Distribution of fragile X mental retardation protein in the human auditory brainstem.
Fragile X mental retardation protein (FMRP) binds select mRNAs, functions in intracellular transport of these mRNAs and represses their translation. FMRP is highly expressed in neurons and lack of FMRP has been shown to result in dendritic dysmorphology and altered synaptic function. FMRP is known to interact with mRNAs for the Kv3.1b potassium channel which is required for neurons to fire action potentials at high rates with remarkable temporal precision. Auditory brainstem neurons are known for remarkably high spike rates and expression of Kv3.1b potassium channels. Fragile X syndrome (FXS) is a genetic disorder caused by a mutation in the fragile X mental retardation 1 gene (Fmr1) resulting in decreased expression of FMRP and subsequent intellectual disability, seizures, attention deficit and hypersensitivity to auditory and other sensory stimuli. We therefore hypothesize that the auditory difficulties in FXS result, at least in part, from dysfunction of auditory brainstem neurons. To examine this hypothesis, we have studied normal human brainstem tissue with immunohistochemical techniques and confocal microscopy. Our results demonstrate that FMRP is widely expressed in cell bodies and dendritic arbors of neurons in the human cochlear nucleus and superior olivary complex and also that coincidence detector neurons of the medial superior olive colocalization of FMRP and Kv3.1b. We interpret these observations to suggest that the lower auditory brainstem is a potential site of dysfunction in FXS.
Lake Erie College of Osteopathic Medicine, Auditory Research Center, Erie, PA, USA.
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Beebe
Virginia Merrill Bloedel Hearing Research Center, Department of Otolaryngology-Head and Neck Surgery, University of Washington School of Medicine, Seattle, WA, USA.
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Wang
Lake Erie College of Osteopathic Medicine, Auditory Research Center, Erie, PA, USA. Electronic address: rkulesza@lecom.edu.
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Kulesza
D000368:Aged; D000369:Aged, 80 and over; D001306:Auditory Pathways / Q000378:metabolism; D001933:Brain Stem / Q000378:metabolism*; D017626:Cochlear Nucleus / Q000378:metabolism; D003712:Dendrites / Q000378:metabolism; D005260:Female; D005455:Fluorescent Antibody Technique; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000378:metabolism*; D006801:Humans; D008297:Male; D018613:Microscopy, Confocal; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism*; D010784:Photomicrography; D051670:Shaw Potassium Channels / Q000378:metabolism; D065832:Superior Olivary Complex / Q000378:metabolism
D051860:Fragile X Messenger Ribonucleoprotein 1; D051670:Shaw Potassium Channels; C497683:FMR1 protein, human; C489597:KCNC1 protein, human
cochlear nucleus; hearing; superior olive