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Calcium-Dependent Networks in Dopamine–Glutamate Interaction: The Role of Postsynaptic Scaffolding Proteins

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Abstract

Dopamine and glutamate systems are both involved in cognitive, behavioral, and motor processes. Dysfunction of dopamine–glutamate interplay has been suggested in several psychotic diseases, above all in schizophrenia, for which there exists a need for novel medications. Intracellular calcium-dependent transduction pathways are key determinants of dopamine–glutamate interactions, which take place mainly, albeit not exclusively, in the postsynaptic density (PSD), a highly specialized postsynaptic ultrastructure. Stimulation of dopamine and glutamate receptors modulates the gene expression and the function of specific PSD proteins, the “scaffolding” proteins (Homer, Shank, and PSD95), belonging to a complex Ca2+-regulated network that integrates and converges dopamine and glutamate signaling to appropriate nuclear targets. Dysfunction of scaffolding proteins leads to severe impairment of Ca2+-dependent signaling, which may underlie the dopamine–glutamate aberrations putatively implicated in the pathogenesis of psychotic disorders. Antipsychotic therapy has been demonstrated to directly and indirectly affect the neuronal Ca2+-dependent pathways through the modulation of PSD scaffolding proteins, such as Homer, therefore influencing both dopaminergic and glutamatergic functions and enforcing Ca2+-mediated long-term synaptic changes. In this review, we will discuss the role of PSD scaffolding proteins in routing Ca2+-dependent signals to the nucleus. In particular, we will address the implication of PSD scaffolding proteins in the intracellular connections between dopamine and glutamate pathways, which involve both Ca2+-dependent and Ca2+-independent mechanisms. Finally, we will discuss how new strategies for the treatment of psychosis aim at developing antipsychotics that may impact both glutamate and dopamine signaling, and what should be the possible role of PSD scaffolding proteins.

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Acknowledgment

We would like to acknowledge Dr. Carmela Dell’Aversano for her helpful suggestions on the first draft of the manuscript.

Andrea de Bartolomeis M.D. Ph.D. is full time employed at Department of Neuroscience University of Naples “Federico II”.

Carmine Tomasetti M.D. is Ph.D. student at Department of Neuroscience, University of Naples “Federico II”.

Conflict of Interest

The authors declare that they have no conflict of interest.

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  1. Laboratory of Molecular Psychiatry and Psychopharmacotherapeutics, Section of Psychiatry, Department of Neuroscience, University School of Medicine “Federico II”, Building n°18, Via Pansini 5, 80131, Naples, Italy

    Andrea de Bartolomeis & Carmine Tomasetti

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  1. Andrea de Bartolomeis
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  2. Carmine Tomasetti
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Correspondence to Andrea de Bartolomeis.

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de Bartolomeis, A., Tomasetti, C. Calcium-Dependent Networks in Dopamine–Glutamate Interaction: The Role of Postsynaptic Scaffolding Proteins. Mol Neurobiol 46, 275–296 (2012). https://doi.org/10.1007/s12035-012-8293-6

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  • DOI: https://doi.org/10.1007/s12035-012-8293-6

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