Treating a novel plasticity defect rescues episodic memory in Fragile X model mice

Abstract

Episodic memory, a fundamental component of human cognition, is significantly impaired in autism. We report the first evidence for this problem in the Fmr1-knockout (KO) mouse model of Fragile X syndrome and describe potentially treatable underlying causes. The hippocampus is critical for the formation and use of episodes, with semantic (cue identity) information relayed to the structure via the lateral perforant path (LPP). The unusual form of synaptic plasticity expressed by the LPP (lppLTP) was profoundly impaired in Fmr1-KOs relative to wild type mice. Two factors contributed to this defect: i) reduced GluN1 subunit levels in synaptic NMDA receptors and related currents, and ii) impaired retrograde synaptic signaling by the endocannabinoid 2-archadonolglycerol (2-AG). Studies using a novel serial cue paradigm showed that episodic encoding is dependent on both the LPP and the endocannabinoid receptor CB1, and is strikingly impaired in Fmr1-KOs. Enhancing 2-AG signaling rescued both lppLTP and learning in the mutants. Thus, two consequences of the Fragile-X mutation converge on plasticity at one site in hippocampus to prevent encoding of a basic element of cognitive memory. Collectively, the results suggest a clinically plausible approach to treatment.

The Alternations of Endocannabinoid System and its Therapeutic Potential in Autism Spectrum Disorder

“…Therefore, we evaluated e cacy of boosting 2-AG levels by hydrolysis inhibitor JZL184 toward repetitive and stereotypical behaviors, hyperactivity, de cits in social and cognitive functioning in VPA-induced rats. Results here presented showed either acute or chronic JZL184 administration was able to relieve ASD-like behaviors, which were in line with previous reports in Fmr1 knock-out mice and Shank3B −/− mice [15,45,46].…”

Lights on Endocannabinoid-Mediated Synaptic Potentiation

“…A homosynaptic CB 1 R-dependent eCB-LTP was also characterized in hippocampal granular cells of the dentate gyrus resulting from postsynaptic 2-AG synthesis upon high-frequency stimulation of the lateral perforant path (LPP; Wang et al, 2016Wang et al, , 2018a; Figure 1B). When activated, CB 1 R, detected presynaptically at LPP terminals using STORM microscopy, engage the presynaptic FAK/ROCK signaling pathway favoring glutamate release.…”

Medical Cannabis in Children

“…104 Reduced endocannabinoid activity was demonstrated in several animal models of ASD, 105 including monogenic (fragile-X, 106 neuroligin 3 107 ), polygenic (BTBR 105 ), and environmental (rat valproic acid 108 ) models. Activation of the endocannabinoid system [105][106][107][108] and administration of CBD 105 have been shown to restore social deficits in some models. A single oral administration of 600 mg CBD to 34 men (17 neurotypicals and 17 with ASD) increased prefrontal gamma-aminobutyric acid (GABA) activity in neurotypicals and decreased GABA activity in those with ASD.…”