Fragile X mental retardation protein is required for rapid experience-dependent regulation of the potassium channel Kv3.1b.
Fragile X mental retardation protein (FMRP) is an RNA-binding protein that regulates synaptic plasticity by repressing translation of specific mRNAs. We found that FMRP binds mRNA encoding the voltage-gated potassium channel Kv3.1b in brainstem synaptosomes. To explore the regulation of Kv3.1b by FMRP, we investigated Kv3.1b immunoreactivity and potassium currents in the auditory brainstem sound localization circuit of male mice. The unique features of this circuit allowed us to control neuronal activity in vivo by exposing animals to high-frequency, amplitude-modulated stimuli, which elicit predictable and stereotyped patterns of input to the anterior ventral cochlear nucleus (AVCN) and medial nucleus of the trapezoid body (MNTB). In wild-type (WT) animals, Kv3.1b is expressed along a tonotopic gradient in the MNTB, with highest levels in neurons at the medial, high-frequency end. At baseline, Fmr1(-/-) mice, which lack FMRP, displayed dramatically flattened tonotopicity in Kv3.1b immunoreactivity and K(+) currents relative to WT controls. Moreover, after 30 min of acoustic stimulation, levels of Kv3.1b immunoreactivity were significantly elevated in both the MNTB and AVCN of WT, but not Fmr1(-/-), mice. These results suggest that FMRP is necessary for maintenance of the gradient in Kv3.1b protein levels across the tonotopic axis of the MNTB, and are consistent with a role for FMRP as a repressor of protein translation. Using numerical simulations, we demonstrate that Kv3.1b tonotopicity may be required for accurate encoding of stimulus features such as modulation rate, and that disruption of this gradient, as occurs in Fmr1(-/-) animals, degrades processing of this information.
Strumbos
John G
JG
Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06511, USA.
Brown
Maile R
MR
Kronengold
Jack
J
Polley
Daniel B
DB
Kaczmarek
Leonard K
LK
D000161:Acoustic Stimulation; D000818:Animals; D001306:Auditory Pathways / Q000502:physiology*; D015153:Blotting, Western; D001933:Brain Stem / Q000502:physiology*; D016057:Evoked Potentials, Auditory, Brain Stem / Q000502:physiology*; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics* / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051670:Shaw Potassium Channels / Q000378:metabolism*; D013017:Sound Localization
D051860:Fragile X Messenger Ribonucleoprotein 1; D012333:RNA, Messenger; D051670:Shaw Potassium Channels; C490839:Kcnc1 protein, mouse