Postnatal Oxytocin Treatment and Cognitive Function in FragileX

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Abstract/Summary of parent award R01HD101642 Autism Spectrum Disorder (ASD) is a prevalent and heterogeneous neurodevelopmental disorder with high co- morbidity for intellectual disability. This includes difficulties forming episodic memories that are critical for orderly thinking and organizing future behaviors. Episodic memory deficits are thus thought to be major contributors to cognitive difficulties associated with autism. Many of the brain changes underlying abnormalities in ASD appear in childhood suggesting the possibility for effective therapeutic strategies targeting brain maturation. One candidate therapeutic is the hypothalamic peptide Oxytocin (OXT). Postnatal OXT treatment improves social behavior in animal models of ASDs and recent work indicates that OXT treatment in childhood improves social interactions in autistic individuals. OXT acutely facilitates forms of synaptic plasticity underlying learning, but there has been little experimental consideration of possible enduring effects of postnatal OXT treatment on learning and no analyses of effects on episodic memory. We examined this possibility using intranasal OXT (iOXT) treatment in the Fmr1 KO mouse model of Fragile X Syndrome (FXS), and novel paradigms for analyses of ‘What, When and Where’ encoding. Our results show that in Fmr1 KOs iOXT treatments during the second postnatal week (P7-13) fully rescue hippocampal field CA1 LTP, object location memory, and object identity learning as assessed in adulthood (i.e., from 2-7 mo of age). iOXT also improved social recognition. These findings raise the exciting possibility that a limited period of early life OXT treatment can effect a life-long rescue of a critical element of cognitive function in ASD. They also raise questions as to the breadth of iOXT effects on behavior and the mechanisms involved. Aim 1 studies will test if postnatal iOXT treatment of male and female Fmr1 KOs rescues hippocampus-dependent encoding for the three major components of episodic memory as assessed in adulthood, if effects depend on native OXT efflux. We will further test the breadth of iOXT effects and, specifically if these treatments attenuate the cardinal behavioral abnormalities in FXS and other ASDs (hyperlocomotion, repetitive behavior). Aim 2 will use electrophysiological recordings, analyses of synaptic proteins and signaling, and measures of neuronal arbors to test if iOXT treatment normalizes neurobiological processes related to encoding in hippocampus. Aim 3 will then test the hypothesis that early life iOXT activates synaptic trophic factor receptors (EGFR, TrkB) in hippocampus, thereby suggesting a direct route for OXT effects on maturational changes in the structure. These studies will greatly expand our current knowledge of oxytocin actions in the young brain, including potential roles in regulating hippocampal development and synaptic function. Moreover, the results will lay the groundwork for designing novel, effective, and well tolerated OXT treatment regimens to optimize hippocampal maturation and function, and thereby rescue episodic memory in ASD and related developmental disorders.