Synapsin II is a member of the neuronal phosphoprotein family. These phosphoproteins are evolutionarily conserved across many organisms and are important in a variety of synaptic functions, including synaptogenesis and the regulation of neurotransmitter release. A number of genome-wide scans, meta-analyses, and genetic susceptibility studies have implicated the synapsin II gene (3p25) in the etiology of schizophrenia (SZ) and other psychiatric disorders. Further studies have found a reduction of synapsin II mRNA and protein in the prefrontal cortex in post-mortem samples from schizophrenic patients. Disruptions in the expression of this gene may cause synaptic dysfunction, which can result in neurotransmitter imbalances, likely contributing to the pathogenesis of SZ. SZ is a costly, debilitating psychiatric illness affecting approximately 1.1% of the world's population, amounting to 51 million people today. The disorder is characterized by positive (hallucinations, paranoia), negative (social withdrawal, lack of motivation), and cognitive (memory impairments, attention deficits) symptoms. This review provides a comprehensive summary of the structure, function, and involvement of the synapsin family, specifically synapsin II, in the pathophysiology of SZ and possible target for therapeutic intervention/implications.

The activity of G protein-coupled receptors (GPCRs) is intricately regulated by a range of intracellular proteins, including G protein-coupled kinases (GRKs) and arrestins. Understanding the effects of ligands on these signaling pathways could provide insights into disease pathophysiologies and treatment. The dopamine D2 receptor is a GPCR strongly implicated in the pathophysiology of a range of neurological and neuropsychiatric disorders, particularly schizophrenia. Previous studies from our lab have shown the preclinical efficacy of a novel allosteric drug, 3(R)- [(2(S)-pyrrolidinylcarbonyl)amino]-2-oxo-1-pyrrolidineacetamide (PAOPA), in attenuating schizophrenia-like behavioural abnormalities in rodent models of the disease. As an allosteric modulator, PAOPA binds to a site on the D2 receptor, which is distinct from the endogenous ligand-binding site, in order to modulate the binding of the D2 receptor ligand, dopamine. The exact signaling pathways affected by this allosteric modulator are currently unknown. The objectives of this study were to decipher the in vivo effects, in rats, of chronic PAOPA administration on D2 receptor regulatory and downstream molecules, including GRK2, arrestin-3 and extracellular receptor kinase (ERK) 1/2. Additionally, an in vitro cellular model was also used to study PAOPA’s effects on D2 receptor internalization. Results from western immunoblots showed that chronic PAOPA treatment increased the striatal expression of GRK2 by 41%, arrestin-3 by 34%, phospho-ERK1 by 51% and phospho-ERK2 by 36%. Results also showed that the addition of PAOPA to agonist treatment in cells increased D2 receptor internalization by 33%. This study provides the foundational evidence of putative signaling pathways, and changes in receptor localization, affected by treatment with PAOPA. It improves our understanding on the diverse mechanisms of action of allosteric modulators, while advancing PAOPA’s development into a novel drug for the improved treatment of schizophrenia.

No abstract

No abstract