# Loss and rescue of endocannabinoid-dependent LTP and memory in Fragile-X model mice

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA-IRVINE · 2020 · $445,081

## Abstract

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 ins...

## Key facts

- **NIH application ID:** 9938322
- **Project number:** 5R01HD089491-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Christine M Gall
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $445,081
- **Award type:** 5
- **Project period:** 2016-09-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9938322

## Citation

> US National Institutes of Health, RePORTER application 9938322, Loss and rescue of endocannabinoid-dependent LTP and memory in Fragile-X model mice (5R01HD089491-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9938322. Licensed CC0.

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