Treating the Synapse in Major Psychiatric Disorders: The Role of Postsynaptic Density Network in Dopamine-Glutamate Interplay and Psychopharmacologic Drugs Molecular Actions
Abstract
:1. Introduction
2. Involvement of PSD Molecules in Psychiatric Drugs Mechanisms of Actions
2.1. Antipsychotic Drugs
2.2. Mood-Stabilizing Drugs
2.3. Antidepressant Drugs
3. Novel Putative Therapeutic Strategies Based on PSD Molecules Modulation
4. Conclusions
Acknowledgments
Conflicts of Interest
References
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PSD Molecule | Involvement in Major Neuropsychiatric Disorders | Modulation by Psychopharmacologic Drugs |
---|---|---|
Homer 1 | -Schizophrenia [2,65,66,115,116,117,118] -Bipolar Disorder [9] -Major Depressive Disorder [119,120] -Drug addiction [121,122,123,124,125,126,127,128] -Chronic inflammatory pain [129,130] -Fragile X Syndrome [131] -Alzheimer’s Disease [132] -Parkinson’s Disease [133,134] -Traumatic brain injury [135,136] | -Homer 1a may be differentially modulated by both first generation and second generation antipsychotics tightly depending on their own individual receptor profile [42,61,62,137,138] -The mood stabilizers lithium and valproate have scarce effects on Homer 1a expression, whereas they deeply impact synaptic structure conformation by modulating constitutive Homer 1b/c gene expression [71] -Combination of antipsychotics and mood stabilizers elicits changes in Homer 1a gene expression that are substantially different from those induced by these drugs individually administered [72] -Antidepressants and serotonin-modulating antipsychotics induce peculiar cortical expression of Homer 1a in brain regions relevant for negative and cognitive symptoms of schizophrenia [62,84] |
Homer 2 | -Schizophrenia [139] -Alcohol abuse [140,141,142] | -Chronic haloperidol and clozapine administration may induce overexpression of Homer 2 in lateral septum in animal models [62] |
Homer 3 | -Cerebellar ataxias [143,144] | |
PSD-95 | -Schizophrenia [46,145] -Autism Spectrum Disorders [46,146] -Bipolar Disorder [9,147] -Major Depressive Disorder [148] | -Lurasidone and fluoxetine decrease PSD-95 expression in prefrontal cortex and hippocampus [81] -Olanzapine and aripiprazole may reverse the immobilization stress-induced decrease in PSD-95 levels in frontal cortex [149] -PSD-95 is crucial for serotonin 5HT2A and 5HT2C receptors expression and abolishing its expression in knockout animals impairs atypical antipsychotics effects [64] -Ketamine impacts PSD-95 expression in cortical and striatal regions [150], and PSD-95 seems to be crucial for ketamine antidepressant effects [95] |
Shank | -Schizophrenia [44,151,152] -Autism Spectrum Disorders [153,154,155] | -The mood stabilizers lithium and valproate may down-regulate Shank cortical expression when chronically administered in animal models [71] |
GSK3β | -Schizophrenia [156,157,158,159] -Major Depressive Disorder [158,159] -Bipolar Disorder [160,161] | -Aripiprazole activates GSK3β signaling in prefrontal cortex and nucleus accumbens, whereas haloperidol activates GSK3β signaling only in nucleus accumbens [162] -Paliperidone exerts protective effects on neurons via decreasing glutamate-induced overactivation of GSK3β signaling [163] -Clozapine may increase GSK3β signaling in prefrontal cortex, but not in striatum, where it is activated by haloperidol [164] -Fluoxetine and imipramine have scarce effects on GSK3β signaling [164] -The inhibition of GSK3β signaling seems to be a crucial mechanism explaining mood stabilizing effects of lithium [165] -Valproate inhibits metamphetamine-induced hyperlocomotion via decreasing GSK3β activity [166] |
DISC1 | -Schizophrenia [157,167] -Bipolar Disorder [168,169] | -Atypical antipsychotics may increase cortical expression of DISC1, whereas typical antipsychotics have no effects [170] -Specific genomic variants in DISC1 gene in humans have been associated to ultra-resistance to antipsychotic treatment [171] |
CAMKII | -Schizophrenia [172] -Major Depressive Disorder [173] | -Clozapine-induced increase in prefrontal cortex activity is crucially mediated by CAMKII-NMDA receptor interactions [174] -Clozapine, haloperidol and risperidone may decrease CAMKII expression in striatum in animal models [175] -CAMKII is essential for clozapine-mediated effects on conditioned avoidance responses in animal models [176] -Fluoxetine may induce changes in CAMKII promoter [177] |
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Tomasetti, C.; Iasevoli, F.; Buonaguro, E.F.; De Berardis, D.; Fornaro, M.; Fiengo, A.L.C.; Martinotti, G.; Orsolini, L.; Valchera, A.; Di Giannantonio, M.; et al. Treating the Synapse in Major Psychiatric Disorders: The Role of Postsynaptic Density Network in Dopamine-Glutamate Interplay and Psychopharmacologic Drugs Molecular Actions. Int. J. Mol. Sci. 2017, 18, 135. https://doi.org/10.3390/ijms18010135
Tomasetti C, Iasevoli F, Buonaguro EF, De Berardis D, Fornaro M, Fiengo ALC, Martinotti G, Orsolini L, Valchera A, Di Giannantonio M, et al. Treating the Synapse in Major Psychiatric Disorders: The Role of Postsynaptic Density Network in Dopamine-Glutamate Interplay and Psychopharmacologic Drugs Molecular Actions. International Journal of Molecular Sciences. 2017; 18(1):135. https://doi.org/10.3390/ijms18010135
Chicago/Turabian StyleTomasetti, Carmine, Felice Iasevoli, Elisabetta Filomena Buonaguro, Domenico De Berardis, Michele Fornaro, Annastasia Lucia Carmela Fiengo, Giovanni Martinotti, Laura Orsolini, Alessandro Valchera, Massimo Di Giannantonio, and et al. 2017. "Treating the Synapse in Major Psychiatric Disorders: The Role of Postsynaptic Density Network in Dopamine-Glutamate Interplay and Psychopharmacologic Drugs Molecular Actions" International Journal of Molecular Sciences 18, no. 1: 135. https://doi.org/10.3390/ijms18010135
APA StyleTomasetti, C., Iasevoli, F., Buonaguro, E. F., De Berardis, D., Fornaro, M., Fiengo, A. L. C., Martinotti, G., Orsolini, L., Valchera, A., Di Giannantonio, M., & De Bartolomeis, A. (2017). Treating the Synapse in Major Psychiatric Disorders: The Role of Postsynaptic Density Network in Dopamine-Glutamate Interplay and Psychopharmacologic Drugs Molecular Actions. International Journal of Molecular Sciences, 18(1), 135. https://doi.org/10.3390/ijms18010135