Abstract
KCNQ2 (Kv7.2) and KCNQ3 (Kv7.3) K(+) channels dampen neuronal excitability and their functional impairment may lead to epilepsy. Less is known about KCNQ5 (Kv7.5), which also displays wide expression in the brain. Here we show an unexpected role of KCNQ5 in dampening synaptic inhibition and shaping network synchronization in the hippocampus. KCNQ5 localizes to the postsynaptic site of inhibitory synapses on pyramidal cells and in interneurons. Kcnq5(dn/dn) mice lacking functional KCNQ5 channels display increased excitability of different classes of interneurons, enhanced phasic and tonic inhibition, and decreased electrical shunting of inhibitory postsynaptic currents. In vivo, loss of KCNQ5 function leads to reduced fast (gamma and ripple) hippocampal oscillations, altered gamma-rhythmic discharge of pyramidal cells and impaired spatial representations. Our work demonstrates that KCNQ5 controls excitability and function of hippocampal networks through modulation of synaptic inhibition.
Highlights
KCNQ2 (Kv7.2) and KCNQ3 (Kv7.3) K þ channels dampen neuronal excitability and their functional impairment may lead to epilepsy
In CA3, KCNQ5 immunoreactivity was shifted from the stratum radiatum and st. oriens to pyramidal cell bodies (Fig. 1b,c)
In addition to spontaneous inhibitory postsynaptic currents (sIPSCs), we investigated effects on inhibitory postsynaptic currents (IPSCs) of pyramidal cells that were evoked by extracellular stimulation in st. radiatum close to the recorded cell
Summary
KCNQ2 (Kv7.2) and KCNQ3 (Kv7.3) K þ channels dampen neuronal excitability and their functional impairment may lead to epilepsy. Kcnq5dn/dn mice lacking functional KCNQ5 channels display increased excitability of different classes of interneurons, enhanced phasic and tonic inhibition, and decreased electrical shunting of inhibitory postsynaptic currents. KCNQ2/KCNQ3 heteromers are considered to be a molecular correlate of the M-current[14,15] These currents are partially active at resting membrane potential and their inhibition by G-protein-coupled receptors increases neuronal excitability. KCNQ5 was reported to localize mainly to neuronal cell somata and dendrites in human cortex and hippocampus[21], to glutamatergic synapses in several rat brain stem nuclei[22,23] and to the postsynaptic membrane of vestibular calyx terminals[24]. KCNQ5 was proposed to be located at the presynaptic membrane of the calyx of Held and to control its properties[23]
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