Ethanol blocks tetanic and calcium-induced long-term potentiation in the hippocampal slice

Sinclair, John G.; Lo, G.F.

doi:10.1016/0306-3623(86)90144-8

Cited by 92 publications

(41 citation statements)

References 18 publications

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“…A number of previous studies have demonstrated that ethanol blocks induction of NMDAR-dependent LTP (23)(24)(25)(26). We predicted that because STEP was necessary for ethanol inhibition of NMDAR function, ethanol effects on LTP would also be abolished in STEP KO mice.…”

Section: Blocking Step Substrates Prevents Ethanol Inhibition Of Nmdarmentioning

confidence: 93%

Alcohol inhibition of the NMDA receptor function, long-term potentiation, and fear learning requires striatal-enriched protein tyrosine phosphatase

Hicklin¹,

Radcliffe

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Alcohol's deleterious effects on memory are well known. Acute alcohol-induced memory loss is thought to occur via inhibition of NMDA receptor (NMDAR)-dependent long-term potentiation in the hippocampus. We reported previously that ethanol inhibition of NMDAR function and long-term potentiation is correlated with a reduction in the phosphorylation of Tyr 1472 on the NR2B subunit and ethanol's inhibition of the NMDAR field excitatory postsynaptic potential was attenuated by a broad spectrum tyrosine phosphatase inhibitor. These data suggested that ethanol's inhibitory effect may involve protein tyrosine phosphatases. Here we demonstrate that the loss of striatal-enriched protein tyrosine phosphatase (STEP) renders NMDAR function, phosphorylation, and long-term potentiation, as well as fear conditioning, less sensitive to ethanol inhibition. Moreover, the ethanol inhibition was "rescued" when the active STEP protein was reintroduced into the cells. Taken together, our data suggest that STEP contributes to ethanol inhibition of NMDAR function via dephosphorylation of tyrosine sites on NR2B receptors and lend support to the hypothesis that STEP may be required for ethanol's amnesic effects.whole-cell currents | null mutant mice A lcohol-induced memory deficits have been well documented in humans, as well as animal studies (1). Long-term potentiation (LTP) is widely accepted as a cellular mechanism underlying learning and memory in the hippocampus, as well as other brain regions (2), and is dependent upon NMDA receptor (NMDAR) activation (3). Acute ethanol application in adult rodents inhibits NMDAR channel activity (4, 5). Ethanol's inhibitory effect on NMDARs is widely thought to underlie both the blockade of LTP and the acute amnesic effects of ethanol. Moreover, recent work suggests that ethanol's effect on the NMDAR may play a role in the addictive nature of ethanol (6, 7).NMDARs in the hippocampus consist of mainly NR1/NR2A, NR1/NR2B, and NR1/NR2A/NR2B receptor-subunit complexes (8). Although NR1 subunits are required to form an active ion channel, incorporation of the various NR2 subunits regulate NMDAR channel activity by altering the channel kinetics and mediating the differential effects of pharmacological agents, including alcohol (9-11). It has previously been shown that activation of members of the Src-family of kinases (SFKs) enhances NMDAR currents (12). Previous studies have demonstrated a correlation between ethanol inhibition of NMDAR function and dephosphorylation of tyrosine residues on the NR2A and NR2B subunits (13). In particular, ethanol was found to reduce the phosphorylation of a site on the NR2B subunit Tyr 1472 that has been shown to regulate endocytosis and function of NMDARs (14,15). Inhibition of protein tyrosine phosphatase activity using a nonspecific inhibitor, bpV(phen), significantly reduced ethanol inhibition of NMDAR field excitatory postsynaptic potentials (fEPSPs), suggesting that ethanol may inhibit NMDARs via activation of a tyrosine phosphatase (13). FerraniKile et al. indepe...

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Section: Blocking Step Substrates Prevents Ethanol Inhibition Of Nmdarmentioning

confidence: 93%

Alcohol inhibition of the NMDA receptor function, long-term potentiation, and fear learning requires striatal-enriched protein tyrosine phosphatase

Hicklin¹,

Radcliffe

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…Indeed, we found that acute ethanol application attenuates an early portion of dlBNST LTP. In the hippocampus, reduction of LTP by acute ethanol exposure is also seen (Sinclair and Lo, 1986;Blitzer et al, 1990). A curious difference, however, is that ethanol more predominantly regulates an early component of LTP in the dlBNST.…”

Section: Ethanol Attenuation Of An Early Component Of Ltp and Nmdar Smentioning

confidence: 99%

High-Frequency Stimulation Induces Ethanol-Sensitive Long-Term Potentiation at Glutamatergic Synapses in the Dorsolateral Bed Nucleus of the Stria Terminalis

Weitlauf¹,

Egli²,

Grueter³

et al. 2004

J. Neurosci.

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Anatomical and functional data support a critical role for the bed nucleus of the stria terminalis (BNST) in the interaction between stress and alcohol/substance abuse. We report here that neurons of the dorsal anterolateral BNST respond to glutamatergic synaptic input in a synchronized way, such that an interpretable extracellular synaptic field potential can be readily measured. High-frequency stimulation of these glutamatergic inputs evoked NMDA receptor (NMDAR)-dependent long-term potentiation (LTP). We found that an early portion of this LTP is reduced by acute exposure to ethanol in a GABA A receptor-dependent manner. This effect of ethanol is accompanied by a significant and reversible dose-dependent attenuation of isolated NMDAR signaling and is mimicked by incomplete NMDAR blockade.

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“…In hippocampal slices, numerous studies have shown that ethanol inhibits long-term potentiation (LTP), a cellular model of memory and learning (Sinclair and Lo, 1986;Morrisett and Swartzwelder, 1993;Schummers and Browning, 2001). The concentration of ethanol required for LTP inhibition, however, has varied widely among reports.…”

Section: Introductionmentioning

confidence: 99%

“…Cognitive and behavioral manifestations associated with acute intoxication are often determined by how ethanol is consumed. Thus, it is possible that both the rate of alcohol consumption and the amount of ethanol consumed are key factors in determining overall effects on the CNS.In hippocampal slices, numerous studies have shown that ethanol inhibits long-term potentiation (LTP), a cellular model of memory and learning (Sinclair and Lo, 1986;Morrisett and Swartzwelder, 1993;Schummers and Browning, 2001). The concentration of ethanol required for LTP inhibition, however, has varied widely among reports.…”

mentioning

confidence: 99%

Modulation of hippocampal long-term potentiation by slow increases in ethanol concentration

2007

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To determine how acute ethanol intoxication may alter memory processing, we examined the effects of stepwise increases in ethanol on long-term potentiation (LTP) in hippocampal slices. LTP was inhibited by acute administration of 60 mM ethanol, but was readily induced if ethanol was increased gradually to 60 mM over 75 min. Administration of 2-amino-5 phosphonovalerate (APV), an Nmethyl-D-aspartate receptor antagonist, during the stepwise increase in ethanol inhibited LTP, suggesting involvement of NMDA receptors in the development of tolerance. However, APV and nifedipine, an inhibitor of L-type calcium channels, failed to inhibit LTP when administered following the slow increase in ethanol. Ethanol-tolerant LTP was inhibited by thapsigargin, suggesting a major role for intracellular calcium release in this form of plasticity. The unique properties of ethanol-tolerant LTP suggest that memories formed during binge drinking are not acquired by standard synaptic mechanisms and that acute tolerance may involve the induction of novel mechanisms to maintain function. KeywordsAlcohol (ethanol); tolerance ; desensitization; allostasis Acute alcohol intoxication is a significant public health problem. During the intoxicated state, problems with motor coordination and cognitive processing are common. Some individuals exhibit profound deficits in memory that may include a complete inability to learn new information, a condition referred to as a 'blackout' (White, 2003). Cognitive and behavioral manifestations associated with acute intoxication are often determined by how ethanol is consumed. Thus, it is possible that both the rate of alcohol consumption and the amount of ethanol consumed are key factors in determining overall effects on the CNS.In hippocampal slices, numerous studies have shown that ethanol inhibits long-term potentiation (LTP), a cellular model of memory and learning (Sinclair and Lo, 1986;Morrisett and Swartzwelder, 1993;Schummers and Browning, 2001). The concentration of ethanol required for LTP inhibition, however, has varied widely among reports. While many studies have found that ethanol inhibits LTP induction at concentrations of 50 mM or more (Randall et al., 1995;Sugiura et al., 1995;Schummers et al., 1997), some reports have shown that concentrations as low as 5 mM also impair LTP induction (Blitzer et al., 1990). The inconsistencies in these studies may reflect experimental differences including slice Correspondence: Yukitoshi Izumi, M.D., Ph.D., Department of Psychiatry, Washington University School of Medicine, 660 South Euclid, Box 8134, St. Louis, MO 63110, USA, Phone: +1 314 362 8659, Fax: +1 314 747 2983, Email: izumiy@psychiatry.wustl.edu Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note tha...

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Ethanol blocks tetanic and calcium-induced long-term potentiation in the hippocampal slice

Cited by 92 publications

References 18 publications

Alcohol inhibition of the NMDA receptor function, long-term potentiation, and fear learning requires striatal-enriched protein tyrosine phosphatase

Alcohol inhibition of the NMDA receptor function, long-term potentiation, and fear learning requires striatal-enriched protein tyrosine phosphatase

High-Frequency Stimulation Induces Ethanol-Sensitive Long-Term Potentiation at Glutamatergic Synapses in the Dorsolateral Bed Nucleus of the Stria Terminalis

Modulation of hippocampal long-term potentiation by slow increases in ethanol concentration

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