Lamotrigine Decreases the Excitability of Dendrites in Hippocampal Pyramidal Neurons by Increasing Activation of I[sub]h[/sub].
Abstract number :
1.259
Submission category :
Year :
2001
Submission ID :
216
Source :
www.aesnet.org
Presentation date :
12/1/2001 12:00:00 AM
Published date :
Dec 1, 2001, 06:00 AM
Authors :
N.P. Poolos, MD, PhD, Neuroscience, Baylor Coll. of Med., Houston, TX; D. Johnston, PhD, Neuroscience, Baylor Coll. of Med., Houston, TX
RATIONALE: Previously we showed that the novel anticonvulsant lamotrigine (LTG) preferentially affected the excitability of hippocampal CA1 pyramidal neuron dendrites compared to the soma of these neurons (Poolos and Johnston, [italic]Soc. Neurosci. Abstr.[/italic], 26:1624, 2000). LTG markedly raised the threshold for action potential (AP) firing when elicited from dendritic current injection, and did so by increasing a slowly-activating [dsquote]sag[dsquote] in membrane potential during long current injections. This sag in membrane potential resembled activation of I[sub]h[/sub], the hyperpolarization-activated cation current, which is present in pyramidal neuron dendrites at high density. In the present study, we have further characterized the action of LTG on I[sub]h[/sub].
METHODS: Visualized dendritic whole-cell and cell-attached patch recordings were performed on CA1 hippocampal pyramidal neurons in the rat hippocampal slice preparation.
RESULTS: LTG (50-100 [mu]M) produced an 83 [plusminus] 5.7% (n=8) decrease in AP firing from dendritic current injection. In the presence of LTG and ZD-7288, a selective I[sub]h[/sub] blocker, AP firing was decreased by only 6 [plusminus] 14.5% (n=5). Further, LTG (100 [mu]M) produced a 5.1 [plusminus] 0.78 mV (n=9) depolarization of resting potential, which was largely blocked by ZD-7288 (2 [plusminus] 0 mV, n=3). Cell-attached patch recordings from the dendrites were used to isolate I[sub]h[/sub]. When LTG (100 [mu]M) was added to the pipette solution, the activation of I[sub]h[/sub] shifted in a depolarizing direction by ~11 mV (V[sub]1/2[/sub] in control: -83 [plusminus] 1.8 mV, n=7; in LTG: -72 [plusminus] 2.3 mV, n=6). LTG did not significantly change maximal I[sub]h[/sub] conductance.
CONCLUSIONS: We conclude that lamotrigine acts on hippocampal pyramidal neuron dendrites by increasing the activation of I[sub]h[/sub], which can significantly reduce neuronal excitability, and may represent a novel mechanism of pharmaceutical action.
Support: Supported by NINDS, the National Epifellows Fdn., and the Hankamer Fdn.
Disclosure: Honoraria - Glaxo Wellcome