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.
Highlights
The post-synaptic density (PSD) is a specialized matrix located at excitatory post-synaptic terminals with a disc-shaped aspect, a surface area of 0.07 μm2 and a thickness of 30–40 nm at the electron microscopy [1].The PSD can be described as a macromolecular complex of several hundreds of proteins acting as a molecular switchboard of multiple interacting neurotransmitter signaling pathways [2,3,4]
Results from PSD preparations obtained with different proteomic purification essays have revealed that more than 400 proteins can be regularly found by mass spectrometry fingerprinting in the PSD proteome [5]
PSD molecules are involved in several functions critical to dopamine and glutamate-dependent synaptic plasticity processes at glutamatergic synapses [8,9]
Summary
The post-synaptic density (PSD) is a specialized matrix located at excitatory post-synaptic terminals with a disc-shaped aspect, a surface area of 0.07 μm and a thickness of 30–40 nm at the electron microscopy [1]. It has been recently reported that microRNAs (miRNAs) precursors can be detected within synaptic fractions tightly associated with the PSD, where they play a role in the direct or indirect regulation of membrane receptors expression [12,13] These findings may reflect regional variations in the molecular mechanisms underlying synaptic plasticity processes in different areas of the brain. Genetic manipulations of PSD molecules cause dendritic spine defects, which are putatively the basis for behavioral aberrations relevant to psychiatric diseases [55,56] This increasing body of evidence supports the view that PSD proteins are crucially implicated in aberrant synaptic plasticity, and thereby in high-order cognitive alterations, which are the core of pathophysiology in psychiatric diseases. We will explore possible new avenues in the horizon of “PSD-targeting” therapeutic strategies
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