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Lawrence N Eisenman

Publications and source records attributed to Lawrence N Eisenman.

7 recordsLinked to original sources
PubMed2006

A spontaneous tonic chloride conductance in solitary glutamatergic hippocampal neurons.

GABA-A receptors mediate both phasic synaptic inhibition and more recently appreciated tonic currents in the vertebrate central nervous system. We addressed discrepancies in the literature regarding the pharmacology of tonic currents by examining tonic currents in a controlled environment of dissociated, solitary glutamatergic neurons. We describe a novel tonically active, bicuculline-sensitive chloride conductance that is insensitive to gabazine and to picrotoxin and thus not mediated by conventional GABA receptors. We exclude a significant contribution from small conductance calcium-gated potassium (SK) channels. We also pharmacologically exclude calcium-gated chloride channels, glycine receptors and the chloride current associated with glutamate transport. Finally, we demonstrate that, although small, this current modulates neuronal excitability. We speculate that this tonic current may provide a complementary mechanism for the regulation of neuronal excitability, particularly in regions with low ambient GABA concentrations. We conclude that this bicuculline-sensitive conductance needs to be accounted for in studies of GABA tonic currents, lest it be confused with currents associated with GABA overflow.

Animals↗
PubMed2005

Self-reported seizure frequency and time to first event in the seizure monitoring unit.

PURPOSE: To compare seizure frequency reported in the clinic with time to first diagnostic event during video-EEG monitoring. The effect of the artificial environment of the monitoring unit on self-reported seizure frequency was explored. METHODS: The 155 consecutive patients were seen in the Washington University Epilepsy Center and subsequently underwent video-EEG monitoring during 2001. Of these, 112 had a diagnostic event during monitoring; 31 left without having a definite event; and 12 could not provide an estimate of seizure frequency in the clinic. The time to first event was compared with self-reported seizure frequency. The patients were then divided into three equal groups (tertiles) based on mean seizure frequency, and time to first seizure was compared between groups. Then the numbers of patients staying >7 days without ever having an event were compared between the low and high seizure-frequency groups. Finally, Kaplan-Meier survival curves were calculated. RESULTS: No correlation was found between self-reported seizure rate and time to diagnostic event (r= 0.18; p = 0.06). Time to first event was 2.8 days in the low seizure-frequency group (mean, 2.2/month), 2.1 days in the medium (mean, 8.8/month), and 2.1 days in the high (mean, 24.1/month) groups, which were not significantly different (p = 0.19). Of patients in the low-frequency group, 79% had an event within 7 days. CONCLUSIONS: In the artificial environment of the monitoring unit, self-reported outpatient seizure frequency is not an accurate predictor of duration of video-EEG monitoring required to make a definitive classification of clinical events and should not contribute to the decision as to whether to refer a patient for monitoring.

Adolescent↗
PubMed2004

Slow actions of neuroactive steroids at GABAA receptors.

Neuroactive steroids are potent and efficacious modulators of GABA(A) receptor activity and are potent sedatives and anesthetics. These positive modulators of GABA(A) receptors both potentiate the actions of GABA at the receptor and, at higher concentrations, directly gate the channel. The contribution of direct gating to the cellular and behavioral effects of neuroactive steroids is considered of little significance because it has been generally found that concentrations well above those needed for anesthesia are required to gate channels. By studying solitary glutamatergic neurons devoid of synaptic GABA input, we show that direct gating occurs and significantly alters membrane excitability at concentrations < or =100 nm. We propose that the relevance of direct gating has been overlooked partly because of the extremely slow kinetics of receptor activation and deactivation. We show that slow deactivation of directly gated currents does not result from an inherently tight ligand-receptor interaction because the slow deactivation is markedly accelerated by gamma-cyclodextrin application. We hypothesize that steroids access the relevant GABA(A) receptor site from a non-aqueous reservoir, likely the plasma membrane, and that it is slow reservoir accumulation and departure that accounts for the slow kinetics of receptor gating by neuroactive steroids.

Animals↗
PubMed2003

Activation-dependent properties of pregnenolone sulfate inhibition of GABAA receptor-mediated current.

Sulfated steroids like pregnenolone sulfate (PS) are found endogenously in the central nervous system where they may modulate GABAA receptors. Understanding the mechanism of steroid inhibition is important for understanding the conditions under which endogenous steroids modulate GABAA receptor function, assessing their potential clinical utility, and for evaluating sulfated steroids as probes of receptor behaviour. Some previous studies suggest that sulfated steroid inhibition exhibits activation dependence, whilst other studies suggest only slow, time-dependent inhibition, perhaps reflecting slow PS association with receptors. We tested activation dependence in several ways. Steroid potency increased 2- to 3-fold with approximately 10-fold change in GABA concentration. PS inhibition of saturating partial agonist responses suggested that the level of channel activation, rather than receptor occupancy by agonist, is important for PS inhibition. Inhibition by sulfated steroids exhibited weak or no voltage dependence. Responses to rapid applications of exogenous GABA differed little whether PS was pre-applied or simply co-applied with GABA, consistent with the hypothesis that the actions of PS are facilitated by receptor activation. PS applied during steady-state GABA responses exhibited slow onset and offset rate constants. The offset, rather than onset, was significantly slowed by elevated GABA concentration. At hippocampal synapses, large, multiquantal IPSCs were inhibited more effectively by a fixed concentration of PS than small quantal content IPSCs, consistent with known 'pooling' of transmitter following multiquantal release. Picrotoxinin, although superficially similar to PS in its activation dependence, was dissimilar from PS in a number of details. In summary, PS inhibition exhibits activation dependence that may be explained by activation-dependent binding and altered desensitization.

Animals↗
PubMed2003

Sleep epilepsy.

BACKGROUND: Seizures during sleep have been recognized for centuries, and it is well known that both sleep and lack of sleep can influence the occurrence of ictal and interictal events. Sleep epilepsy refers to the subset of epilepsy in which seizures occur exclusively or predominantly during sleep. Primary generalized, secondarily generalized, and focal partial epilepsy syndromes can all manifest as sleep epilepsy. The spread of polysomnography has increased our ability to accurately diagnose sleep epilepsy and facilitated the discovery of an autosomal dominant sleep epilepsy. REVIEW SUMMARY: This review summarizes the epidemiology of sleep epilepsy and reviews a number of epilepsies that can manifest as sleep epilepsy as well as some nonepileptic sleep disorders from which sleep epilepsy must be differentiated.

Diagnosis, Differential↗
PubMed2002

3beta -hydroxypregnane steroids are pregnenolone sulfate-like GABA(A) receptor antagonists.

Endogenous neurosteroids have rapid actions on ion channels, particularly GABA(A) receptors, which are potentiated by nanomolar concentrations of 3alpha-hydroxypregnane neurosteroids. Previous evidence suggests that 3beta-hydroxypregnane steroids may competitively antagonize potentiation induced by their 3alpha diastereomers. Because of the potential importance of antagonists as experimental and clinical tools, we characterized the functional effect of 3beta-hydroxysteroids. Although 3beta-hydroxysteroids reduced the potentiation induced by 3alpha-hydroxysteroids, 3beta-hydroxysteroids acted noncompetitively with respect to potentiating steroids and inhibited the largest degrees of potentiation most effectively. Potentiation by high concentrations of barbiturates was also reduced by 3beta-hydroxysteroids. 3beta-Hydroxysteroids are also direct, noncompetitive GABA(A) receptor antagonists. 3beta-Hydroxysteroids coapplied with GABA significantly inhibited responses to > or =15 microm GABA. The profile of block was similar to that exhibited by sulfated steroids, known blockers of GABA(A) receptors. This direct, noncompetitive effect of 3beta-hydroxysteroids was sufficient to account for the apparent antagonism of potentiating steroids. Mutated receptors exhibiting decreased sensitivity to sulfated steroid block were insensitive to both the direct effects of 3beta-hydroxysteroids on GABA(A) responses and the reduction of potentiating steroid effects. At concentrations that had little effect on GABAergic synaptic currents, 3beta-hydroxysteroids and low concentrations of sulfated steroids significantly reversed the potentiation of synaptic currents induced by 3alpha-hydroxysteroids. We conclude that 3beta-hydroxypregnane steroids are not direct antagonists of potentiating steroids but rather are noncompetitive, likely state-dependent, blockers of GABA(A) receptors. Nevertheless, these steroids may be useful functional blockers of potentiating steroids when used at concentrations that do not affect baseline neurotransmission.

Amino Acid Substitution↗