Long-term memory deficits are associated with elevated synaptic ERK1/2 activation and reversed by mGluR5 antagonism in an animal model of autism.
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.
Department of Anatomy and Neurobiology, University of California, Irvine, CA, USA.
Ronald R
RR
Seese
Department of Anatomy and Neurobiology, University of California, Irvine, CA, USA.
Anna R
AR
Maske
1] Department of Anatomy and Neurobiology, University of California, Irvine, CA, USA [2] Department of Psychiatry and Human Behavior, University of California, Irvine, CA, USA.
Gary
G
Lynch
1] Department of Anatomy and Neurobiology, University of California, Irvine, CA, USA [2] Department of Neurobiology and Behavior, University of California, Irvine, CA, USA.
Christine M
CM
Gall
D000818:Animals; D001321:Autistic Disorder / Q000150:complications* / Q000235:genetics; D050882:CREB-Binding Protein / Q000378:metabolism; D003505:Cyclodextrins / Q000494:pharmacology; D004195:Disease Models, Animal; D000076122:Disks Large Homolog 4 Protein; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics; D051528:Guanylate Kinases / Q000378:metabolism; D006624:Hippocampus / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008565:Membrane Proteins / Q000378:metabolism; D008569:Memory Disorders / Q000209:etiology* / Q000473:pathology; D057567:Memory, Long-Term / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008815:Mice, Inbred Strains; D011725:Pyridines / Q000494:pharmacology; D013239:Stereotyped Behavior / Q000187:drug effects; D013569:Synapses / Q000378:metabolism*
D050882:CREB-Binding Protein; D003505:Cyclodextrins; D000076122:Disks Large Homolog 4 Protein; D018691:Excitatory Amino Acid Antagonists; D051860:Fragile X Messenger Ribonucleoprotein 1; D051528:Guanylate Kinases; D008565:Membrane Proteins; D011725:Pyridines; C501447:Dlg4 protein, mouse; C497684:Fmr1 protein, mouse; C121465:6-methyl-2-(phenylethynyl)pyridine