Abstracts

RATIONALE:_The dendrites of CA1 hippocampal pyramidal neurons have electrical properties that differ from those at the soma, owing to the non-uniform distribution of ionic currents in the cell. Since some anticonvulsants are known to affect ion channels, we hypothesized that certain of these drugs might act on ion channels which exist in higher density in the dendrites, and thus preferentially decrease dendritic excitability. We tested this hypothesis for phenytoin and lamotrigine. METHODS:_Somatic and dendritic patch clamp whole-cell recordings were made from visualized CA1 pyramidal neurons in adult rat hippocampal slices, and drug effects were measured on action potential (AP) firing elicited by current steps and antidromic activation. RESULTS:_Phenytoin had a minimal effect on both somatic and dendritic excitability in the concentration range tested (10-50 mM). Lamotrigine (LTG; 50-100 mM), modestly decreased AP firing at the soma in response to long current steps (13 +/- 10% [n=5] decrease in average firing rate over a range of current steps). In contrast, LTG had a dramatic effect on AP firing elicited from dendritic current injection, with a 83 +/- 5.7% (n=8) decrease in firing rate, selectively raising the threshold for AP firing from dendritic current injection sites. Dual whole-cell recordings showed that LTG increased a slowly activating hyperpolarizing "sag" during long current pulses, which effectively decreased the current transmitted from dendrite to soma. LTG also caused a 3-5 mV depolarization in resting potential. Blockade of the mixed cationic h-current (Ih) by extracellular CsCl (3-5 mM) blocked some of the effects of LTG. CONCLUSIONS:_These results indicate that LTG appears to preferentially decrease the excitability of dendrites, at least in part by increasing the activation of Ih, a current known to be present in much higher density in hippocampal pyramidal neuron dendrites than in the soma (Magee, 1998). Supported by NINDS, National Epifellows Fdn., and Hankamer Fdn.