Barone, Annarita (2022) The effects of D2/D1R antagonists in an animal model of acute NMDAR hypofunction: translational inference from postsynaptic density Immediate-Early Gene-based network analyses. [Tesi di dottorato]

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Abstract

Background: Although extensively studied, the effect of antipsychotics has not been fully elucidated at the network level. We tested the hypothesis that acute administration of ketamine, haloperidol, and asenapine would modulate the functional connectivity of brain regions relevant to the pathophysiology of schizophrenia. To assess putative changes in brain network parameters and regional interactivity, we studied the transcript of Homer1a, an Immediate Early Gene that encodes a key molecule of the dendritic spine and that is involved in synaptic plasticity and metaplasticity, after typical and atypical antipsychotic administration. Methods: We conducted two sets of experiments based on quantitative topographic imaging of Homer1a transcripts and analyzed the pattern of expression for each of them in a connectivity-based framework. In the first experiment, we analyzed Homer1 induction in different brain regions following the administration of haloperidol. Sprague-Dawley rats (n =26) were assigned to vehicle (VEH; NaCl 0.9%) or haloperidol (HAL; 0.8 mg/kg). In the second experiment, we analyzed gene expression after the administration of asenapine in rats pre-treated or not with ketamine, mimicking acute glutamatergic psychosis vs naturalistic conditions, respectively. Sprague-Dawley rats (n=20) were assigned to VEH or ketamine (KET; 30 mg/kg). Each pre-treatment group (n=10) was randomly split into two arms, receiving asenapine (ASE, 0.3 mg/kg), or saline (VEH). Homer1a mRNA levels were 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. We computed all possible pairwise Pearson correlations among signal intensity values in each ROI and generated a network for each treatment group in both experiments. We explored and compared network parameters (e.g., network topography, integration, segregation, small-world organization, and node attributes). Results: Global efficiency and clustering coefficient of VEH and HAL networks were significantly different. The caudate putamen subdivisions and cortical and striatal regions displayed increased interactivity in the HAL network. On the other hand, it showed diminished associations between the caudate-putamen and nucleus accumbens, as well as the cingulate cortex and the anterior insula. Acute KET challenge was associated with negative correlations between Indusium griseum (Ig) and remaining ROIs, which were not detectable in other treatment groups. KET/ASE group showed significantly higher inter-correlations between Ig and lateral putamen, the upper lip of the primary somatosensory cortex, septal area nuclei, and claustrum, in comparison to the KET/VEH network. ASE was able to modulate subcortical-cortical connectivity and increase the centrality of cingulate cortex and lateral septal nuclei. Conclusions: These results confirm and extend the clinical evidence that antipsychotics may affect particular brain network features and the interaction of disease-related circuits.

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