Immune dysfunction has been extensively reported in the literature as a risk factor contributing to neurodevelopmental disorders characterized by social deficits, e.g., autism spectrum disorder (ASD) and schizophrenia. From an evolutionary perspective, for many millions of years, human behavior, especially sociality, has been shaped by two ancient battling forces: pathogens and the immune system. Sickness behavior or avoidance of social interaction in ASD could thus be viewed as an immune input into the brain to evade the spreading of the pathogens. Emerging research within the last decade starts to reveal that immune inputs (e.g., meningeal immunity) can indeed affect neural circuits. The critical questions remain unanswered include whether, when and how a dysfunctional immunity can cause neurodevelopmental disorders characterized by social deficits? Besides, whether the immune system can be therapeutically targeted to ameliorate social symptoms in autism and schizophrenia? Recently, several large-scale genome-wide association studies (GWAS) pinpointed a Copy Number Variation (CNV) at the chromosomal locus 7q36.6 that is highly represented in schizophrenia and autism, with all of the microduplications (triplications) occurring within a single gene: vasoactive intestinal peptide receptor 2 (VIPR2). Importantly, VIPR2 ligand, vasoactive intestinal peptide (VIP) has been found almost tripled the normal level in the neonatal blood of children with autism. It has been well established that VIP/VIPR2 signaling modulates immunity and shifts the Th1/Th2 balance in favor of Th2 cells. All these genetic findings pinpoint a long-sought link between the social deficits and dysfunctional immunity consistently observed in neurodevelopmental disorders. To translate such a genetic vulnerability into a mechanistic and pathophysiologic insight, we have developed a series of conditional VIPR2 Bacterial Artificial Chromosome (BAC) transgenic mouse models of VIPR2 CNV. The conditional design of the BAC allows switching-off the transgene in desired spatial-temporal patterns, controlled by Cre recombinase, thus facilitating dissection of the inflicted cell populations. Genetically over-activated VIPR2 signaling elicits early postnatal microglial pruning deficits and manifests robust social deficits. Therefore, we propose the central hypothesis that over-activated VIP/VIPR2 signaling in T cells elicits abnormal immune transformation to disrupt social brain development and/or social behavior. The hypothesis will be examined in the following specific aims:
Aim 1 will examine the potential pathogenic role of VIPR2 CNV in T cells to elicit systemic immune imbalance to disrupt early postnatal brain development.
This aim represents the first to employ a chemogenetic approach with Designer Receptors Exclusively Activated by Designer Drugs (DREADD) together with CREB-luciferase reporter transgenesis to remotely control T cell-type-specific G?s GPCR/PKA signaling to determine whether VIPR2 driven Th2 preferential differentiation is sufficient to elicit social deficits and brain developmental deficits. Our proposed genetic interrogation in an etiology-relevant animal model will shift the paradigm of the field by providing for the first time unequivocal causal evidence to that a dysfunctional immunity is sufficient and necessary to disrupt brain development and/or to manifest social behavioral deficits. Given that there is no disease-modifying therapy for autism and schizophrenia, our results will have an important positive impact because they lay the groundwork to the idea of tailoring of treatments (e.g., small molecule VIPR2 antagonist) targeting T cell immunity for resolution of social symptoms, which is highly innovative, and with tremendous translational value.
