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

International audienceAutism spectrum disorder (ASD) is characterized by early onset of behavioral and cognitive alterations. Low plasma levels of oxytocin (OT) have also been found in ASD patients; recently, a critical role for the enzyme CD38 in the regulation of OT release was demonstrated. CD38 is important in regulating several Ca 2+-dependent pathways, but beyond its role in regulating OT secretion, it is not known whether a deficit in CD38 expression leads to functional modifications of the prefrontal cortex (PFC), a structure involved in social behavior. Here, we report that CD38 2/2 male mice show an abnormal cortex development, an excitation-inhibition balance shifted toward a higher excitation, and impaired synaptic plasticity in the PFC such as those observed in various mouse models of ASD. We also show that a lack of CD38 alters social behavior and emotional responses. Finally, examining neu-romodulators known to control behavioral flexibility, we found elevated monoamine levels in the PFC of CD38 2/2 adult mice. Overall, our study unveiled major changes in PFC physiologic mechanisms and provides new evidence that the CD38 2/2 mouse could be a relevant model to study pathophysiological brain mechanisms of mental disorders such as ASD.-Martucci, L. A multiscale analysis in CD38-/-mice unveils major prefrontal cortex dysfunctions. FASEB J. 33, 000-000 (2019). www.fasebj.org KEY WORDS: behavior • oxytocin • autism • monoamines • excitation Autism spectrum disorder (ASD) covers a group of neu-rodevelopmental disorders characterized by behavior-al and cognitive disturbances with early-onset deficits in language acquisition and social interaction. ASD is highly inherited but the genetic determinants are poorly understood. The genetic basis of ASD has been associated with copy-number variations or single-nucleotide poly-morphism (SNP) in genes involved in brain development, synapse formation, or cell signaling (1). ASD is frequently associated with excessive cortical growth (2), and a current hypothesis is that the behavioral defects observed in ASD are due to impairments in synaptic functioning and plasticity (1, 3-5). For example, some mutations affect gluta-matergic synaptic transmission such as for the SH3 and multiple ankyrin repeat domain (SHANK) proteins (4-6) or the neuroligins (3, 7). One important consequence of these mutations is that the mechanisms of synaptic plasticity are altered and affect ionotropic NMDA receptors or metabotropic glutamate receptors regulating learning processes and cognitive functions (8, 9). Recently, the hypothesis of an increase in the excitation-inhibition (E-I) ratio in neuronal circuits emerged as a common patho-physiological principle that could explain the genesis of cognitive and social behavior deficits in ASD (10)