Fragile X Mental Retardation Protein Is Required for Rapid Experience-Dependent Regulation of the Potassium Channel Kv3.1b

Abstract

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 (AM) 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, following 30 minutes 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.

Disrupted-in-schizophrenia 1 regulates transport of ITPR1 mRNA for synaptic plasticity

“…It has been reported that FMRP directly binds to KCNC1 mRNA 43 . DISC1 and FMRP may cooperatively regulate the localization and translation of Kcnc1 mRNA for synaptic plasticity.…”

Therapeutic Strategies in Fragile X Syndrome: From Bench to Bedside and Back

“…In vitro screening assays have identified several voltage-gated potassium, sodium, and calcium channels as potential FMRP mRNA targets [44,67,100,101]. Two of them, the voltage-gated potassium channels Kv3.1b and Kv4.2, were validated in independent studies as FMRP mRNA targets [74,102,103]. While Kv3.1b was shown to be translationally repressed by FMRP, the exact modalities of FMRP-mediated regulation of Kv4.2 are not fully understood yet, and it is still controversial if FMRP acts as a translational suppressor or activator of Kv4.2 [74,103].…”

Therapeutic Strategies in Fragile X Syndrome: Dysregulated mGluR Signaling and Beyond

“…In vitro screens have suggested that FMRP might associate with up to 4% of all mRNAs present in the brain Miyashiro et al, 2003), and the identified mRNA targets encode proteins important for various cellular mechanisms, such as cytoskeletal regulation, AMPA receptor trafficking, synaptic structure and composition, and synaptic signal transmission (Zalfa et al, 2003;Lu et al, 2004;Muddashetty et al, 2007;Schutt et al, 2009;Strumbos et al, 2010). FMRP is not only a multifaceted regulator of numerous target mRNAs, but is also itself activity-regulated at multiple steps, such as FMRP synthesis at synapses (Weiler et al, 1997), protein and mRNA localization in dendrites and at synapses (Antar et al, 2004), and posttranslational modifications and protein stability (reviewed in Bassell and Warren, 2008;De Rubeis and Bagni, 2010;Pfeiffer and Huber, 2009).…”