Treating the Synapse in Major Psychiatric Disorders: The Role of Postsynaptic Density Network in Dopamine-Glutamate Interplay and Psychopharmacologic Drugs Molecular Actions

Abstract

Dopamine-glutamate interplay dysfunctions have been suggested as pathophysiological key determinants of major psychotic disorders, above all schizophrenia and mood disorders. For the most part, synaptic interactions between dopamine and glutamate signaling pathways take part in the postsynaptic density, a specialized ultrastructure localized under the membrane of glutamatergic excitatory synapses. Multiple proteins, with the role of adaptors, regulators, effectors, and scaffolds compose the postsynaptic density network. They form structural and functional crossroads where multiple signals, starting at membrane receptors, are received, elaborated, integrated, and routed to appropriate nuclear targets. Moreover, transductional pathways belonging to different receptors may be functionally interconnected through postsynaptic density molecules. Several studies have demonstrated that psychopharmacologic drugs may differentially affect the expression and function of postsynaptic genes and proteins, depending upon the peculiar receptor profile of each compound. Thus, through postsynaptic network modulation, these drugs may induce dopamine-glutamate synaptic remodeling, which is at the basis of their long-term physiologic effects. In this review, we will discuss the role of postsynaptic proteins in dopamine-glutamate signals integration, as well as the peculiar impact of different psychotropic drugs used in clinical practice on postsynaptic remodeling, thereby trying to point out the possible future molecular targets of “synapse-based” psychiatric therapeutic strategies.

Characterization of striatal phenotypes in heterozygous Disc1 mutant mice, a model of haploinsufficiency

“…The density of dendritic spines and the diameter of the spine head were significantly reduced in the MSNs of Het mice (Figure b,c). The level of postsynaptic density 95 (PSD95), a postsynaptic scaffold protein for excitatory synapses (Tomasetti et al, ), was reduced in Het mice compared to that in WT mice (Figure d). Together, defects in dendritic arbors, spines and postsynaptic density protein in the MSNs of Het mice suggest impaired glutamatergic synaptic transmission in the striatal neural network.…”

“…The density of dendritic spines and the diameter of the spine head were significantly reduced in the MSNs of Het mice (Figure 7b,c). The level of postsynaptic density 95 (PSD95), a postsynaptic scaffold protein for excitatory synapses (Tomasetti et al, 2017), was reduced in Het mice compared to that in WT mice (Figure 7d).…”

Electroretinographic Abnormalities and Sex Differences Detected with Mesopic Adaptation in a Mouse Model of Schizophrenia: A and B Wave Analysis

“…Proteomic and genomic analyses of synapses in human brain samples from controls or individuals with schizophrenia found altered expression of multiple proteins with known specific roles in NMDA function. 15,16 Although the proportion of individuals with schizophrenia in this subtype is not known, the NMDAR-related molecules are well represented in the identified risk genes. 15,16 The serine racemase (SR) gene is one of several risk genes for schizophrenia that affect NMDAR function and its downstream signaling.…”

Translating striatal activity from brain slice to whole animal neurophysiology: A guide for neuroscience research integrating diverse levels of analysis

“…Early work suggested that the similar effects were not obtained in other brain regions (Huang & Kandel, 1995;Law-Tho, Hirsch, & Crepel, 1994). Recent studies have found that other brain regions do express a synergy between dopamine and glutamate receptor and greater details have uncovered the molecular foundation for these interactions (Sarantis, Matsokis, & Angelatou, 2009;Tomasetti et al, 2017). There are both similarities and differences obtained for DA-glutamate interaction making neostriatal modulation distinctive and an influence from the internal, local neural connectivity in each brain region important (Sesack, Carr, Omelchenko, & Pinto, 2003).…”

“…The next step was to examine whether this differential modulation also applies to components of synaptic responses evoked by electrical stimulation of neostriatal afferents and mediated by activation of specific subtypes of EAA receptors (Levine, Li, Cepeda, Cromwell & Altemus, 1996). Recent studies have found that other brain regions do express a synergy between dopamine and glutamate receptor and greater details have uncovered the molecular foundation for these interactions (Sarantis, Matsokis, & Angelatou, 2009;Tomasetti et al, 2017). The specific subtype of EAA receptor activated was crucial to the direction of effect.…”