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...

The entorhinal cortex (EC) provides the predominant excitatory drive to the hippocampal CA1 and subicular neurons in chronic epilepsy. Discerning the mechanisms underlying signal integration within EC neurons is essential for understanding network excitability alterations involving the hippocampus during epilepsy. Twenty-four hours following a single seizure episode when there were no behavioral or electrographic seizures, we found enhanced spontaneous activity still present in the rat EC in vivo and in vitro. The increased excitability was accompanied by a profound reduction in I(h) in EC layer III neurons and a significant decline in HCN1 and HCN2 subunits that encode for h channels. Consequently, dendritic excitability was enhanced, resulting in increased neuronal firing despite hyperpolarized membrane potentials. The loss of I(h) and the increased neuronal excitability persisted for 1 week following seizures. Our results suggest that dendritic I(h) plays an important role in determining the excitability of EC layer III neurons and their associated neural networks.

M‐type K+ currents (IK(M)) play a key role in regulating neuronal excitability. In sympathetic neurons, M‐channels are thought to be composed of a heteromeric assembly of KCNQ2 and KCNQ3 K+ channel subunits. Here, we have tried to identify the KCNQ subunits that are involved in the generation of IK(M) in hippocampal pyramidal neurons cultured from 5‐ to 7‐day‐old rats. RT‐PCR of either CA1 or CA3 regions revealed the presence of KCNQ2, KCNQ3, KCNQ4 and KCNQ5 subunits. Single‐cell PCR of dissociated hippocampal pyramidal neurons gave detectable signals for only KCNQ2, KCNQ3 and KCNQ5; where tested, most also expressed mRNA for the vesicular glutamate transporter VGLUT1. Staining for KCNQ2 and KCNQ5 protein showed punctate fluorescence on both the somata and dendrites of hippocampal neurons. Staining for KCNQ3 was diffusely distributed whereas KCNQ4 was undetectable. In perforated patch recordings, linopirdine, a specific M‐channel blocker, fully inhibited IK(M) with an IC50 of 3.6 ± 1.5 μM. In 70 % of these cells, TEA fully suppressed IK(M) with an IC50 of 0.7 ± 0.1 mm. In the remaining cells, TEA maximally reduced IK(M) by only 59.7 ± 5.2 % with an IC50 of 1.4 ± 0.3 mm; residual IK(M) was abolished by linopirdine. Our data suggest that KCNQ2, KCNQ3 and KCNQ5 subunits contribute to IK(M) in these neurons and that the variations in TEA sensitivity may reflect differential expression of KCNQ2, KCNQ3 and KCNQ5 subunits.

The first international colloquium on basal cell nevus syndrome (BCNS) was held at Saint Louis University School of Medicine and supported by the Basal Cell Carcinoma Nevus Syndrome (BCCNS) Life Support Network (www.gorlinsyndrome.org). The foremost goal of the conference was to review and revise the prior diagnostic criteria and define the surveillance recommendations for affected pediatric and adult patients to allow for early intervention. The invited consensus group participants included geneticists, dermatologists, orthopedists, neurologists, and dental/oral medicine specialists, who treat patients with BCNS or related disorders. This group also included individuals who have a research interest in BCNS and who additionally serve on the medical advisory board of the BCCNS Life Support Network. Expert opinion was based on the collective clinical and research experience of the consensus group participants after presentation and review of the previously published literature regarding diagnosis and treatment of BCNS. A consensus was achieved and agreed upon by open roundtable discussion of the group participants. The consensus statement outlines the proposed diagnostic and management protocols that will hopefully limit morbidity and mortality for affected individuals until more specific and targeted therapies are widely available.