Dysregulated Signaling at Postsynaptic Density: A Systematic Review and Translational Appraisal for the Pathophysiology, Clinics, and Antipsychotics’ Treatment of Schizophrenia

Abstract

Emerging evidence from genomics, post-mortem, and preclinical studies point to a potential dysregulation of molecular signaling at postsynaptic density (PSD) in schizophrenia pathophysiology. The PSD that identifies the archetypal asymmetric synapse is a structure of approximately 300 nm in diameter, localized behind the neuronal membrane in the glutamatergic synapse, and constituted by more than 1000 proteins, including receptors, adaptors, kinases, and scaffold proteins. Furthermore, using FASS (fluorescence-activated synaptosome sorting) techniques, glutamatergic synaptosomes were isolated at around 70 nm, where the receptors anchored to the PSD proteins can diffuse laterally along the PSD and were stabilized by scaffold proteins in nanodomains of 50–80 nm at a distance of 20–40 nm creating “nanocolumns” within the synaptic button. In this context, PSD was envisioned as a multimodal hub integrating multiple signaling-related intracellular functions. Dysfunctions of glutamate signaling have been postulated in schizophrenia, starting from the glutamate receptor’s interaction with scaffolding proteins involved in the N-methyl-D-aspartate receptor (NMDAR). Despite the emerging role of PSD proteins in behavioral disorders, there is currently no systematic review that integrates preclinical and clinical findings addressing dysregulated PSD signaling and translational implications for antipsychotic treatment in the aberrant postsynaptic function context. Here we reviewed a critical appraisal of the role of dysregulated PSD proteins signaling in the pathophysiology of schizophrenia, discussing how antipsychotics may affect PSD structures and synaptic plasticity in brain regions relevant to psychosis.

Schizophrenia Synaptic Pathology and Antipsychotic Treatment in the Framework of Oxidative and Mitochondrial Dysfunction: Translational Highlights for the Clinics and Treatment

“…In addition, glutathione depletion was associated with disruptions in myelin formation and maturation [ 149 , 150 , 151 , 152 ]. Overall, these alterations are consistent with the modification observed in dendritic spines reported in schizophrenia [ 1 ] and possibly related to abnormalities in synaptic and circuit connectivity, representing the neurobiological underpinning of psychotic symptoms and a possible target for antipsychotic treatment [ 6 ]. In preclinical models of schizophrenia, treatments with antioxidant agents, such as NAC, that increase glutathione levels were associated with improvement in cognitive and social behaviors [ 153 , 154 , 155 ], an elevation in the number of parvalbumin cells [ 156 , 157 ], prevention of deficits in evoked-related potentials measured by electroencephalography (EEG) electrodes and in the prepulse inhibition of the acoustic startle response [ 157 ], an increase in mitochondria numbers and myelin-related mRNA expression [ 155 ], with higher benefits if the administration occurred at an early stage of neurodevelopment.…”

“…One splicing isoform of G72 encodes for a mitochondrial protein endowed with the capability to enhance mitochondrial fragmentation and dendritic arborization [ 181 ]. Three common disrupted in schizophrenia 1 (DISC1) gene variants as well as several rare and ultrarare variants, have been associated with schizophrenia [ 1 ]. Beyond the well-established role in the PSD composition, splicing isoforms of DISC1 have also been localized in cell mitochondria [ 182 ].…”

“…The PSD is considered a multimodal molecular hub where different signaling inputs may converge and are dispatched at intracellular levels [ 243 ]. There is substantial evidence that treatment with antipsychotics in a preclinical setting may affect the gene expression of PSD proteins, potentially impacting the architecture and function of the synapse [ 1 ]. Here, we will consider some of the most documented oxidative-stress effects on major PSD proteins.…”

“…The “quantal” alteration at both structural and functional levels of schizophrenia pathophysiology is believed to reside in the dynamics of synapse microdomains with specific involvement of dopaminergic and glutamatergic sites and a dysfunctional dopamine-glutamate interaction [ 1 , 2 , 3 , 4 , 5 ]. Alterations at the synaptic level can impair integrative processes on brain macroscale networks, ensuing in a global dysconnectivity pattern, which may be associated, at least in part, with the pathophysiology and clinics of the disorder [ 4 , 6 , 7 ].…”

Dopamine Dynamics and Neurobiology of Non-Response to Antipsychotics, Relevance for Treatment Resistant Schizophrenia: A Systematic Review and Critical Appraisal

“…However, several studies have also explored putative dysfunctions of D2 receptor levels at both pre and postsynaptic sites, as well as disturbance of D2-related postreceptor signaling [ 15 ]. One putative crucial pathophysiological mechanism, which may also be relevant to TRS, is an imbalance of dopamine–glutamate interplay occurring at the postsynaptic density, which is a protein mesh of the glutamatergic postsynapse devoted to integrating synaptic signaling from different afferent neurons [ 16 ].…”