2-Deoxyglucose–Induced Long-Term Potentiation in CA1 Is Not Prevented by Intraneuronal Chelator

Abstract

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-Deoxyglucose–Induced Long-Term Potentiation of Monosynaptic IPSPs in CA1 Hippocampal Neurons

“…Unlike 2-DG-LTP of EPSPs (Tekkök and Krnjević 1995;Zhao et al 1997;Zhao and Krnjević 2000), 2-DG-LTP of IPSPs proved to be a quite variable phenomenon. In every group studied, at least one or two cells showed a sharp LTP (marked enhancement of G IPSP , lasting without major decrement for Ͼ30 min), but many did not yield such convincing results.…”

“…Although generated by quite different receptors and ionic channels , they showed strongly correlated changes. Because 2-DG is unlikely to have a similar effect on the very different GABA A and GABA B receptors, a presynaptic mechanism must be viewed as a serious possibility; in keeping with a similar conclusion about 2-DG-LTP of EPSPs, partly based on the finding that 2-DG-LTP of EPSPs is associated with marked reduction of paired-pulse facilitation (Tekkök and Krnjević 1996) and is not sensitive to chelation of postsynaptic Ca 2ϩ (Zhao and Krnjević 2000). A possible objection that GABA receptors are saturated during normal transmission (De Koninck and Mody 1994) does not exclude a presynaptic mechanism that enables previously "silent" synapses (Kullmann and Siegelbaum 1995).…”

“…How 2-DG might have such a presynaptic effect, whether it is directly or indirectly mediated, and the location of relevant NMDA receptors remain open to speculation. If the mechanism is indeed mainly presynaptic and NMDA receptors do play a significant role, as appears to be the case for 2-DG-LTP of EPSPs (Tekkök et al 1999;Zhao and Krnjević 2000), the most likely target is syntaxin, which is involved in synaptic vesicle docking (Bennett et al 1992), as well having NMDA receptor properties (Smirnova et al 1993).…”

“…Although 2-DG suppresses glycolysis by selectively blocking hexokinase (Tower 1958), even prolonged removal of glucose has no comparable effect on EPSPs (Krnjević and Tekkök 1996). Like many other forms of LTP, 2-DG-induced LTP (2-DG LTP) is NMDA receptor dependent, but it is not suppressed by intracellular application of a chelator (Zhao and Krnjević 2000).…”

Enhancement of Glutamate Release by l-Fucose Changes Effects of Glutamate Receptor Antagonists on Long-Term Potentiation in the Rat Hippocampus

“…Ragozzino et al (1996) discussed some mechanisms for glucose that also may be relevant for L-fucose, e.g., increase of transmitter synthesis, direct antagonism at opiate receptors that govern transmitter release, or direct influence on glutamate release. In addition, the role of 2-deoxy-D-glucose, which induces long-term potentiation in the CA1 region, in increasing glutamate release and presynaptic NMDA receptor-mediated Ca ++ influx has been discussed (Zhao & Krnjevic 2000). Because receptors and ion channels are glycoproteins (Hullebroeck and Hampson 1992;Kawamoto et al 1995, Clark et al 1998, Smalla et al 1998, the application of L-fucose can interfere with interactions between these glycoproteins and endogenous lectins, which could serve as functional modulators.…”