The dendrites of pyramidal neurons have markedly different electrical properties from those of the soma, owing to the non-uniform distribution of voltage-gated ion channels in dendrites. It is thus possible that drugs acting on ion channels might preferentially alter dendritic, but not somatic, excitability. Using dendritic and somatic whole-cell and cell-attached recordings in rat hippocampal slices, we found that the anticonvulsant lamotrigine selectively reduced action potential firing from dendritic depolarization, while minimally affecting firing at the soma. This regional and input-specific effect resulted from an increase in the hyperpolarization-activated cation current (I(h)), a voltage-gated current present predominantly in dendrites. These results demonstrate that neuronal excitability can be altered by drugs acting selectively on dendrites, and suggest an important role for I(h) in controlling dendritic excitability and epileptogenesis.

Under certain conditions, regenerative voltage spikes can be initiated locally in the dendrites of CA1 pyramidal neurons. These are interesting events that could potentially provide neurons with additional computational abilities. Using whole-cell dendritic recordings from the distal apical trunk and proximal tuft regions and realistic computer modeling, we have determined that highly synchronized and moderately clustered inputs are required for dendritic spike initiation: ϳ50 synaptic inputs spread over 100 m of the apical trunk/tuft need to be activated within 3 msec. Dendritic spikes are characterized by a more depolarized voltage threshold than at the soma [Ϫ48 Ϯ 1 mV (n ϭ 30) vs Ϫ56 Ϯ 1 mV (n ϭ 7), respectively] and are mainly generated and shaped by dendritic Na ϩ and K ϩ currents. The relative contribution of AMPA and NMDA currents is also important in determining the actual spatiotemporal requirements for dendritic spike initiation. Once initiated, dendritic spikes can easily reach the soma, but their propagation is only moderately strong, so that it can be modulated by physiologically relevant factors such as changes in the V m and the ionic composition of the extracellular solution. With effective spike propagation, an extremely short-latency neuronal output is produced for greatly reduced input levels. Therefore, dendritic spikes function as efficient detectors of specific input patterns, ensuring that the neuronal response to high levels of input synchrony is a precisely timed action potential output.

Members of the Kv7 family (Kv7.2-Kv7.5) generate a subthreshold K ؉ current, the M؊ current. This regulates the excitability of many peripheral and central neurons. Recent evidence shows that Kv7.2 and Kv7.3 subunits are targeted to the axon initial segment of hippocampal neurons by association with ankyrin G. Further, spontaneous mutations in these subunits that impair axonal targeting cause human neonatal epilepsy. However, the precise functional significance of their axonal location is unknown. Using electrophysiological techniques together with a peptide that selectively disrupts axonal Kv7 targeting (ankyrin G-binding peptide, or ABP) and other pharmacological tools, we show that axonal Kv7 channels are critically and uniquely required for determining the inherent spontaneous firing of hippocampal CA1 pyramids, independently of alterations in synaptic activity. This action was primarily because of modulation of action potential threshold and resting membrane potential (RMP), amplified by control of intrinsic axosomatic membrane properties. Computer simulations verified these data when the axonal Kv7 density was three to five times that at the soma. The increased firing caused by axosomatic Kv7 channel block backpropagated into distal dendrites affecting their activity, despite these structures having fewer functional Kv7 channels. These results indicate that axonal Kv7 channels, by controlling axonal RMP and action potential threshold, are fundamental for regulating the inherent firing properties of CA1 hippocampal neurons.axon initial segment ͉ CA1 pyramidal neurons ͉ M-current ͉ KCNQ channels N euronal Kv7 (KCNQ) channels form a noninactivating K ϩ current (also known as the MϪ current); this turns on at subthreshold potentials and regulates the excitability of a variety of peripheral and central neurons (1-3). Recent immunohistochemical evidence has shown that the principal subunits forming native M channels, Kv7.2 and Kv7.3 (3,4), are concentrated at the axon initial segment (AIS) and nodes of Ranvier of central and peripheral principal neurons (5-9), where they colocalize with Na ϩ channels. Like Na ϩ channels, they contain an ankyrin G-binding motif that targets them to the AIS (5, 8). They are also expressed at lower densities at the soma and possibly dendrites and synaptic terminals (4,6,7,10,11).Spontaneous mutations in Kv7 subunits cause epilepsy in humans (2) and mice (12). The hippocampus is strongly implicated in epilepsy (13) and accordingly, previous somatic recordings from these neurons have indicated that the Kv7 current is involved in determining several aspects of neuronal excitability, including the resting membrane potential (RMP), spike frequency adaptation, and burst suppression (e.g., refs. 14-16). However, the specific contribution made by Kv7 channels in the AIS to these or other manifestations of excitability has not been determined. This is important, because some human epileptogenic mutations impair axonal Kv7 subunit expression (7).We have used selective pharmacological and mol...

No abstract

A key goal in neuroscience is to explain how the operations of a neuron emerge from sets of active channels with specific dendritic distributions. If general principles can be identified for these distributions, dendritic channels should reflect the computational role of a given cell type within its functional neural circuit. Here, we discuss insights from experimental and computational data on the distribution of voltage-gated channels in dendrites, and attempt to derive rules for how their interactions implement different dendritic functions. We propose that this type of analysis will be important for understanding behavioural processes in terms of single-neuron properties, and that it constitutes a step towards a 'functional proteomics' of nerve cells, which will be essential for defining neuronal phenotypes.

We investigated the role of A-type K ؉ channels for the induction of long-term potentiation (LTP) of Schaffer collateral inputs to hippocampal CA1 pyramidal neurons. When low-amplitude excitatory postsynaptic potentials (EPSPs) were paired with two postsynaptic action potentials in a theta-burst pattern, N-methyl-D-aspartate (NMDA)-receptor-dependent LTP was induced. The amplitudes of the back-propagating action potentials were boosted in the dendrites only when they were coincident with the EPSPs. Mitogen-activated protein kinase (MAPK) inhibitors PD 098059 or U0126 shifted the activation of dendritic K ؉ channels to more hyperpolarized potentials, reduced the boosting of dendritic action potentials by EPSPs, and suppressed the induction of LTP. These results support the hypothesis that dendritic K ؉ channels and the boosting of back-propagating action potentials contribute to the induction of LTP in CA1 neurons. P airing subthreshold excitatory postsynaptic potentials (EPSPs) with back-propagating action potentials has been reported to result in the amplification of dendritic action potentials and the induction of long-term potentiation (LTP) in the dendrites of hippocampal CA1 pyramidal neurons (1). Furthermore, the presence of the action potentials in the dendrites was shown to be required for this LTP-induction protocol. These findings led to the suggestion that amplification or boosting of dendritic action potentials might provide the postsynaptic depolarization required for the unblocking of N-methyl-Daspartate (NMDA) receptors to induce Ca influx that is necessary for induction of LTP (2-4).Several studies have shown that induction of LTP by pairing postsynaptic action potentials with EPSPs requires that the spikes coincide with the EPSPs within a narrow time window (5-8). If the spikes occur about 10-20 ms before the EPSP, long-term depression is induced; if they occur within about 10-20 ms from the beginning of the EPSP, LTP is induced; and if AP and EPSP are separated by more than 100 ms, no plasticity is elicited (5, 6). This precise timing relationship between the postsynaptic action potentials and the EPSPs is somewhat surprising, given that the deactivation rate for NMDA receptors is around 200 ms (9). One possible explanation for this narrow time window is that the boosting of the amplitude of the dendritic action potential by the increased activation of dendritic Na ϩ channels (10) and͞or inactivation of dendritic K ϩ channels (2) is required for LTP induction. Here, we explore the relationship between the boosting of action potential and LTP induction in terms of spike-timing. We also tested the involvement of K ϩ channels in this relationship by using the mitogen-activated protein kinase (MAPK) inhibitor U0126, which was found to increase dendritic K ϩ currents. The results provide strong support for the hypothesis that spike boosting is required for this form of pairing-induced LTP, and that dendritic K ϩ channels play a critical role in this phenomenon. Materials and Methods Preparation of S...

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Mutations in the K V 7.2 gene encoding for voltage-dependent K + channel subunits cause neonatal epilepsies with wide phenotypic heterogeneity. Two mutations affecting the same positively charged residue in the S 4 domain of K V 7.2 have been found in children affected with benign familial neonatal seizures (R213W mutation) or with neonatal epileptic encephalopathy with severe pharmacoresistant seizures and neurocognitive delay, suppression-burst pattern at EEG, and distinct neuroradiological features (R213Q mutation). To examine the molecular basis for this strikingly different phenotype, we studied the functional characteristics of mutant channels by using electrophysiological techniques, computational modeling, and homology modeling. Functional studies revealed that, in homomeric or heteromeric configuration with K V 7.2 and/or K V 7.3 subunits, both mutations markedly destabilized the open state, causing a dramatic decrease in channel voltage sensitivity. These functional changes were (i) more pronounced for channels incorporating R213Q-than R213W-carrying K V 7.2 subunits; (ii) proportional to the number of mutant subunits incorporated; and (iii) fully restored by the neuronal K v 7 activator retigabine. Homology modeling confirmed a critical role for the R213 residue in stabilizing the activated voltage sensor configuration. Modeling experiments in CA1 hippocampal pyramidal cells revealed that both mutations increased cell firing frequency, with the R213Q mutation prompting more dramatic functional changes compared with the R213W mutation. These results suggest that the clinical disease severity may be related to the extent of the mutation-induced functional K + channel impairment, and set the preclinical basis for the potential use of K v 7 openers as a targeted anticonvulsant therapy to improve developmental outcome in neonates with K V 7.2 encephalopathy.H eteromeric assembly of K V 7.2 (KCNQ2) and K V 7.3 (KCNQ3) voltage-dependent K + channel subunits underlies the M-current (I KM ) (1), a slowly activating and deactivating K + neuronal current that regulates excitability in the subthreshold range for action potential (AP) generation (2, 3) and is also involved in network oscillation and synchronization control (4).Mutations in K V 7.2 (5, 6) and, more rarely, K V 7.3 (7) genes are responsible for benign familial neonatal seizures (BFNS), a rare, autosomal-dominant epilepsy of newborns characterized by recurrent seizures that begin in the very first days of life in otherwise healthy newborns and remit after a few weeks or months; BFNS-affected individuals mostly display normal interictal EEG, neuroimaging findings, and psychomotor development.More recently, K V 7.2 mutations have been described in neonates affected with pharmacoresistant seizures with psychomotor retardation, suppression-burst pattern at EEG, and distinct neuroradiological features, thus defining a so-called "K V 7.2 encephalopathy" (8), as well as in children with Ohtahara syndrome or early infantile epileptic encephalopathy with supp...