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Nicholas P Poolos

Publications and source records attributed to Nicholas P Poolos.

8 recordsLinked to original sources

Reversed somatodendritic I(h) gradient in a class of rat hippocampal neurons with pyramidal morphology.

In CA1 and neocortical pyramidal neurons, I(h) is present primarily in the dendrites. We asked if all neurons of a pyramidal morphology have a similar density of I(h). We characterized a novel class of hippocampal neurons with pyramidal morphology found in the stratum radiatum, which we termed the 'pyramidal-like principal' (PLP) neuron. Morphological similarities to pyramidal neurons were verified by filling the neurons with biocytin. PLPs did not stain for markers associated with interneurons, and projected to both the septum and olfactory bulb. By using cell-attached patch-clamp recordings, we found that these neurons expressed a high density of I(h) in the soma that declined to a lower density in the dendrites, a pattern that is reversed compared to pyramidal neurons. The voltage-dependent activation and activation time constants of I(h) in the PLPs were similar to pyramidal neurons. Whole-cell patch-clamp recordings from the soma and dendrites of PLP neurons showed no significant differences in input resistance and local temporal summation between the two locations. Blockade of I(h) by ZD7288 increased the input resistance and temporal summation of simulated EPSPs, as in pyramidal neurons. When NMDA receptors were blocked, temporal summation at the soma of distal synaptic potentials was similar to that seen with current injections at the soma, suggesting a 'normalization' of temporal summation similar to that observed in pyramidal neurons. Thus, we have characterized a principal neuronal subtype in the hippocampus with a similar morphology but reversed I(h) somatodendritic gradient to that previously observed in CA1 hippocampal and neocortical pyramidal neurons.

Animals↗

Modulation of h-channels in hippocampal pyramidal neurons by p38 mitogen-activated protein kinase.

Hyperpolarization-activated cyclic nucleotide-gated ion channels (h-channels; I(h); HCN) modulate intrinsic excitability in hippocampal and neocortical pyramidal neurons, among others. Whereas I(h) mediated by the HCN2 isoform is regulated by cAMP, there is little known about kinase modulation of I(h), especially for the HCN1 isoform predominant in pyramidal neurons. We used a computational method to identify a novel kinase modulator of h-channels, p38 mitogen-activated protein kinase (p38 MAPK). Inhibition of p38 MAPK in hippocampal pyramidal neurons caused a approximately 25 mV hyperpolarization of I(h) voltage-dependent activation. This downregulation of I(h) produced hyperpolarization of resting potential, along with increased input resistance and temporal summation of excitatory inputs. Activation of p38 MAPK caused a approximately 11 mV depolarizing shift in I(h) activation, along with depolarized resting potential, and decreased input resistance and temporal summation. Inhibition of related MAPKs, ERK1/2 (extracellular signal-related kinase 1/2) and JNK (c-Jun N-terminal kinase), produced no effect on I(h). These results show that p38 MAPK is a strong modulator of h-channel biophysical properties and may deserve additional exploration as a link between altered I(h) and pathological conditions such as epilepsy.

Adaptation, Physiological↗

The h-channel: a potential channelopathy in epilepsy?

Ion channelopathy is a proven cause of inherited human epilepsy, and may play a role in acquired epileptic syndromes as well. Of the many ion channel causes of epilepsy, the h-channel is a potential new addition. H-channels are voltage-gated ion channels with unique biophysical properties. The h-channel exerts a significant modulatory influence on neuronal excitability, and is a target of antiepileptic drugs. Further, its activity is influenced by seizures, raising the question of whether it may play a role in epileptogenesis as well. This review summarizes the evidence for the contribution of h-channels to seizures and epilepsy, and outlines hypotheses concerning the existence of an "h-channelopathy" in human epilepsy.

Animals↗

Acquired dendritic channelopathy in temporal lobe epilepsy.

Inherited channelopathies are at the origin of many neurological disorders. Here we report a form of channelopathy that is acquired in experimental temporal lobe epilepsy (TLE), the most common form of epilepsy in adults. The excitability of CA1 pyramidal neuron dendrites was increased in TLE because of decreased availability of A-type potassium ion channels due to transcriptional (loss of channels) and posttranslational (increased channel phosphorylation by extracellular signal-regulated kinase) mechanisms. Kinase inhibition partly reversed dendritic excitability to control levels. Such acquired channelopathy is likely to amplify neuronal activity and may contribute to the initiation and/or propagation of seizures in TLE.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

Pharmacological upregulation of h-channels reduces the excitability of pyramidal neuron dendrites.

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.

Action Potentials↗