Treating a Novel Plasticity Defect Rescues Episodic Memory in Fragile X Model Mice

Mol Psychiatry. 2018 Aug;23(8):1798-1806. doi: 10.1038/mp.2017.221. Epub 2017 Nov 14.


Episodic memory, a fundamental component of human cognition, is significantly impaired in autism. We believe 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-arachidonoylglycerol (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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Arachidonic Acids / metabolism
  • Discrimination, Psychological / drug effects
  • Discrimination, Psychological / physiology
  • Disease Models, Animal
  • Endocannabinoids / metabolism
  • Excitatory Postsynaptic Potentials / drug effects
  • Excitatory Postsynaptic Potentials / physiology
  • Fragile X Syndrome / drug therapy
  • Fragile X Syndrome / metabolism*
  • Fragile X Syndrome / pathology
  • Glycerides / metabolism
  • Hippocampus / drug effects
  • Hippocampus / metabolism*
  • Hippocampus / pathology
  • Long-Term Potentiation / drug effects
  • Long-Term Potentiation / physiology*
  • Male
  • Memory, Episodic*
  • Mice, Knockout
  • Nerve Tissue Proteins / metabolism
  • Neurotransmitter Agents / pharmacology
  • Olfactory Perception / drug effects
  • Olfactory Perception / physiology
  • Patch-Clamp Techniques
  • Receptor, Cannabinoid, CB1 / metabolism
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Tissue Culture Techniques


  • Arachidonic Acids
  • CNR1 protein, mouse
  • Endocannabinoids
  • Glycerides
  • Gprin1 protein, mouse
  • Nerve Tissue Proteins
  • Neurotransmitter Agents
  • Receptor, Cannabinoid, CB1
  • Receptors, N-Methyl-D-Aspartate
  • glyceryl 2-arachidonate