Alterations in microRNA-124 and AMPA receptors contribute to social behavioral deficits in frontotemporal dementia.
Neurodegenerative diseases, such as frontotemporal dementia (FTD), are often associated with behavioral deficits, but the underlying anatomical and molecular causes remain poorly understood. Here we show that forebrain-specific expression of FTD-associated mutant CHMP2B in mice causes several age-dependent neurodegenerative phenotypes, including social behavioral impairments. The social deficits were accompanied by a change in AMPA receptor (AMPAR) composition, leading to an imbalance between Ca(2+)-permeable and Ca(2+)-impermeable AMPARs. Expression of most AMPAR subunits was regulated by the brain-enriched microRNA miR-124, whose abundance was markedly decreased in the superficial layers of the cerebral cortex of mice expressing the mutant CHMP2B. We found similar changes in miR-124 and AMPAR levels in the frontal cortex and induced pluripotent stem cell-derived neurons from subjects with behavioral variant FTD. Moreover, ectopic miR-124 expression in the medial prefrontal cortex of mutant mice decreased AMPAR levels and partially rescued behavioral deficits. Knockdown of the AMPAR subunit Gria2 also alleviated social impairments. Our results identify a previously undescribed mechanism involving miR-124 and AMPARs in regulating social behavior in FTD and suggest a potential therapeutic avenue.
Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Eduardo
E
Gascon
Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Kelleen
K
Lynch
Division of Neurosciences, New England Primate Research Center, Harvard Medical School, Southborough, Massachusetts, USA.
Hongyu
H
Ruan
Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Sandra
S
Almeida
Gladstone Institute of Neurological Disease, San Francisco, California, USA.
Jamie M
JM
Verheyden
Memory and Aging Center, Department of Neurology, University of California, San Francisco, California, USA.
William W
WW
Seeley
Department of Neuroscience, Mayo Clinic Florida, Jacksonville, Florida, USA.
Dennis W
DW
Dickson
Department of Neuroscience, Mayo Clinic Florida, Jacksonville, Florida, USA.
Leonard
L
Petrucelli
Gladstone Institute of Neurological Disease, San Francisco, California, USA.
Danqiong
D
Sun
Gladstone Institute of Neurological Disease, San Francisco, California, USA.
Jian
J
Jiao
Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Hongru
H
Zhou
Brudnick Neuropsychiatric Research Institute, Department of Psychiatry, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Mira
M
Jakovcevski
Brudnick Neuropsychiatric Research Institute, Department of Psychiatry, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Schahram
S
Akbarian
Division of Neurosciences, New England Primate Research Center, Harvard Medical School, Southborough, Massachusetts, USA.
Wei-Dong
WD
Yao
Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Fen-Biao
FB
Gao
D000818:Animals; D001522:Behavior, Animal; D002118:Calcium / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D004195:Disease Models, Animal; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics*; D005625:Frontal Lobe / Q000378:metabolism*; D057180:Frontotemporal Dementia / Q000235:genetics* / Q000378:metabolism / Q000523:psychology; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009474:Neurons / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000378:metabolism; D018091:Receptors, AMPA / Q000378:metabolism*; D012919:Social Behavior
C525139:CHMP2B protein, mouse; D056827:Endosomal Sorting Complexes Required for Transport; D035683:MicroRNAs; C540079:Mirn124 microRNA, mouse; D009419:Nerve Tissue Proteins; D018091:Receptors, AMPA; D002118:Calcium