Long-term memory deficits are associated with elevated synaptic ERK1/2 activation and reversed by mGluR5 antagonism in an animal model of autism

Neuropsychopharmacology. 2014 Jun;39(7):1664-73. doi: 10.1038/npp.2014.13. Epub 2014 Jan 22.


A significant proportion of patients with autism exhibit some degree of intellectual disability. The BTBR T(+) Itpr3(tf)/J mouse strain exhibits behaviors that align with the major diagnostic criteria of autism. To further evaluate the BTBR strain's cognitive impairments, we quantified hippocampus-dependent object location memory (OLM) and found that one-third of the BTBR mice exhibited robust memory, whereas the remainder did not. Fluorescence deconvolution tomography was used to test whether synaptic levels of activated extracellular signal-regulated kinase 1/2 (ERK1/2), a protein that contributes importantly to plasticity, correlate with OLM scores in individual mice. In hippocampal field CA1, the BTBRs had fewer post-synaptic densities associated with high levels of phosphorylated (p-) ERK1/2 as compared with C57BL/6 mice. Although counts of p-ERK1/2 immunoreactive synapses did not correlate with OLM performance, the intensity of synaptic p-ERK1/2 immunolabeling was negatively correlated with OLM scores across BTBRs. Metabotropic glutamate receptor (mGluR) 5 signaling activates ERK1/2. Therefore, we tested whether treatment with the mGluR5 antagonist MPEP normalizes synaptic and learning measures in BTBR mice: MPEP facilitated OLM and decreased synaptic p-ERK1/2 immunolabeling intensity without affecting numbers of p-ERK1/2+ synapses. In contrast, semi-chronic ampakine treatment, which facilitates memory in other models of cognitive impairment, had no effect on OLM in BTBRs. These results suggest that intellectual disabilities associated with different neurodevelopmental disorders on the autism spectrum require distinct therapeutic strategies based on underlying synaptic pathology.

Publication types

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

MeSH terms

  • Animals
  • Autistic Disorder / complications*
  • Autistic Disorder / genetics
  • CREB-Binding Protein / metabolism
  • Cyclodextrins / pharmacology
  • Disease Models, Animal
  • Disks Large Homolog 4 Protein
  • Excitatory Amino Acid Antagonists / pharmacology*
  • Female
  • Fragile X Mental Retardation Protein / genetics
  • Guanylate Kinases / metabolism
  • Hippocampus / pathology
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / physiology
  • Male
  • Maze Learning / drug effects
  • Maze Learning / physiology
  • Membrane Proteins / metabolism
  • Memory Disorders / etiology*
  • Memory Disorders / pathology
  • Memory, Long-Term / drug effects
  • Memory, Long-Term / physiology*
  • Mice
  • Mice, Inbred Strains
  • Pyridines / pharmacology
  • Stereotyped Behavior / drug effects
  • Synapses / metabolism*


  • Cyclodextrins
  • Disks Large Homolog 4 Protein
  • Dlg4 protein, mouse
  • Excitatory Amino Acid Antagonists
  • Fmr1 protein, mouse
  • Membrane Proteins
  • Pyridines
  • Fragile X Mental Retardation Protein
  • 6-methyl-2-(phenylethynyl)pyridine
  • CREB-Binding Protein
  • Guanylate Kinases