Editors' ChoiceNeuroscience

Unable to Filter the Signal

Science Signaling  05 Mar 2013:
Vol. 6, Issue 265, pp. ec56
DOI: 10.1126/scisignal.2004121

Through its mRNA binding capacity, Fragile X mental retardation protein (FMRP) has established roles in regulation of postsynaptic activity–dependent regulation of translation (see Contractor). Deng et al. found that loss of FMRP increased presynaptic action potential duration under conditions of repetitive stimulation in both cortical and hippocampal neurons in slice preparations from mice. Pharmacological analysis indicated that BK, a calcium-sensitive, voltage-gated potassium channel, was responsible for the effect of loss of FMRP on action potential duration. FMRP coimmunoprecipitated with the β4 subunit of the BK channel. Genetic knockout of Fmr1 (encoding FMRP) or blocking FMRP activity with an antibody delivered with the electrophysiological pipette reduced the BK channel responsiveness to calcium and reduced conductance in hippocampal neurons in slice preparations from mice. Experiments with anisomycin, an inhibitor of protein synthesis, confirmed that the effect of FMRP on BK activity was not due to altered protein synthesis. Because of the reduction in BK conductance in nerves lacking FMRP, there was an increase in calcium influx and enhanced neurotransmitter release. Using information theory, the authors showed that this change in the electrophysiological properties of the presynaptic nerve would result in a loss of information processing, such that the nerve would no longer discriminate among differing frequencies of stimulation and would essentially be activated by “noise” that would normally be filtered out. Thus, this effect on presynaptic BK channel activity could contribute to the altered information processing of Fragile X patients.

P.-Y. Deng, Z. Rotman, J. A. Blundon, Y. Cho, J. Cui, V. Cavalli, S. S. Zakharenko, V. A. Klyachko, FMRP regulates neurotransmitter release and synaptic information transmission by modulating action potential duration via BK channels. Neuron 77, 696–711 (2013). [PubMed]

A. Contractor, Broadening roles for FMRP: Big news for big potassium (BK) channels. Neuron 77, 601–603 (2013). [PubMed]