Modulation of glutamatergic functional connectivity by a prototypical antipsychotic: Translational inference from a postsynaptic density immediate-early gene-based network analysis

Antipsychotics-Induced Changes in Synaptic Architecture and Functional Connectivity: Translational Implications for Treatment Response and Resistance

“…However, haloperidol, a strong D2R blocker, was effective in modulating functional connectivity between the substantia nigra and several brain regions, including the cingulate and prefrontal cortices, hippocampus, ventral pallidum, and motor cortex, as detected by fMRI [ 136 ]. These results were partially confirmed by an ISH study assessing Homer1a gene expression in 33 regions of interest (ROIs) and performing a network analysis, which showed reduced intercorrelations between brain areas, such as cingulate cortex, anterior insula, caudate-putamen, and nucleus accumbens, as well as enhanced interactivity between cortical and striatal regions, and within caudate putamen subdivisions [ 8 ]. A previous study assessed the expression of zif268 , an IEG, in 83 ROIs after haloperidol administration via an ISH protocol and found increased intercorrelations between the dorsolateral striatum and thalamus, and between different subdivisions of the thalamus [ 9 ].…”

“…Clozapine, the only drug approved for treatment-resistant schizophrenia [ 156 ], was found to fine-tune cortical functional connectivity, neuronal synchrony in high-gamma bands, and PFC-medial ventral striatum coherence by reverting the alterations induced by PCP and ketamine in preclinical models via modulation of serotonin receptors [ 40 , 127 , 129 , 134 ]. Therefore, the beneficial action of first-generation compounds on psychotic symptoms may rely on their capability to modulate subcortical-cortical networks by tackling the dopamine receptors sited at the striatal pathways, whereas clozapine and other atypical antipsychotics may mainly target functional circuits linking the hippocampus and ventral striatum with the PFC [ 8 , 9 , 128 , 129 , 134 ]. Even novel molecules with presumptive antipsychotic efficacy, such as modulators of the NMDAR, mGluR, adrenergic, serotonergic, and muscarinic receptors, were tested in a preclinical setting and showed to be able to counteract the effects of psychomimetic compounds by affecting the structure of functional networks and cortical synchrony [ 127 , 140 , 145 , 146 ].…”

“…To overcome these limitations, two studies explored changes in functional connectivity after antipsychotic administration by directly assessing IEGs expression through an in situ hybridization (ISH) protocol and generating group-specific correlation matrices to obtain details on differential patterns of co-activation between brain areas [ 8 , 9 ]. The simultaneous detection of molecular markers of postsynaptic activity and spatial information offers a unique opportunity to relate alterations in neuronal plasticity to connectivity dysregulation and represents a novel method for testing the effectiveness of antipsychotics in preclinical models.…”

“…Mounting evidence suggests that antipsychotics can lead to morphological and synaptic changes in the brain through the modulation of processes that regulate synaptic plasticity, dendritic spine architecture, and postsynaptic density [ 5 , 7 ]. In addition, antipsychotics may promote a functional reorganization of neural connections and modify the correlation pattern existing between pairs of brain regions [ 8 , 9 ].…”

Rational and Translational Implications of D-Amino Acids for Treatment-Resistant Schizophrenia: From Neurobiology to the Clinics

“…The PSD has been described as a thickening of the glutamatergic postsynaptic terminals, composed of glutamate receptors, ion channels, scaffolding proteins, adaptors, cytoskeletal proteins, and modulators of signaling processes [ 97 , 98 , 99 ]. Several lines of evidence point to PSD proteins as key molecules implicated in schizophrenia pathophysiology and possibly in its pharmacological treatment [ 100 , 101 , 102 , 103 , 104 ].…”