CB<SUB>1</SUB> CANNABINOID RECEPTOR SIGNALING REGULATION OF CORTICAL AND BEHAVIORAL ALTERATIONS INDUCED BY SATB2 DEFICIENCY

The disruption of the balance between the generation of superficial and deep-layer cortical neurons contributes to the etiopathology of neuropsychiatric disorders, including SATB2-associated syndrome (SAS). This syndrome is characterized by intellectual disability and behavioral traits, such as autistic features, and is caused by mutations in the SATB2 gene locus, which encodes a transcription factor essential for the specification of interhemispheric projection neurons predominant in superficial cortical layers. Since the endocannabinoid system (ECS) regulates the differentiation and migration of pyramidal neurons and modulates synaptic activity, we hypothesize that regulating cannabinoid signaling during adolescence may attenuate some of the behavioral alterations involved in SAS.
We generated a conditional knockout (cKO) mouse model lacking SATB2 in forebrain pyramidal neurons from early embryonic development (Emx1-driven cKO). Behavioral characterization shows that adult SATB2 cKO mice exhibit hyperactivity, increased impulsivity, reduced anxiety and impaired social interaction. Immunofluorescence studies reveal that SATB2 cKO mice present a loss of superficial layer cortical neurons concomitant with an expansion of deep layer neurons. Furthermore, corpus callosum development is severely affected in these mice. We administered between postnatal days 22-36 the inverse CB₁R agonist SR141716 or the CB₁R signaling-specific inhibitor AEF0117 and determined their impact in SATB2 cKO behavioral alterations. Results revealed that CB₁R negative modulation induces changes in postnatal mortality and weight gain during development. These were followed by rescue of some described behavioral alterations in a sex-dependent manner. Together, these results highlight ECS modulation as a potential therapeutic strategy for addressing some of the behavioral symptoms of SAS.