Temporary block of glycolysis by 2-deoxy-D-glucose (2-DG) reversibly suppresses synaptic transmission in the CA1 region of hippocampal slices. Recovery of responses is followed by a sustained potentiation of field excitatory postsynaptic potentials (EPSPs) (2-DG-LTP). To investigate the mechanisms involved in this type of LTP, we studied the effects of 2-DG on membrane properties of CA1 neurons (in slices from Sprague-Dawley rats), recorded with sharp intracellular electrodes containing 3 M KCl, as well as patch electrodes, filled mainly with 150 mM KMeSO4 and Hepes. The predominant change produced by 15- to 20-min applications of 2-DG (10 mM, replacing glucose) was hyperpolarization (-5.6 +/- 1.1 mV for 18 intracellular recordings and -7.2 +/- 0.80 mV for 17 whole-cell recordings) accompanied by a fall in resistance (-33 +/- 2.5% for 14 intracellular recordings and -11.6 +/- 7.1% for 15 whole-cell recordings). Virtually identical hyperpolarizations were recorded in the presence of 20 microM glyburide (-5.5 +/- 1.5 mV, n = 6), but they were abolished by adenosine antagonists 8-(p-sulfophenyl)theophylline (8-SPT) and 8-cyclopentyl-3,7-dihydro-1,3-dipropyl-1H-purine-2,6-dione (DPCPX) (2.8 +/- 1.6 and 4.0 +/- 1.7 mV, respectively; n = 5 for both). It was concluded that the hyperpolarization is most likely caused by an increase in K+ conductance, activated by a 2-DG-induced rise in adenosine release. After such applications of 2-DG, a sustained potentiation of EPSPs (similar to the 2-DG-LTP of field EPSPs) was evident in five neurons recorded with intracellular electrodes but not in any of nine whole-cell recordings, where it was replaced by sustained, LTD-like depression. We conclude that a factor essential for 2-DG-LTP induction is lost during whole-cell recording.

Temporary block of glycolysis by 2-deoxy-D-glucose (2-DG) reversibly suppresses synaptic transmission in the CA1 region of hippocampal slices. Recovery of responses is followed by a sustained potentiation of field excitatory postsynaptic potentials (EPSPs) (2-DG-LTP). To investigate the mechanisms involved in this type of LTP, we studied the effects of 2-DG on membrane properties of CA1 neurons (in slices from Sprague-Dawley rats), recorded with sharp intracellular electrodes containing 3 M KCl, as well as patch electrodes, filled mainly with 150 mM KMeSO4 and Hepes. The predominant change produced by 15- to 20-min applications of 2-DG (10 mM, replacing glucose) was hyperpolarization (-5.6 +/- 1.1 mV for 18 intracellular recordings and -7.2 +/- 0.80 mV for 17 whole-cell recordings) accompanied by a fall in resistance (-33 +/- 2.5% for 14 intracellular recordings and -11.6 +/- 7.1% for 15 whole-cell recordings). Virtually identical hyperpolarizations were recorded in the presence of 20 microM glyburide (-5.5 +/- 1.5 mV, n = 6), but they were abolished by adenosine antagonists 8-(p-sulfophenyl)theophylline (8-SPT) and 8-cyclopentyl-3,7-dihydro-1,3-dipropyl-1H-purine-2,6-dione (DPCPX) (2.8 +/- 1.6 and 4.0 +/- 1.7 mV, respectively; n = 5 for both). It was concluded that the hyperpolarization is most likely caused by an increase in K+ conductance, activated by a 2-DG-induced rise in adenosine release. After such applications of 2-DG, a sustained potentiation of EPSPs (similar to the 2-DG-LTP of field EPSPs) was evident in five neurons recorded with intracellular electrodes but not in any of nine whole-cell recordings, where it was replaced by sustained, LTD-like depression. We conclude that a factor essential for 2-DG-LTP induction is lost during whole-cell recording.

In hippocampal slices, temporary (10-20 min) replacement of glucose with 10 mM 2-deoxyglucose is followed by marked and very sustained potentiation of EPSPs (2-DG LTP). To investigate its mechanism, we examined 2-DG's effect in CA1 neurons recorded with sharp 3 M KCl electrodes containing a strong chelator, 50 or 100 mM ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA). In most cases, field EPSPs were simultaneously recorded and conventional LTP was also elicited in some cells by tetanic stimulation of stratum radiatum. 2-DG potentiated intracellular EPSP slopes by 48 +/- 5.1% (SE) in nine cells recorded with plain KCl electrodes and by 52 +/- 6.2% in seven cells recorded with EGTA-containing electrodes. In four of the latter cells, tetanic stimulation (twice 100 Hz for 1 s) failed to evoke LTP (2 +/- 1.1%), although field EPSPs were clearly potentiated (by 28 +/- 6.9%). Thus unlike tetanic LTP, 2-DG LTP is not readily prevented by postsynaptic intraneuronal injection of EGTA. These findings agree with other evidence that the rise in postsynaptic (somatic) [Ca(2+)](i) caused by 2-DG is not the principal trigger for the subsequent 2-DG LTP and that it may be a purely presynaptic phenomenon.

2-Deoxyglucuse (2-DG; 10 mM) replacing glucose for --15 min regularly causes a very sustained enhancement of synaptic transmission in the CA1 hippocampal zone (2-DG-induced long-term potentiation, 2-DG-LTP). This LTP is prevented by dantrolene (10 pM) or by the NMDA antagonist aminophosphonovalerate (APV; 50-100 pM); it is Ca-dependent [1, 2], and is not depressed by adeno6ine antagonists (DPCPX and 8-SPT), which prevent the initial block of EPSP caused by 2-DG, but is not observed if glu~ is replaced by sucrose instead of 2-DG. To clarify the role of [Call in 2-DG-LTP, we monitored fluo-3 fluorescence In CAI neurons, in submerged slices kept at 30"C. 2-DG applied as above consistently led to a rapid, but reversible rise in fluorescence, lsomolar sucrose (for 15-40 rain) elicited smaller, but significant increases in fluorescence. Dantrolene and APV greatly reduced 2-DG's effect, but Ca-free medium did not abolish it. Paradoxically, it was fully suppre,~ed by 8-SPT, but not at all by DPCPX. The discrepancies between the effects of sucrose and 8-SPT on the fluorescence changes and on 2-DG-LTP suggest that the observed increases in the postsynaptic [Ca]t are not essential for 2-DG-LTP. In further experiments, lntracellular recordings showed that 2-DG applications consistently hyperpolarize CAI neurons, probably owing to adenosine-mediated activation of K § conductance (which could be prevented by DPCPX or 8-SPT, but not by a KATI' antagonist, glyburide). The 2-DG-LTP of EPSP was not suppressed by EGTA leakage from electrodes, in keeping with the above evidence that the [Ca]/changes needed for the induction of 2-DG-LTP are not those observed postsynaptically. In this respect, as welt as in the absence of postsynaptic depolarization, 2-DG-LTP offers a marked contrast to more conventional forms of LTP.

In previous experiments on excitatory synaptic transmission in CA1, temporary (10-20 min) replacement of glucose with 10 mM 2-deoxyglucose (2-DG) consistently caused a marked and very sustained potentiation (2-DG LTP). To find out whether 2-DG has a similar effect on inhibitory synapses, we recorded pharmacologically isolated mononosynaptic inhibitory postsynaptic potentials (IPSPs; under current clamp) and inhibitory postsynaptic currents (IPSCs; under voltage clamp); 2-DG was applied both in the presence and the absence of antagonists of N-methyl-D-aspartate (NMDA). In spite of sharply varied results (some neurons showing large potentiation, lasting for >1 h, and many little or none), overall there was a significant and similar potentiation of IPSP conductance, both for the early (at approximately 30 ms) and later (at approximately 140 ms) components of IPSPs or IPSCs: by 35.1 +/- 10.25% (mean +/- SE; for n = 24, P = 0.0023) and 36.5 +/- 16.3% (for n = 19, P = 0.038), respectively. The similar potentiation of the early and late IPSP points to a presynaptic mechanism of LTP. Overall, the LTP was statistically significant only when 2-DG was applied in the absence of glutamate antagonists. Tetanic stimulations (in presence or absence of glutamate antagonists) only depressed IPSPs (by half). In conclusion, although smaller and more variable, 2-DG-induced LTP of inhibitory synapses appears to be broadly similar to the 2-DG-induced LTP of excitatory postsynaptic potentials previously observed in CA1.