Changes In Voltage-gated Potassium Currents Of Hippocampal Fast-spiking Interneurons From Fmr1Knockout Mice

Background&objectiveFragile X syndrome (FXS)，one of the common inheritable form of mentalretardation，is caused by transcriptional silencing of the fragile X mental retardationprotein(FMRP). A common feature of the FXS is neuronal hyperexcitability，and itsclinical symptoms include mental retardation，attention deficit，autism and a highincidence of epilepsy. Normal neural physiological activities are depended on abalance between excitability and inhibition loop in the nervous system.Network interactions between inhibitory interneurons and pyramidal cellscontribute to regulating neuronal excitability and abnormal discharges. Kv channelsare critical in regulation of firing rate, action potential waveform, and dendriticsignaling. Our previous studies found that hyperexcitability of cortical pyramidalneurons in Fmr1KO mice might associated with increased potassium currents. Wealso found that sodium current density and number of inhibitory interneurons arealtered in the hippocampal interneurons in Fmr1knockout mice. FMRP is highlyexpressed in hippocampal interneurons, suggesting that electrophysiological properties of hippocampal interneurons might be altered in the absence of FMRP andconsequently lead to hyperexcitability of hippcampal local circuitry.Given the importance of potassium currents in control of neuronal excitabilityand the facts that FMRP negatively regulates several subtypes of potassium channels,we speculate that the absence of FMRP expression may cause changes in propertiesof potassium channels in specific interneuron subpopulations and thus influencefiring pattern of hippocampal network. Fast-spiking (FS) interneurons withcharacteristic firing patterns play a key role in feedback of the discharges ofpyramidal neurons. However，the electrophysiological properties on FS interneuronsof FXS mice remain largely unclear. Here we attempted to uncover the possiblechanges in potassium currents in the FS interneurons from Fmr1KO mice usingacute hippocampus slice.Methods1. Preparation of acute brain slices from the KO and WT mice at10days of age.2. Use the whole-cell patch clamp technique for electrophysiological recording.3. Curves of I-V，activation，inactivation and recovery after inactivation wereobtained via Clampfit10.2and Origin8.0. The related parameters，such as halfactivation voltage，half inactivation voltage，recovery time constant，were fittedaccording to appropriate equations.Results1. Peak amplitude of ISAin the FS interneurons of KO mice was significantlydecreased, as compared to that of WT mice (P<0.05, n=6). At a higherdepolarization voltage (30-40mV), peak amplitude of IADwere lower in KOinterneurons (P<0.05, n=6), while ISSremained unaltered (P>0.05, n=6).2. Activation curves, inactivation curves and recovery curves of ISAin FSinterneurons of KO mice shift to the right. Half activation voltage and halfinactivation voltage in KO interneruons were significantly higher (P<0.05, n=4).And the time constant (τ) of recovery for slow phase in KO interneurons was significantly increased, indicating a more significant portion of channelsinactivated (P<0.05，n=4).ConclusionOur findings identify changes in potassium currents in a specific interneuronsubpopulation FS interneuons of Fmr1knockout mice, in which transient outwardpotassium currents（ISA）as well as slow inactivate outward potassium currents (IAD)decreased, and gating kinetics of A-type potassium channels changed. Thesealterations may be associated with functional abnormalities in hippocampalinterneurons, and implicate an impact on hippocampal activity and processingassociated with FXS.