M‐type potassium channels modulate Schaffer collateral–CA1 glutamatergic synaptic transmission

Abstract

Key points• M-type potassium channels play a key role in modulating neuronal excitability. However, the effects of M-channel activation on synaptic transmission are poorly understood.• This study found that an M1 receptor agonist and M-channel blockers increased action potential-independent glutamate release at Schaffer collateral-CA1 pyramidal neuron synapses in acute hippocampus slices.• This enhancement was dependent on Ca 2+ influx from extracellular space but not intracellular calcium stores.• Inhibition of M-channels results in the depolarization of CA3 pyramidal neurons and activated presynaptic voltage-gated P/Q-and N-type calcium channels, which in turn causes Ca 2+ influx and increased glutamate release.• Thus, M1 muscarinic agonists modulate action potential-independent glutamatergic synaptic transmission in the hippocampus by inhibition of presynaptic M-channels.Abstract Previous studies have suggested that muscarinic receptor activation modulates glutamatergic transmission. M-type potassium channels mediate the effects of muscarinic activation in the hippocampus, and it has been proposed that they modulate glutamatergic synaptic transmission. We tested whether M1 muscarinic receptor activation enhances glutamatergic synaptic transmission via the inhibition of the M-type potassium channels that are present in Schaffer collateral axons and terminals. Miniature excitatory postsynaptic currents (mEPSCs) were recorded from CA1 pyramidal neurons. The M1 receptor agonist, NcN-A-343, increased the frequency of mEPSCs, but did not alter their amplitude. The M-channel blocker XE991 and its analogue linopirdine also increased the frequency of mEPSCs. Flupirtine, which opens M-channels, had the opposite effect. XE991 did not enhance mEPSCs frequency in a calcium-free external medium. Blocking P/Q-and N-type calcium channels abolished the effect of XE991 on mEPSCs. These data suggested that the inhibition of M-channels increases presynaptic calcium-dependent glutamate release in CA1 pyramidal neurons. The effects of these agents on the membrane potentials of presynaptic CA3 pyramidal neurons were studied using current clamp recordings; activation of M1 receptors and blocking M-channels depolarized neurons and increased burst firing. The input resistance of CA3 neurons was increased by the application of McN-A-343 and XE991; these effects were consistent with the closure of M-channels. Muscarinic activation inhibits M-channels in CA3 pyramidal neurons and its efferents -Schaffer collateral, which causes the depolarization, activates voltage-gated calcium channels, and ultimately elevates Abbreviations M1, muscarinic type 1; mEPSCs, miniature excitatory postsynaptic currents; CNQX, 6-cyano-7-nitroquinoxalene-2,3-dione; K-S, Kolmogorov-Smirnov; NcN-A-343, (4-hydroxy-2-butynyl)-1-trimethylammonium-3-chlorocarbanilate chloride; sEPSC, spontaneous excitatory postsynaptic current; XE-991,10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone.

Enhanced AMPA receptor-mediated neurotransmission on CA1 pyramidal neurons during status epilepticus

“…Action potential-independent miniature excitatory post-synaptic currents (mEPSCs) were recorded from CA1 pyramidal neurons (supplementary figure 1) and DGCs, spontaneous EPSCs (sEPSCs) were also recorded from CA1 pyramidal neurons. Synaptic currents were analyzed using the MiniAnalysis software as described previously (Sun & Kapur, 2012). The threshold for detecting synaptic currents was set at 5 times the root mean square noise.…”

Modulation of Kv7 channels and excitability in the brain

“…Augmentation of Kv7 channels at this location attenuates neurotransmitter release [99] whereas suppression of Kv7 current by Gq activation increases activation of voltage-gated calcium channels leading to increased transmission [145]. …”

Voltage-Gated Potassium Channels at the Crossroads of Neuronal Function, Ischemic Tolerance, and Neurodegeneration

“…These channels critically contribute to the after-hyperpolarizing potential, aid in maintaining resting membrane potential and firing thresholds, and importantly, reduce intrinsic burst firing and repetitive action potential firing in response to excitatory stimuli [12, 198, 200, 201, 203, 259, 261–265]. Increasing Kv7 channel function decreases excitability, while suppressing Kv7 channel K + currents enhances excitability in hippocampal pyramidal, and superior cervical and dorsal root ganglionic neurons, and promotes epileptiform activity in hippocampal neurons [202, 264–271].…”