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REPORT
1Departments of Psychiatry and 2Pharmacology, Duke University Medical Center; and 3Neurobiology Research Laboratory, Veterans Affairs Medical Center, Durham, North Carolina
Submitted 30 January 2007; accepted in final form 18 March 2007
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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), and occurs during a developmental period when the brain undergoes rapid changes in structure and function that make it uniquely vulnerable to negative consequences of ethanol exposure (Monti et al. 2005). Memory impairment is one of many behavioral effects of ethanol, and several lines of research suggest that adolescents are highly sensitive to this effect (White and Swartzwelder 2004). Adolescent rats show greater ethanol-induced learning impairment than adults (Land and Spear 2004; Markwiese et al. 1998), and humans in their early 20s are more sensitive to ethanol-induced memory impairment than those in their late 20s (Acheson et al. 1998). Despite the striking implications of such studies, little is known about the mechanisms that underlie these developmental differences in ethanol sensitivity. One plausible hypothesis is that memory-mediating mechanisms within the hippocampal formation are more powerfully suppressed by ethanol during adolescence, and there is growing support for this view (Li et al. 2006; Pyapali et al. 1999; Swartzwelder et al. 1995).
Ethanol has powerful effects on GABAergic neurotransmission, and some of these effects may be mediated by ethanol interactions with type-A GABA receptors (GABAARs). Although traditionally associated primarily with ethanol-induced sedation and anxiolysis, it is now clear that GABAARs are also likely to be involved in regulating memory mechanisms and information processing in the hippocampal formation (Paulsen and Moser 1998). Synaptic GABAAR subtypes are relatively insensitive to physiologically relevant concentrations of ethanol (Criswell et al. 2003; Sapp and Yeh 1998; Whitten et al. 1996). Therefore it is possible that extrasynaptic GABAAR subtypes containing the 
subunit mediate the effects of low to moderate ethanol concentrations that are known to affect learning and other cognitive functions (Eckardt et al. 1998; Wallner et al. 2003). Because low to moderate concentrations of ethanol have been shown to impair learning (Markwiese et al. 1998) and learning-related neurophysiological activity (Pyapali et al. 1999; Swartzwelder et al. 1995) more potently in adolescent animals than in adults, the present study was designed to test the hypothesis that ethanol promotes extrasynaptic GABAAR function more potently in hippocampal neurons from adolescent, compared with adult rats.
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METHODS |
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Hippocampal brain slices were prepared from adolescent (30- to 40-day old) or adult (70- to 80-day old) male Sprague-Dawley rats (Charles River). The age group used for each preparation was randomized. Rats were anesthetized with halothane vapor and decapitated. The brain was removed, and 350-µm sagittal slices containing the hippocampus were cut using a Vibratome Series 1000. The ice-cold cutting solution consisted of (in mM) 120 NaCl, 3.3 KCl, 25 NaHCO3, 1.23 NaH2PO4, 15 D-glucose, 3 myo-inositol, 2 Na pyruvate, 0.4 Na ascorbate, 0.1 CaCl2, and 12 MgCl equilibrated with a gas mixture of 95% O2-5% CO2. Slices were incubated at room temperature (RT: 21–23°C) for a minimum of 1 h in a holding chamber containing artificial cerebral spinal fluid (ACSF: in mM, 120 NaCl, 3.3 KCl, 25 NaHCO3, 1.23 NaH2PO4, 15 D-glucose, 3 myo-inositol, 2 Na pyruvate, 0.4 Na ascorbate, 2.0 CaCl2, and 1.3 MgCl) bubbled with 95% O2-5% CO2.
Drug perfusion
Drugs were diluted in ACSF and applied under pressure (2–3 psi) using a manually controlled four-channel valve manifold system and a Millimanifold (ALA Scientific Instruments) with a tip inner diameter of 200 µm. This system allows for rapid replacement of the solution surrounding the target neuron. Under a x5 objective, Fast Green dissolved in ACSF was used to visualize the drug flow, and the center of the perfused area was positioned on the soma of the recorded neuron. To reduce turbulence that could result in dilution of drug by mixing with bath ACSF, the tip angle and height was carefully adjusted to produce laminar flow of the drug solution over the slice. However, it is possible that in some cases concentration of drug at the site of the neuron may be lower than that stated.
Electrophysiology
Individual dentate gyrus granule cells (DGCs) were visually identified (Zeiss Axioskop, IR-DIC videomicroscopy, x40 water-immersion objective). Slices were perfused with RT 95% O2-5% CO2-bubbled ACSF at a rate of 2–4 ml/min. Microelectrodes with a tip resistance of 5–10 M
when filled were pulled from thin-walled borosilicate glass capillaries (World Precision Instruments) using a Sutter Instrument Co. P-2000 puller. The electrode solution consisted of (in mM) 130 CsCl, 10 HEPES, 4 NaCl, 0.2 EGTA, 10 Na2CreatinePO4, 4 MgATP, 0.3 TrisGTP, 6 QX-314, pH 7.2, 290 osM. Whole cell voltage-clamp recordings were performed using an Axopatch 200B amplifier (Axon Instruments). Signals were low-pass filtered at 2 kHz and digitized at 10 kHz using a National Instruments PCI-6251 DAQ board and WinWCP (V3.2.9, University of Strathclyde). Series and input resistance were continuously monitored using a 200-ms, –10-mV pulse applied every 12.6 s.
Data analysis and statistics
All data analysis was performed on data records that had been stripped of age group information. Tonic current measurement was performed using an in-house function written for MATLAB (V7.1, The Mathworks). Transients produced by voltage steps were removed from the data. For each condition, all-point histograms were generated for 57.5 s of data and the function f(x) = A·exp[–(x – µ)2/2
2] was fitted to each histogram. The center of this distribution (µ) represented the mean holding current, while represented the root-mean-square (RMS) noise over the 57.5-s interval. Spontaneous inhibitory postsynaptic potentials (sIPSCs) were detected using the Mini Analysis program by Synaptosoft (Ver. 6.0.3). For each condition, IPSC frequency and average peak amplitude were calculated. Rise time and decay time constant (
d) of a single-exponential fit were calculated from a "typical" IPSC produced by scaling and averaging all individual events. Statistical analysis within age groups was performed using paired t-test to compare predrug baseline recordings to recordings made under drug conditions. Comparisons across groups were made using independent samples t-test. The criterion for significance was set at P < 0.05, all data are presented as means ± SE.
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RESULTS |
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). In rats, a developmental period analogous to human adolescence begins at postnatal day 30, whereas rats older than 60 days are considered adult (Spear 2000). Therefore we measured tonic inhibitory currents in two groups of rats, 30–40 days old and 70–80 days old. Inhibitory currents were isolated by including 2 mM kynurenic acid in the bath perfusate. Granule cells were voltage clamped at –80 mV and the holding current was recorded during three 3-min periods: a no-drug baseline, during application of 30 mM ethanol, and during application of 200 µM picrotoxin. Figure 1 shows current traces recorded from DGCs from two adolescent (C) and two adult rats (D). All-point histograms and fitted distributions for the same cells are shown in A and B. Average baseline holding current (µ) and RMS noise () did not differ between the two age groups (µ in pA: –61.8 ± 9.0 adolescents, –72.5 ± 9.5 adults; in pA: 3.4 ± 0.2 adolescents, 4.2 ± 0.3 adults).
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Tonic current was measured as the difference between the centers of the fitted distributions obtained for the baseline and picrotoxin conditions (µpicrotoxin – µbaseline), and tonic noise was measured as the difference in RMS noise between these two conditions (baseline – picrotoxin). GABAAR-mediated tonic current was detected in cells from both adolescent and adult rats. As shown in Fig. 2A, in the absence of ethanol, tonic current was significantly greater in neurons from adult rats (17.3 ± 1.9 pA, n = 8 cells, 7 rats) compared with those from adolescents (8.2 ± 0.7 pA n = 8 cells, 7 rats). Average tonic noise was also larger in adults compared with adolescents (2.1 ± 0.2 pA for adults and 1.0 ± 0.2 pA for adolescents, Fig. 2B). These findings are consistent with greater activation of extrasynaptic GABAARs in DGCs from adults compared with adolescents.
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Ethanol increased the size of the holding current in both adolescent and adult rats [µEtOH (pA): adolescent –70.0 ± 9.7, adult –80.5 ± 10.1] but had little effect on RMS noise [µEtOH (pA): adolescent 4.0 ± 0.4, adult 4.6 ± 0.4)]. Within-group comparisons of the holding currents in the absence and presence of ethanol indicated that ethanol increased the currents in slices from both adolescent (P < 0.001) and adult (P = 0.004) rats. For each cell, ethanol enhancement of tonic current was calculated as the increase in holding current during ethanol exposure as percentage of the tonic current in the absence of ethanol: (µbaseline – µEtOH)/(µpicrotoxin – µbaseline)·100. Ethanol enhancement of tonic current was significantly greater in adolescent rats (107.8 ± 18.4%) than in adults (46.7 ± 9.7%, Fig. 3).
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We also investigated whether ethanol altered the frequency, amplitude, or kinetics of sIPSCs in DGCs from adolescent and adult rats. As shown in Table 1, in the baseline condition, sIPSCs occurred with similar frequency in cells from adolescents and adults, and sIPSC peak amplitude, rise time, and decay time constant (d) also did not differ between the two age groups. Ethanol did not significantly alter frequency, rise time, or d in either adolescents or adults. However, in adolescent rats, ethanol increased sIPSC amplitude, whereas in adult rats, ethanol did not increase sIPSC amplitude. These findings are generally consistent with those previously reported by Wei et al. (2004), who found that 30 mM ethanol selectively enhanced tonic, but not synaptic, inhibition in DCGs from adult mice.
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DISCUSSION |
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Tonic inhibitory current mediated by extrasynaptic GABAARs has been described in several types of neurons including granule cells from DG (Nusser and Mody 2002) and cerebellum (Kaneda et al. 1995) and interneurons in CA1 (Semyanov et al. 2003). Extrasynaptic GABAARs are expressed diffusely on the dendrites and cell body of neurons where they are activated by the low ambient GABA levels present in the extracellular space. Specifically, in granule cells of the cerebellum and dentate gyrus, tonic current is meditated by GABAARs that contain the subunit (Stell et al. 2003). These -type GABAARs are more sensitive to ethanol than any other subtypes (Wallner et al. 2003). In fact, it has been suggested that this subtype may be the primary target for direct effects of ethanol on GABAAR function and may play a role in mediating ethanol's anmestic and motor-incoordinating effects (Hanchar et al. 2005; Wei et al. 2004).
Ethanol and tonic current in DGCs
Although several labs have reported that intoxicating concentrations of ethanol potentiate -type GABAARs both in expression systems and in neurons (Hanchar et al. 2005; Liang et al. 2006; Wallner et al. 2003; Wei et al. 2004), recent work has failed to replicate this effect (Borghese et al. 2006; Yamashita et al. 2006). In particular, Borghese et al. (2006) found that 30 mM ethanol did not alter tonic currents in mouse DGCs, and Yamashita et al. (2006) found that 30 mM ethanol had either no effect or a small inhibitory effect on responses to exogenously applied GABA in cultured cerebellar granule cells. These inconsistent findings suggest that ethanol effects on these receptors may be highly sensitive to experimental variation among laboratories. Our results, indicating that 30 mM ethanol increased tonic current in DGCs from both adolescent and adult animals, provide additional confirmation that intoxicating concentrations of ethanol can enhance inhibitory tonic currents. Although this finding is consistent with others' claims that ethanol acts directly at -type GABAARs, it should be noted that our experiments do not conclusively demonstrate this. In cerebellar granule cells, some evidence suggests that increases in tonic current during ethanol exposure may occur indirectly as a result of increased spillover from sIPSC events (Carta et al. 2004), but this finding is also controversial. Hanchar et al. (2005) have reported ethanol-induced increases in tonic current in cerebellar granule cells in the absence of increases in GABA release. Furthermore, they have shown that this effect is altered by mutation of extrasynaptic GABAARs on granule cells, which also suggests a "postsynaptic" mechanism (Hanchar et al. 2005). We did not find increases in sIPSC frequency during ethanol exposure, suggesting that increased spillover does not contribute to increases in tonic current in this preparation. However, it is possible that other mechanisms that modulate extracellular GABA concentration could have contributed to our results; see Semyanov et al. (2004) for review.
Extrasynaptic GABAARs and learning
Activation of extrasynaptic GABAARs produces shunting inhibition that decreases the excitability of a neuron and alters its membrane time constant. These changes in membrane properties alter both the time window for summation of inputs and the threshold for action potential firing and could thereby influence memory mechanisms such as long-term potentiation (LTP) (Semyanov et al. 2004). In the hippocampus, extrasynaptic receptors have been shown to play a role in learning and memory. In CA1 pyramidal cells, GABAAR 
5 subunits are expressed extrasynaptically (Fritschy and Brunig 2003) and in mice, reduction or loss of the 5 subunit improves performance in trace fear conditioning and water maze tasks (Collinson et al. 2002; Crestani et al. 2002). Similarly, 5 selective inverse agonists also improve performance in the water maze (Chambers et al. 2003). In DGCs, ethanol sensitive -type GABAARs mediate a tonic current that that is about four times larger than the average total current carried by spontaneous synaptic activity (Nusser and Mody 2002), suggesting that these receptors are powerful regulators of DGC function. Knockout of the subunit enhances trace fear conditioning in female mice (Wiltgen et al. 2005), providing further evidence that tonic current mediated by extrasynaptic GABAARs suppresses hippocampal-dependent learning.
GABAAR tonic inhibition in the dentate gyrus increases during development
We have found that the size of tonic currents measured in DGCs in the absence of ethanol increases as rats mature from adolescence to adulthood. Developmental changes in tonic inhibition have been reported in other neurons (Brickley et al. 1996; Semyanov et al. 2004), but this is the first time such studies have been conducted in the dentate. In the hippocampus, levels of mRNA for the subunit increase during development with the highest levels of expression occurring in adult animals (Laurie et al. 1992). The neurosteroid sensitivity of GABAARs on DGCs also increases during postnatal development (Mtchedlishvili et al. 2003). Because -type GABAARs are highly sensitive to neurosteroids (Brown et al. 2002), this provides additional evidence that the number of -type GABAARs increases in DGCs as animals mature. Thus greater expression of extrasynaptic receptors could contribute to the larger tonic currents that we measured in adult animals.
However, if -type GABAARs are the most ethanol sensitive of the GABAAR subtypes and if extrasynaptic expression of these receptors by DGCs increases between adolescence and adulthood, one would predict greater ethanol sensitivity of tonic currents from adult animals. In fact our data show the reverse, that ethanol enhancement of tonic current is greater in adolescent animals. This finding suggests that developmental regulation of ethanol's effect on tonic inhibition is more complex than a simple switch in GABAAR subunits. Several other potential mechanisms are also plausible. First, the amount of ambient GABA present under the baseline condition could change during brain maturation, altering the degree of saturation of extrasynaptic receptors and changing their apparent ethanol sensitivity, even if the mechanism of ethanol action were directly at extrasynaptic GABAARs. Second, developmental changes in intracellular signaling in DGCs could reduce ethanol sensitivity of -type GABAARs in adult animals. GABAAR function is constitutively regulated by phosphorylation, and GABAAR sensitivity to ethanol is regulated by intracellular signaling mechanisms in both the cerebellum (Freund and Palmer 1997) and hippocampus (Weiner et al. 1997). Furthermore, differences in phosphorylation have been invoked to explain the greater ethanol sensitivity of GABAARs when expressed in Xenopus oocytes rather than mammalian cells (Yamashita et al. 2006). More work is needed to determine whether either of these mechanisms may underlie our results.
Increased levels of tonic current in adults relative to adolescents are consistent with continued maturation of the inhibitory network in the DG during the adolescent period. Recently it has been shown that hippocampal expression of several GABAAR subunits changes throughout adolescence and early adulthood (Yu et al. 2006). Furthermore, maturation of inhibition in the hippocampus is thought to be important in determining the rules for the induction of LTP, although this work has been done in CA1 rather than in the dentate. In slices prepared from juvenile hippocampus, pairing a presynaptic stimulus with a single postsynaptic action potential can produce spike-timing dependent LTP of excitatory synapses. However, in slices from adult animals a single postsynaptic action potential is insufficient and presynaptic stimulation must be paired with a burst of action potentials to produce potentiation. Blocking all GABAARs in adult slices restores the ability of a single postsynaptic action potential to produce LTP (Meredith et al. 2003). Although this study did not discriminate between the synaptic and extrasynaptic GABAAR populations, the powerful effects that extrasynaptic GABAARs have on cell excitability suggest that they may have a role in mediating this effect. Thus our finding that tonic inhibition on DGCs increases as rats age from adolescent to adult suggests that the inhibitory mechanisms that modulate learning in this brain region are still maturing and may help explain differences in memory performance between adolescents and adults.
Developmental differences in ethanol enhancement of tonic inhibition
Adolescents are highly sensitive to ethanol's effects on memory (White and Swartzwelder 2004). In rats, ethanol produces greater impairment in the Morris water maze task in adolescents than in adults (Markwiese et al. 1998). Furthermore, ethanol interferes with memory of a discrimination task in adolescents at doses that do not affect adults (Land and Spear 2004). It is likely that ethanol's effects on memory are mediated by alterations in neurotransmission and plasticity in the hippocampus (White et al. 2000), and in fact, in vitro experiments have shown that ethanol inhibits LTP more powerfully in hippocampal slices from adolescent animals (Pyapali et al. 1999). Although some of this is likely due to developmental differences in ethanol sensitivity of NMDA receptors (Swartzwelder et al. 1995), a growing body of evidence suggests that in the hippocampus, increased activation of extrasynaptic GABAARs impairs learning and memory and that extrasynaptic GABAARs play a role in regulating LTP. Therefore it seems likely that the increased ethanol enhancement of inhibitory tonic current that we report in DGCs from adolescent rats contributes to the greater vulnerability of adolescents to EtOH-induced memory impairment. This study provides the first evidence to link differences in the effect of ethanol on GABAAR-mediated tonic inhibition in the hippocampus to differences in sensitivity to ethanol's effects on memory.
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FOOTNOTES |
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Address for reprint requests and other correspondence: R. L. Fleming, Bldg. 16, VA Medical Center, 508 Fulton St., Durham, NC 27705 (E-mail: rebekah.fleming{at}duke.edu)
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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Borghese CM, Storustovu S, Ebert B, Herd MB, Belelli D, Lambert JJ, Marshall G, Wafford KA, Harris RA. The delta subunit of gamma-aminobutyric acid type A receptors does not confer sensitivity to low concentrations of ethanol. J Pharmacol Exp Ther 316: 1360–1368, 2006.
Brickley SG, Cull-Candy SG, Farrant M. Development of a tonic form of synaptic inhibition in rat cerebellar granule cells resulting from persistent activation of GABAA receptors. J Physiol 497: 753–759, 1996.
Brown N, Kerby J, Bonnert TP, Whiting PJ, Wafford KA. Pharmacological characterization of a novel cell line expressing human alpha(4)beta(3)delta GABA(A) receptors. Br J Pharmacol 136: 965–974, 2002.[CrossRef][ISI][Medline]
Carta M, Mameli M, Valenzuela CF. Alcohol enhances GABAergic transmission to cerebellar granule cells via an increase in Golgi cell excitability. J Neurosci 24: 3746–3751, 2004.
Chambers MS, Atack JR, Broughton HB, Collinson N, Cook S, Dawson GR, Hobbs SC, Marshall G, Maubach KA, Pillai GV, Reeve AJ, MacLeod AM. Identification of a novel, selective GABA(A) alpha5 receptor inverse agonist which enhances cognition. J Med Chem 46: 2227–2240, 2003.[CrossRef][ISI][Medline]
Collinson N, Kuenzi FM, Jarolimek W, Maubach KA, Cothliff R, Sur C, Smith A, Otu FM, Howell O, Atack JR, McKernan RM, Seabrook GR, Dawson GR, Whiting PJ, Rosahl TW. Enhanced learning and memory and altered GABAergic synaptic transmission in mice lacking the alpha 5 subunit of the GABAA receptor. J Neurosci 22: 5572–5580, 2002.
Crestani F, Keist R, Fritschy JM, Benke D, Vogt K, Prut L, Bluthmann H, Mohler H, Rudolph U. Trace fear conditioning involves hippocampal alpha5 GABA(A) receptors. Proc Natl Acad Sci USA 99: 8980–8985, 2002.
Criswell HE, Ming Z, Griffith BL, Breese GR. Comparison of effect of ethanol on N-methyl-D-aspartate- and GABA-gated currents from acutely dissociated neurons: absence of regional differences in sensitivity to ethanol. J Pharmacol Exp Ther 304: 192–199, 2003.
Eckardt MJ, File SE, Gessa GL, Grant KA, Guerri C, Hoffman PL, Kalant H, Koob GF, Li TK, Tabakoff B. Effects of moderate alcohol consumption on the central nervous system. Alcohol Clin Exp Res 22: 998–1040, 1998.[CrossRef][ISI][Medline]
Freund RK, Palme MR. Beta adrenergic sensitization of gamma-aminobutyric acid receptors to ethanol involves a cyclic AMP/protein kinase A second-messenger mechanism. J Pharmacol Exp Ther 280: 1192–1200, 1997.
Fritschy JM, Brunig I. Formation and plasticity of GABAergic synapses: physiological mechanisms and pathophysiological implications. Pharmacol Ther 98: 299–323, 2003.[CrossRef][ISI][Medline]
Hanchar HJ, Dodson PD, Olsen RW, Otis TS, Wallner M. Alcohol-induced motor impairment caused by increased extrasynaptic GABA(A) receptor activity. Nat Neurosci 8: 339–345, 2005.[CrossRef][ISI][Medline]
Kaneda M, Farrant M, Cull-Candy SG. Whole-cell and single-channel currents activated by GABA and glycine in granule cells of the rat cerebellum. J Physiol 485: 419–435, 1995.
Land C, Spear NE. Ethanol impairs memory of a simple discrimination in adolescent rats at doses that leave adult memory unaffected. Neurobiol Learn Mem 81: 75–81, 2004.[CrossRef][ISI][Medline]
Laurie DJ, Wisden W, Seeburg PH. The distribution of thirteen GABAA receptor subunit mRNAs in the rat brain. III. Embryonic and postnatal development. J Neurosci 12: 4151–4172, 1992.[Abstract]
Li Q, Wilson WA, Swartzwelder HS. Developmental differences in the sensitivity of spontaneous and miniature IPSCs to ethanol. Alcohol Clin Exp Res 30: 119–126, 2006.[CrossRef][ISI][Medline]
Liang J, Zhang N, Cagetti E, Houser CR, Olsen RW, Spigelman I. Chronic intermittent ethanol-induced switch of ethanol actions from extrasynaptic to synaptic hippocampal GABAA receptors. J Neurosci 26: 1749–1758, 2006.
Markwiese BJ, Acheson SK, Levin ED, Wilson WA, Swartzwelder HS. Differential effects of ethanol on memory in adolescent and adult rats. Alcohol Clin Exp Res 22: 416–421, 1998.[CrossRef][ISI][Medline]
Meredith RM, Floyer-Lea AM, Paulsen O. Maturation of long-term potentiation induction rules in rodent hippocampus: role of GABAergic inhibition. J Neurosci 23: 11142–11146, 2003.
Monti PM, Miranda R Jr, Nixon K, Sher KJ, Swartzwelder HS, Tapert SF, White A, Crews FT. Adolescence: booze, brains, and behavior. Alcohol Clin Exp Res 29: 207–220, 2005.[CrossRef][ISI][Medline]
Mtchedlishvili Z, Sun CS, Harrison MB, Kapur J. Increased neurosteroid sensitivity of hippocampal GABAA receptors during postnatal development. Neuroscience 118: 655–666, 2003.[CrossRef][ISI][Medline]
NIAAA. Special Report to the U.S. Congress on Alcohol and Health. U.S. Deparment of Health and Human Services, 2000.
Nusser Z, Mody I. Selective modulation of tonic and phasic inhibitions in dentate gyrus granule cells. J Neurophysiol 87: 2624–2628, 2002.
Paulsen O, Moser EI. A model of hippocampal memory encoding and retrieval: GABAergic control of synaptic plasticity. Trends Neurosci 21: 273–278, 1998.[CrossRef][ISI][Medline]
Pyapali GK, Turner DA, Wilson WA, Swartzwelder HS. Age and dose-dependent effects of ethanol on the induction of hippocampal long-term potentiation. Alcohol 19: 107–111, 1999.[CrossRef][ISI][Medline]
Sapp DW, Yeh HH. Ethanol-GABAA receptor interactions: a comparison between cell lines and cerebellar Purkinje cells. J Pharmacol Exp Ther 284: 768–776, 1998.
Semyanov A, Walker MC, Kullmann DM. GABA uptake regulates cortical excitability via cell type-specific tonic inhibition. Nat Neurosci 6: 484–490, 2003.[ISI][Medline]
Semyanov A, Walker MC, Kullmann DM, Silver RA. Tonically active GABAA receptors: modulating gain and maintaining the tone. Trends Neurosci 27: 262–269, 2004.[CrossRef][ISI][Medline]
Spear LP. The adolescent brain and age-related behavioral manifestations. Neurosci Biobehav Rev 24: 417–463, 2000.[CrossRef][ISI][Medline]
Stell BM, Brickley SG, Tang CY, Farrant M, Mody I. Neuroactive steroids reduce neuronal excitability by selectively enhancing tonic inhibition mediated by delta subunit-containing GABAA receptors. Proc Natl Acad Sci USA 100: 14439–14444, 2003.
Swartzwelder HS, Wilson WA, Tayyeb MI. Differential sensitivity of NMDA receptor-mediated synaptic potentials to ethanol in immature versus mature hippocampus. Alcohol Clin Exp Res 19: 320–323, 1995.[CrossRef][ISI][Medline]
Wallner M, Hanchar HJ, Olsen RW. Ethanol enhances alpha 4 beta 3 delta and alpha 6 beta 3 delta gamma-aminobutyric acid type A receptors at low concentrations known to affect humans. Proc Natl Acad Sci USA 100: 15218–15223, 2003.
Wei W, Faria LC, Mody I. Low ethanol concentrations selectively augment the tonic inhibition mediated by delta subunit-containing GABAA receptors in hippocampal neurons. J Neurosci 24: 8379–8382, 2004.
Weiner JL, Valenzuela CF, Watson PL, Frazier CJ, Dunwiddie TV. Elevation of basal protein kinase C activity increases ethanol sensitivity of GABA(A) receptors in rat hippocampal CA1 pyramidal neurons. J Neurochem 68: 1949–1959, 1997.[ISI][Medline]
White AM, Matthews DB, Best PJ. Ethanol, memory, and hippocampal function: a review of recent findings. Hippocampus 10: 88–93, 2000.[CrossRef][ISI][Medline]
White AM, Swartzwelder HS. Hippocampal function during adolescence: a unique target of ethanol effects. Ann N Y Acad Sci 1021: 206–220, 2004.
Whitten RJ, Maitra R, Reynolds JN. Modulation of GABAA receptor function by alcohols: effects of subunit composition and differential effects of ethanol. Alcohol Clin Exp Res 20: 1313–1319, 1996.[CrossRef][ISI][Medline]
Wiltgen BJ, Sanders MJ, Ferguson C, Homanics GE, Fanselow MS. Trace fear conditioning is enhanced in mice lacking the delta subunit of the GABAA receptor. Learn Mem 12: 327–333, 2005.
Yamashita M, Marszalec W, Yeh JZ, Narahashi T. Effects of ethanol on tonic GABA currents in cerebellar granule cells and mammalian cells recombinantly expressing GABA(A) receptors. J Pharmacol Exp Ther 319: 431–438, 2006.
Yu ZY, Wang W, Fritschy JM, Witte OW, Redecker C. Changes in neocortical and hippocampal GABAA receptor subunit distribution during brain maturation and aging. Brain Res 1099: 73–81, 2006.[CrossRef][ISI][Medline]
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