functional connectivity of brain regions relevant to schizophrenia pathophysiology. To assess putative changes in brain network properties and regional interactivity, we studied the expression ofHomer1a, an Immediate Early Gene (IEG) demonstrated to be induced by antipsychotic administration and coding for a protein involved in glutamatergic synapses remodeling.METHODS: Sprague-Dawley rats (n=26) assigned to vehicle (VEH; NaCl 0.9%) or haloperidol (HAL; 0.8mg/kg) were included in the network analysis.Homer1a mRNA induction was evaluated by in situ hybridization. Signal intensity analysis was performed in 33 Regions of Interest (ROIs) in the cortex, the caudate putamen, and the nucleus accumbens. A signal correlation analysis was performed, computing all possible pairwise Pearson correlations among ROIs in the two groups. Two networks were generated for HAL and VEH groups, and their properties and topography were explored.RESULTS: VEH and HAL networks showed qualitative differences inglobal efficiency and clustering coefficient. The HAL network showed enhanced interactivity between cortical and striatal regions, and within caudate putamen subdivisions. On the other hand, it exhibited reduced inter-correlations between cingulate cortex and anterior insula and caudate putamen and nucleus accumbens. Moreover, haloperidol was able to modulate centrality of crucial functional hubs. These preclinical results corroborate and expand the clinical evidence that antipsychotics may modulate specific brain network properties and disease-related circuits' interactivity.