Search

Dopamine (DA) is a key neurotransmitter in the basal ganglia, implicated in the control of movement and motivation. Alteration of DA levels is central in Parkinson’s disease (PD), a common neurodegenerative disorder characterized by motor and non-motor manifestations and deposition of alpha-synuclein (α-syn) aggregates. Previous studies have hypothesized a link between PD and viral infections. Indeed, different cases of parkinsonism have been reported following COVID-19. However, whether SARS-CoV-2 may trigger a neurodegenerative process is still a matter of debate. Interestingly, evidence of brain inflammation has been described in postmortem samples of patients infected by SARS-CoV-2, which suggests immune-mediated mechanisms triggering the neurological sequelae. In this review, we discuss the role of proinflammatory molecules such as cytokines, chemokines, and oxygen reactive species in modulating DA homeostasis. Moreover, we review the existing literature on the possible mechanistic interplay between SARS-CoV-2-mediated neuroinflammation and nigrostriatal DAergic impairment, and the cross-talk with aberrant α-syn metabolism.

Schizophrenia (SCZ) is a mental illness characterized by aberrant synaptic plasticity and connectivity. A large bulk of evidence suggests genetic and functional links between postsynaptic abnormalities and SCZ. Here, we performed quantitative PCR and Western blotting analysis in the dorsolateral prefrontal cortex (DLPFC) and hippocampus of SCZ patients to investigate the mRNA and protein expression of three key spine shapers: the actin-binding protein cyclase-associated protein 2 (CAP2), the sheddase a disintegrin and metalloproteinase 10 (ADAM10), and the synapse-associated protein 97 (SAP97). Our analysis of the SCZ post-mortem brain indicated increased DLG1 mRNA in DLPFC and decreased CAP2 mRNA in the hippocampus of SCZ patients, compared to non-psychiatric control subjects, while the ADAM10 transcript was unaffected. Conversely, no differences in CAP2, SAP97, and ADAM10 protein levels were detected between SCZ and control individuals in both brain regions. To assess whether DLG1 and CAP2 transcript alterations were selective for SCZ, we also measured their expression in the superior frontal gyrus of patients affected by neurodegenerative disorders, like Parkinson’s and Alzheimer’s disease. Interestingly, also in Parkinson’s disease patients, we found a selective reduction of CAP2 mRNA levels relative to controls but unaltered protein levels. Taken together, we reported for the first time altered CAP2 expression in the brain of patients with psychiatric and neurological disorders, thus suggesting that aberrant expression of this gene may contribute to synaptic dysfunction in these neuropathologies.

N-Methyl-d-Aspartate Receptors (NMDARs) are ionotropic glutamate-gated receptors. NMDARs are tetramers composed by several homologous subunits of GluN1-, GluN2-, or GluN3-type, leading to the existence in the central nervous system of a high variety of receptor subtypes with different pharmacological and signaling properties. NMDAR subunit composition is strictly regulated during development and by activity-dependent synaptic plasticity. Given the differences between GluN2 regulatory subunits of NMDAR in several functions, here we will focus on the synaptic pool of NMDARs containing the GluN2A subunit, addressing its role in both physiology and pathological synaptic plasticity as well as the contribution in these events of different types of GluN2A-interacting proteins.