The Role of Dopamine D3 Receptors, Dysbindin, and Their Functional Interaction in the Expression of Key Genes for Neuroplasticity and Neuroinflammation in the Mouse Brain

Abstract

Cognitive impairment in schizophrenia remains a clinically and pharmacologically unsolved challenge. Clinical and preclinical studies have revealed that the concomitant reduction in dysbindin (DYS) and dopamine receptor D3 functionality improves cognitive functions. However, the molecular machinery underlying this epistatic interaction has not yet been fully elucidated. The glutamate NMDA receptors and the neurotrophin BDNF, with their established role in promoting neuroplasticity, may be involved in the complex network regulated by the D3/DYS interaction. Furthermore, as inflammation is involved in the etiopathogenesis of several psychiatric diseases, including schizophrenia, the D3/DYS interaction may affect the expression levels of pro−inflammatory cytokines. Thus, by employing mutant mice bearing selective heterozygosis for D3 and/or DYS, we provide new insights into the functional interactions (single and synergic) between these schizophrenia susceptibility genes and the expression levels of key genes for neuroplasticity and neuroinflammation in three key brain areas for schizophrenia: the prefrontal cortex, striatum, and hippocampus. In the hippocampus, the epistatic interaction between D3 and DYS reversed to the wild-type level the downregulated mRNA levels of GRIN1 and GRIN2A were observed in DYS +/− and D3 +/− mice. In all the areas investigated, double mutant mice had higher BDNF levels compared to their single heterozygote counterparts, whereas D3 hypofunction resulted in higher pro−inflammatory cytokines. These results may help to clarify the genetic mechanisms and functional interactions involved in the etiology and development of schizophrenia.

Association of schizophrenia, major depression, and bipolar disorder with sarcopenia-related traits: a bidirectional two-sample Mendelian randomization study

“…Subsequent treatment with N-acetylcysteine (NAC) or omega-3 polyunsaturated fatty acids (PUFAs), both anti-in ammatory agents, resulted in a reduction in the severity of schizophrenia in offspring. Another study by V. Rivi et al [29] examined the expression levels of NF-κB-related pro-in ammatory factors IL-6, TNF-a, and IL-1β in patients with schizophrenia and found a close association between their levels of onset of schizophrenia. Furthermore, in an upper interaction between dopamine receptor D3 and schizophrenia-associated proteins (DYS), it was found that lower dopamine receptor D3 function led to higher pro-in ammatory cytokines in double-mutant mice compared to single heterozygous mice (DYS +/− and D3 +/−) with down-regulated GRIN1 and GRIN2A mRNA levels.…”