A multiscale analysis in CD38 ^−/− mice unveils major prefrontal cortex dysfunctions

Abstract

Autism Spectrum Disorder (ASD) is characterized by early onset of behavioural and cognitive alterations. Low plasma levels of oxytocin have also been found in ASD patients and recently, a critical role for the enzyme CD38 in the regulation of oxytocin release was demonstrated. CD38 is important in regulating several Ca2+ dependent pathways, but beyond its role in regulating oxytocin secretion, it is not known whether a deficit in CD38 expression leads to functional modifications of the prefrontal cortex, a structure involved in social behaviour. Here, we report that CD38-/- male mice show an abnormal cortex development, an excitation-inhibition balance shifted towards a higher excitation, and impaired synaptic plasticity in the prefrontal cortex such as those observed in various mouse models of ASD. We also show that a lack of CD38 alters social behaviour and emotional responses. Finally, examining neuromodulators known to control behavioural flexibility, we found elevated monoamine levels in the prefrontal cortex of CD38-/- adult mice. Overall our study unveiled major changes in prefrontal cortex physiological mechanisms and provides new evidence that the CD38-/- mouse could be a relevant model to study pathophysiological brain mechanisms of mental disorders such as ASD.

Preliminary Evidence That CD38 Moderates the Association of Neuroticism on Amygdala-Subgenual Cingulate Connectivity

“…would be consistent with elevated levels of anxiety and emotional reactivity to negative events that have been seen in mice with deletion of the CD38 gene (Martucci et al, 2019). Exploratory whole brain analyses showed main effects of neuroticism on regions that are considered part of the default mode network, such as the temporoparietal junction, precuneus, and sgACC (Menon, 2011;Li et al, 2014).…”

Genetics of structural and functional brain changes in autism spectrum disorder

“…Reduced levels of oxytocin have been found in ASD patients, and CD38 is a vital enzyme that controls oxytocin production. A CD38 −/− mice study showed abnormal development of the cortex and impaired synaptic plasticity in the prefrontal cortex region with impaired social and emotional responses 108 (Table 1). Genetic variations in the 1A gene of the arginine vasopressin receptor (AVPR1A) were linked to autism.…”

CD38 in Neurodegeneration and Neuroinflammation

“…This reduction in cADPR levels in these brain areas led to a reduction of oxytocin and vasopressin release, explaining the observed defects in maternal nurturing and social behavior characteristics of CD38 KO mice [39]. This effect is not limited to the posterior pituitary hormone family of neurotransmitters since norepinephrine, serotonin and the dopamine metabolites dopac and homovanillic acid are strongly increased in prefrontal cortex from CD38 KO mice [40]. CD38 KO mice also had reduced dopamine release in the nucleus accumbens [41].…”