Memory for the ?what?, when? and ?where? of serial events, termed ?episodic memory?, is a critical element in human cognition and is particularly disturbed in conditions of congenital intellectual disability (ID) including autism spectrum disorders (ASDs). The encoding of episodic-like memory depends upon the entorhinal cortex with medial (MEC) and lateral (LEC) fields supporting processing of spatial and non-spatial memories, respectively. With the goal of understanding the neurobiological processes contributing to ID in autism disorders and other forms of congenital cognitive dysfunction, we have evaluated mechanisms of transmission and enduring synaptic plasticity in LEC projections to hippocampus in the Fmr1 KO mouse model for Fragile-X Syndrome (FXS), the most common inherited form of ID which is also co-morbid for autism. Our results show that Fmr1 KOs have particularly severe deficits in the expression of Long-Term Potentiation (LTP) in the LEC- hippocampal connection (the lateral perforant path, LPP) and fail to learn episodic memory tasks that, in wild type (WT) mice, depend upon the LPP. Proposed studies build on these results with goals to identify mechanisms underlying the failure of LTP in Fmr1 KOs and to test manipulations predicted to rescue both potentiation and episodic memory. The project takes advantage of our recent discovery that LTP in the LPP involves novel substrates: LPP potentiation is induced postsynaptically but expressed presynaptically, via increased transmitter release, with the endocannabinoid (eCB) 2-arachidonoylglycerol (2-AG) as the critical retrograde messenger. The presynaptic adjustments underlying this eCB-dependent LTP (ecLTP) involve CB1 ?mediated signaling and cytoskeletal reorganization within LPP terminals. Collectively, the results suggest that encoding episodic memories depends upon an unusual, pathway specific-form of synaptic plasticity. The three specific aims will test the hypothesis that mechanisms of this ecLTP are severely impaired in Fmr1 KO mice, thus (i) accounting for disturbances in episodic memory and (ii) identifying therapeutic targets to improve learning in this and potentially other forms of ID associated with autism.
Aim 1 will identify postsynaptic processes required for ecLTP that are defective in Fmr1 KOs:
this aim builds upon preliminary results indicating that on-demand production of 2-AG is impaired in Fmr1 KO mice.
Aim 2 will test if presynaptic events that regulate the expression of ecLTP are impaired in the KOs and, in particular, if there are disturbances in the regulation of 2-AG breakdown and CB1 signaling to actin. Finally, Aim 3 will test if in Fmr1 KOs ecLTP, and episodic memory that depends upon it, are rescued by manipulations that enhance 2-AG levels. These studies use a new learning paradigm that tests the `what' component of episodic memory for which WT learning depends on the LPP and Fmr1 KO encoding is severely impaired. Together, results will provide unique insights into the bases of disturbances in episodic memory with congenital ID and identify novel therapeutic targets, and candidate treatments, for enhancement of this specific component of cognition.

Public Health Relevance

In many forms of congenital intellectual disability, including autism spectrum disorders (ASDs), there are impairments in encoding the `what', `when' and `where' information of narrative memories; elements collectively referred to as episodic memory. Our studies have determined that mechanisms of encoding at specific link in the neuronal network that is essential for episodic memory (i) depends upon activities of an endogenous cannabinoid and (ii) are impaired in the mouse model of fragile X syndrome, the most common inherited form of intellectual disability which is comorbid for autism. Proposed studies will identify specific synaptic processes that are impaired at this network link in the fragile X model mice and test if enhancing levels of the endogenous cannabinoid can rescue both synaptic plasticity and episodic memory, and thus critical aspects of higher cognitive function.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Developmental Brain Disorders Study Section (DBD)
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King, Tracy
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University of California Irvine
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United States
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Wang, W; Cox, B M; Jia, Y et al. (2018) Treating a novel plasticity defect rescues episodic memory in Fragile X model mice. Mol Psychiatry 23:1798-1806