Sex differences in cognitive dysfunction: mitigation by RNA editing - SUMMARY: Prenatal stress (PRS) disrupts brain development 1-3 resulting in higher risk of depression and anxiety5, 6 in female offspring and a higher risk of cognitive disorders such as autism and schizophrenia in males7. Data from our laboratory reveal sex differences in important molecular pathways in the corticolimbic circuit in psychiatric disorders, particularly in the glutamatergic system12-16. Glutamatergic transmission within the hippocampus and amygdala plays an important role in cognition, and resilience to stress19-24. Similar to humans, rodents show sex-specific reductions in spatial learning and increased anxiety-like behaviors after exposure to PRS 2, 32, 33. We propose that the pathology of PRS may include an epitranscriptomic process known as `RNA EDITING'35. Preliminary data from our laboratory demonstrate disruptions in the patterns of highly variable RNA editing in GluA subunits of the AMPA-type glutamate receptor (AMPAR) in the hippocampus of mice exposed to PRS, with associated deficits of social cognition. Similar patterns of RNA editing occur in the hippocampus of patients with impaired cognition38-40. The goal of the proposed research is to determine if GluA2 editing mediates the long-term impact of PRS. Our central hypothesis is that PRS triggers reduced GluA2 editing, leading to long- term detrimental function of the hippocampus and amygdala. To test a causal effect of GluA2 editing we have developed two novel GluA2 knockin mice: GluA-A mice that mimic 0% immutable RNA editing and GluA-G mice that mimic 100% immutable RNA editing. Preliminary data show that GluA-G mutant mice have improved spatial learning. Male but not female GluA-G mice have relative resilience to social isolation stress and there are sex differences in resilience to the effects of PRS. To elucidate the mechanisms that underlie these evidential connections between sex, RNA editing, stress, and behavior, we propose the following Aims: 1: Sex differences in the mitigation of stress-induced cognitive deficits by GluA2 RNA editing, and 2: Sex differences in the enhancement of resilience to adult stress by GluA2 RNA editing. We will expose GluA-G, GluA-A and WT mice to PRS and test for differences between genotype, stress exposure and sex in the following measures: (i) synaptic plasticity and morphology in the DG, CA1, CA2 and CA3 regions of the ventral and dorsal hippocampus and basolateral amygdala. (ii) AMPAR trafficking in these regions using immunohistochemistry. (iii) Gene expression in these regions using mmRNAseq and western blotting. (iv) measurement of sex and steroid hormones, (v) Social behavior, and cognitive behavior. This research will increase our understanding of the molecular and cellular mechanisms triggered by stress that differentially damage the glutamatergic circuitry of the hippocampus and amygdala in males and females. We will also ascertain whether RNA editing can mitigate stress-induced deficits. This research has the potential to identify novel targets for psychotropic drug development and identify an exciting new genetic mechanism for the safe manipulation of synaptic plasticity to enhance cognition and stress resilience.
