Abstract
Background
Schizophrenia has been conceptualized both as synaptic plasticity and a functional connectivity disorder. Data on brain connectivity can be rendered in the form of network models. In our study we want to evaluate a particular kind of the structural and functional interaction between region of interest (ROI) relevant to schizophrenia pathophysiology: we evaluated the expression of Immediate Early Gene (IEG), Homer1a (H1a), in the different ROI and its functional interaction after Haloperidol (antipsychotic drug) acute administration. H1a is an IEG expressed in an activity-dependent manner, coding for a protein involved in the activity-induced reorganization of glutamatergic synapses.
Methods
Sprague-Dawley rats were randomly assigned to two treatment groups (n=23), receiving vehicle (NaCl 0.9%; VEH) or haloperidol 0.8 mg/kg (HAL) i.p. injection. H1a induction was evaluated using in situ hybridization. Signal intensity analysis was performed in 34 ROIs in the cortex, in the caudate-putamen and the nucleus accumbens. Student’s t-test was used to detect treatment effects. A signal correlation analysis was performed, computing all possible pairwise Pearson correlations among ROIs separately in the two groups. Using significant correlations, two networks were created for HAL and VEH groups, and their network, node, and edge properties were assessed.
Results
Bonferroni-corrected Student’s t-tests revealed statistically significant differences between the two treatment groups. Haloperidol significantly induced Homer1a gene expression compared to vehicle in all ROIs of the striatum (dmCP: p<.0001, t=9.089, df=44; dlCP: p<.0001, t=10.684, df=44; vlCP: p<.0001, t=10.870, df=44; vmCP: p<.0001, t=9.760, df=44; AcCo: p<.0001, t=8,573, df= 44; AcSh: p<.0001, t=6.615, df=44), a result that is consistent with our previous observations. No significant statistical differences were detected among cortical ROIs explored. Correlations between dmCP-AcSh, dlCP-AcSh, vlCP-AcCo, vlCP-AcSh and vmCP-AcSh were significantly different between the VEH and the HAL group (p<.01); correlations between I-vlCP and dlCP-AcCo were also significantly different between the two treatment groups (p<.05); the I-dlCP and I-vmCP showed a trend towards significance.
Discussion
Haloperidol acute administration led to a modification of the gene expression pattern in the brain regions considered herein, and consequently to differential functional connectivity. The observed disruption in the functional correlations of the nucleus accumbens may play a role in the affective, motivational and emotional consequences of haloperidol administration, with the loss of functional correlations with the lateral subregions of the caudate-putamen being potentially more relevant to the motor side-effects of haloperidol. These functional connectivity changes are potentially related to neural activity and synaptic plasticity within the glutamate system and may play a role in antipsychotic therapeutic and side effects. As far as we know, this is the first network analysis study on after haloperidol acute treatment of a gene deeply correlated to dendritic spine architecture.
Reduced d-serine levels in the nucleus accumbens of cocaine-treated rats hinder the induction of NMDA receptor-dependent synaptic plasticity