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ABSTRACT: Synaptic input to a neuron may undergo various filtering steps, both locally and during transmission to the soma. Using simultaneous whole-cell recordings from soma and apical dendrites from rat CA1 hippocampal pyramidal cells, and biophysically detailed modeling, we found two complementary resonance (bandpass) filters of subthreshold voltage signals. Both filters favor signals in the theta (3-12 Hz) frequency range, but have opposite location, direction, and voltage dependencies: (1) dendritic H-resonance, caused by h/HCN-channels, filters signals propagating from soma to dendrite when the membrane potential is close to rest; and (2) somatic M-resonance, caused by M/Kv7/KCNQ and persistent Na(+) (NaP) channels, filters signals propagating from dendrite to soma when the membrane potential approaches spike threshold. Hippocampal pyramidal cells participate in theta network oscillations during behavior, and we suggest that that these dual, polarized theta resonance mechanisms may convey voltage-dependent tuning of theta-mediated neural coding in the entorhinal/hippocampal system during locomotion, spatial navigation, memory, and sleep.
Journal of Neuroscience 11/2009; 29(46):14472-83. · 7.11 Impact Factor
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ABSTRACT: Calcium-activated K(+) channels of the K(Ca)2 type (SK channels) are prominently expressed in the mammalian brain, including hippocampus. These channels are thought to underlie neuronal excitability control and have been implicated in plasticity, memory, and neural disease. Contrary to previous reports, we found that somatic spike-evoked medium afterhyperpolarizations (mAHPs) and corresponding excitability control were not caused by SK channels but mainly by Kv7/KCNQ/M channels in CA1 hippocampal pyramidal neurons. Thus apparently, these SK channels are hardly activated by somatic Na(+) spikes. To further test this conclusion, we used sharp electrode, whole cell, and perforated-patch recordings from rat CA1 pyramidal neurons. We found that SK channel blockers consistently failed to suppress mAHPs under a range of experimental conditions: mAHPs following single spikes or spike trains, at -60 or -80 mV, at 20-30 degrees C, in low or elevated extracellular [K(+)], or spike trains triggered by synaptic stimulation after blocking N-methyl-d-aspartic acid receptors (NMDARs). Nevertheless, we found that SK channels in these cells were readily activated by artificially enhanced Ca(2+) spikes, and an SK channel opener (1-ethyl-2-benzimidazolinone) enhanced somatic AHPs following Na(+) spikes, thus reducing excitability. In contrast to CA1 pyramidal cells, bursting pyramidal cells in the subiculum showed a Na(+) spike-evoked mAHP that was reduced by apamin, indicating cell-type-dependent differences in mAHP mechanisms. Testing for other SK channel functions in CA1, we found that field excitatory postsynaptic potentials mediated by NMDARs were enhanced by apamin, supporting the idea that dendritic SK channels are activated by NMDAR-dependent calcium influx. We conclude that SK channels in rat CA1 pyramidal cells can be activated by NMDAR-mediated synaptic input and cause feedback regulation of synaptic efficacy but are normally not appreciably activated by somatic Na(+) spikes in this cell type.
Journal of Neurophysiology 09/2008; 100(5):2589-604. · 3.32 Impact Factor
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ABSTRACT: To understand how electrical signal processing in cortical pyramidal neurons is executed by ion channels, it is essential to know their subcellular distribution. M-channels (encoded by Kv7.2-Kv7.5/KCNQ2-KCNQ5 genes) have multiple important functions in neurons, including control of excitability, spike afterpotentials, adaptation, and theta resonance. Nevertheless, the subcellular distribution of these channels has remained elusive. To determine the M-channel distribution within CA1 pyramidal neurons, we combined whole-cell patch-clamp recording from the soma and apical dendrite with focal drug application, in rat hippocampal slices. Both a M-channel opener (retigabine [N-(2-amino-4-(4-fluorobenzylamino)-phenyl) carbamic acid ethyl ester]) and a blocker (XE991 [10,10-bis(4-pyridinylmethyl)-9(10H)-antracenone]) changed the somatic subthreshold voltage response but had no observable effect on local dendritic responses. Under conditions promoting dendritic Ca2+ spikes, local somatic but not dendritic application of M-channel blockers (linopirdine and XE991) enhanced the Ca2+ spikes. Simultaneous dendritic and somatic whole-cell recordings showed that the medium afterhyperpolarization after a burst of spikes underwent strong attenuation along the apical dendrite and was fully blocked by somatic XE991 application. Finally, by combining patch-clamp and extracellular recordings with computer simulations, we found that perisomatic M-channels reduce the summation of EPSPs. We conclude that functional M-channels appear to be concentrated in the perisomatic region of CA1 pyramidal neurons, with no detectable M-channel activity in the distal apical dendrites.
Journal of Neuroscience 03/2007; 27(8):1853-67. · 7.11 Impact Factor
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ABSTRACT: Ion channel regulation by cyclic AMP and protein kinase A is a major effector mechanism for monoamine transmitters and neuromodulators in the CNS. Surprisingly, there is little information about the speed and kinetic limits of cAMP-PKA-dependent excitability changes in the brain. To explore these questions, we used flash photolysis of caged-cAMP (DMNB-cAMP) to provide high temporal resolution. The resultant free cAMP concentration was calculated from separate experiments in which this technique was used, in excised patches, to activate cAMP-sensitive cyclic nucleotide-gated (CNG) channels expressed in Xenopus oocytes. In hippocampal pyramidal neurones we studied the modulation of a potassium current (slow AHP current, I(sAHP)) known to be targeted by multiple transmitter systems that use cAMP-PKA. Rapid cAMP elevation by flash photolyis of 200 microm DMNB-cAMP completely inhibited the K(+) current. The estimated yield (1.3-3%) suggests that photolysis of 200 microm caged precursor is sufficient for full PKA activation. By contrast, extended gradual photolysis of 200 microm DMNB-cAMP caused stable but only partial inhibition. The kinetics of rapid cAMP inhibition of the K(+) conductance (time constant 1.5-2 s) were mirrored by changes in firing patterns commencing within 500 ms of rapid cAMP elevation. Maximal increases in firing were short-lasting (< 60 s) and gave way to moderately enhanced levels of spiking. The results demonstrate how the fidelity of phasic monoamine signalling can be preserved by the cAMP-PKA pathway.
The Journal of Physiology 10/2006; 576(Pt 2):403-17. · 4.72 Impact Factor
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ABSTRACT: The persistent Na+ current, INaP, is known to amplify subthreshold oscillations and synaptic potentials, but its impact on action potential generation remains enigmatic. Using computational modeling, whole-cell recording, and dynamic clamp of CA1 hippocampal pyramidal cells in brain slices, we examined how INaP changes the transduction of excitatory current into action potentials. Model simulations predicted that INaP increases afterhyperpolarizations, and, although it increases excitability by reducing rheobase, INaP also reduces the gain in discharge frequency in response to depolarizing current (f/I gain). These predictions were experimentally confirmed by using dynamic clamp, thus circumventing the longstanding problem that INaP cannot be selectively blocked. Furthermore, we found that INaP increased firing regularity in response to sustained depolarization, although it decreased spike time precision in response to single evoked EPSPs. Finally, model simulations demonstrated that I(NaP) increased the relative refractory period and decreased interspike-interval variability under conditions resembling an active network in vivo.
Neuron 02/2006; 49(2):257-70. · 14.74 Impact Factor
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ABSTRACT: In hippocampal pyramidal cells, a single action potential (AP) or a burst of APs is followed by a medium afterhyperpolarization (mAHP, lasting approximately 0.1 s). The currents underlying the mAHP are considered to regulate excitability and cause early spike frequency adaptation, thus dampening the response to sustained excitatory input relative to responses to abrupt excitation. The mAHP was originally suggested to be primarily caused by M-channels (at depolarized potentials) and h-channels (at more negative potentials), but not SK channels. In recent reports, however, the mAHP was suggested to be generated mainly by SK channels or only by h-channels. We have now re-examined the mechanisms underlying the mAHP and early spike frequency adaptation in CA1 pyramidal cells by using sharp electrode and whole-cell recording in rat hippocampal slices. The specific M-channel blocker XE991 (10 microm) suppressed the mAHP following 1-5 APs evoked by current injection at -60 mV. XE991 also enhanced the excitability of the cell, i.e. increased the number of APs evoked by a constant depolarizing current pulse, reduced their rate of adaptation, enhanced the after depolarization and promoted bursting. Conversely, the M-channel opener retigabine reduced excitability. The h-channel blocker ZD7288 (4-ethylphenylamino-1,2-dimethyl-6-methylaminopyrimidinium chloride; 10 microm) fully suppressed the mAHP at -80 mV, but had little effect at -60 mV, whereas XE991 did not measurably affect the mAHP at -80 mV. Likewise, ZD7288 had little or no effect on excitability or adaptation during current pulses injected from -60 mV, but changed the initial discharge during depolarizing pulses injected from -80 mV. In contrast to previous reports, we found that blockade of Ca2+-activated K+ channels of the SK/KCa type by apamin (100-400 nm) failed to affect the mAHP or adaptation. A computational model of a CA1 pyramidal cell predicted that M- and h-channels will generate mAHPs in a voltage-dependent manner, as indicated by the experiments. We conclude that M- and h-channels generate the somatic mAHP in hippocampal pyramidal cells, with little or no net contribution from SK channels.
The Journal of Physiology 09/2005; 566(Pt 3):689-715. · 4.72 Impact Factor
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ABSTRACT: In humans, mutations in the KCNQ2 or KCNQ3 potassium-channel genes are associated with an inherited epilepsy syndrome. We have studied the contribution of KCNQ/M-channels to the control of neuronal excitability by using transgenic mice that conditionally express dominant-negative KCNQ2 subunits in brain. We show that suppression of the neuronal M current in mice is associated with spontaneous seizures, behavioral hyperactivity and morphological changes in the hippocampus. Restriction of transgene expression to defined developmental periods revealed that M-channel activity is critical to the development of normal hippocampal morphology during the first postnatal weeks. Suppression of the M current after this critical period resulted in mice with signs of increased neuronal excitability and deficits in hippocampus-dependent spatial memory. M-current-deficient hippocampal CA1 pyramidal neurons showed increased excitability, reduced spike-frequency adaptation, attenuated medium afterhyperpolarization and reduced intrinsic subthreshold theta resonance. M channels are thus critical determinants of cellular and neuronal network excitability, postnatal brain development and cognitive performance.
Nature Neuroscience 02/2005; 8(1):51-60. · 15.53 Impact Factor
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ABSTRACT: Coherent network oscillations in the brain are correlated with different behavioural states. Intrinsic resonance properties of neurons provide a basis for such oscillations. In the hippocampus, CA1 pyramidal neurons show resonance at theta (theta) frequencies (2-7 Hz). To study the mechanisms underlying theta-resonance, we performed whole-cell recordings from CA1 pyramidal cells (n = 73) in rat hippocampal slices. Oscillating current injections at different frequencies (ZAP protocol), revealed clear resonance with peak impedance at 2-5 Hz at approximately 33 degrees C (increasing to approximately 7 Hz at approximately 38 degrees C). The theta-resonance showed a U-shaped voltage dependence, being strong at subthreshold, depolarized (approximately -60 mV) and hyperpolarized (approximately -80 mV) potentials, but weaker near the resting potential (-72 mV). Voltage clamp experiments revealed three non-inactivating currents operating in the subthreshold voltage range: (1) M-current (I(M)), which activated positive to -65 mV and was blocked by the M/KCNQ channel blocker XE991 (10 microM); (2) h-current (I(h)), which activated negative to -65 mV and was blocked by the h/HCN channel blocker ZD7288 (10 microM); and (3) a persistent Na(+) current (I(NaP)), which activated positive to -65 mV and was blocked by tetrodotoxin (TTX, 1 microM). In current clamp, XE991 or TTX suppressed the resonance at depolarized, but not hyperpolarized membrane potentials, whereas ZD7288 abolished the resonance only at hyperpolarized potentials. We conclude that these cells show two forms of theta-resonance: "M-resonance" generated by the M-current and persistent Na(+) current in depolarized cells, and "H-resonance" generated by the h-current in hyperpolarized cells. Computer simulations supported this interpretation. These results suggest a novel function for M/KCNQ channels in the brain: to facilitate neuronal resonance and network oscillations in cortical neurons, thus providing a basis for an oscillation-based neural code.
The Journal of Physiology 01/2003; 545(Pt 3):783-805. · 4.72 Impact Factor
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ABSTRACT: Small-conductance Ca2+-activated K+ (SK) channels are important for excitability control and afterhyperpolarizations in vertebrate neurons and have been implicated in regulation of the functional state of the forebrain. We have examined the distribution, functional expression, and subunit composition of SK channels in rat brain. Immunoprecipitation detected solely homotetrameric SK2 and SK3 channels in native tissue and their constitutive association with calmodulin. Immunohistochemistry revealed a restricted distribution of SK1 and SK2 protein with highest densities in subregions of the hippocampus and neocortex. In contrast, SK3 protein was distributed more diffusely in these brain regions and predominantly expressed in phylogenetically older brain regions. Whole-cell recording showed a sharp segregation of apamin-sensitive SK current within the hippocampal formation, in agreement with the SK2 distribution, suggesting that SK2 homotetramers underlie the apamin-sensitive medium afterhyperpolarizations in rat hippocampus.
Journal of Neuroscience 12/2002; 22(22):9698-707. · 7.11 Impact Factor
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Hua Hu,
Li-Rong Shao,
Sorush Chavoshy,
Ning Gu,
Maria Trieb,
Ralf Behrens,
Petter Laake,
Olaf Pongs,
Hans Gunther Knaus,
Ole Petter Ottersen,
Johan F. Storm
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ABSTRACT: Large-conductance Ca 2-activated K channels (BK, also called Maxi-K or Slo channels) are widespread in the vertebrate nervous system, but their functional roles in synaptic transmis- sion in the mammalian brain are largely unknown. By combining electrophysiology and immunogold cytochemistry, we demon- strate the existence of functional BK channels in presynaptic terminals in the hippocampus and compare their functional roles in somata and terminals of CA3 pyramidal cells. Double- labeling immunogold analysis with BK channel and glutamate receptor antibodies indicated that BK channels are targeted to the presynaptic membrane facing the synaptic cleft in terminals of Schaffer collaterals in stratum radiatum. Whole-cell, intracel- lular, and field-potential recordings from CA1 pyramidal cells showed that the presynaptic BK channels are activated by calcium influx and can contribute to repolarization of the pre- synaptic action potential (AP) and negative feedback control of Ca 2 influx and transmitter release. This was observed in the presence of 4-aminopyridine (4-AP, 40-100 M), which broad- ened the presynaptic compound action potential. In contrast, the presynaptic BK channels did not contribute significantly to regulation of action potentials or transmitter release under basal experimental conditions, i.e., without 4-AP, even at high stimulation frequencies. This is unlike the situation in the parent cell bodies (CA3 pyramidal cells), where BK channels contrib- ute strongly to action potential repolarization. These results indicate that the functional role of BK channels depends on their subcellular localization.
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ABSTRACT: Small-conductance Ca 2-activated K (SK) channels are im- portant for excitability control and afterhyperpolarizations in vertebrate neurons and have been implicated in regulation of the functional state of the forebrain. We have examined the distribution, functional expression, and subunit composition of SK channels in rat brain. Immunoprecipitation detected solely homotetrameric SK2 and SK3 channels in native tissue and their constitutive association with calmodulin. Immunohisto- chemistry revealed a restricted distribution of SK1 and SK2 protein with highest densities in subregions of the hippocam- pus and neocortex. In contrast, SK3 protein was distributed more diffusely in these brain regions and predominantly ex- pressed in phylogenetically older brain regions. Whole-cell re- cording showed a sharp segregation of apamin-sensitive SK current within the hippocampal formation, in agreement with the SK2 distribution, suggesting that SK2 homotetramers un- derlie the apamin-sensitive medium afterhyperpolarizations in rat hippocampus.
