Abstracts

2DG reduces abnormal hippocampal network synaptic excitability without changing membrane properties.

Abstract number : 3.247
Submission category : 7. Antiepileptic Drugs
Year : 2015
Submission ID : 2325913
Source : www.aesnet.org
Presentation date : 12/7/2015 12:00:00 AM
Published date : Nov 13, 2015, 12:43 PM

Authors :
YuZhen Pan, Thomas Sutula, Paul Rutecki

Rationale: 2-deoxy-D-glucose (2DG) inhibits glycolysis and has both acute and chronic antiepileptic effects. The chronic antiepileptic mechanisms involve metabolic transcriptional regulation of seizure-induced increases in brain-derived neurotophic factor (BDNF) and tyrosine kinase B (TrkB) required for progressive adverse effects of kindled seizures. The acute antiepileptic mechanisms are not fully defined and we evaluated synaptic and membrane properties of CA3 pyramidal neurons in hippocampal slices to better understand the mechanism of 2DG’s acute antiepileptic effects.Methods: Hippocampal slices from Sprague-Dawley rats were prepared and maintained in either a submerged chamber for whole-cell patch-clamp studies or an interface chamber for sharp electrode recordings. Synaptic activity was recorded in CA3 neurons using Cs-methylsulfonate filled electrodes and with whole-cell techniques. Excitatory synaptic activity was recorded at -70 mV and inhibitory synaptic activity at 0 mV. Tetrotoxin (1 µM) was used to study miniature post synaptic currents (mPSCs). Membrane properties were studied using sharp electrode recordings and KCl filled electrodes in the presence of GABA and glutamate receptor antagonists. Neurons were studied at [K+]o concentrations of 3.5 and 7.5 mM. Either 20 mM glucose or 10 mM 2DG and 10 mM glucose artificial cerebrospinal fluid was applied to slices and changes in membrane or synaptic properties were evaluated.Results: High glucose or addition of DG did not alter the resting potential, input resistance, action potential threshold or amplitude, fast or slow afterhyperpolarization, or firing patterns in either 3.5 or 7.5 mM [K+]o. 2DG had no effects on spontaneously occurring excitatory post synaptic potentials (EPSC) in 3.5 mM [K+]o . 2DG, but not high glucose, produced a significant reduction in the frequency of high [K+]o induced epileptiform bursting. 2DG, but not high glucose, reduced spontaneously occurring inhibitory and excitatory PSCs in 7.5 mM [K+]o. The reduction in charge carried by excitatory currents was greater than that of inhibitory currents (71 vs 40%). The frequency of mEPSCs was not affected by 2DG when applied after TTX, but was reduced when 2DG was applied in 7.5 mM [K+]o before TTX. There was not a change in mEPSC amplitude. 2DG had no effects on mIPSCs; however, did reduce the frequency of isolated sIPSCs in 7.5 mM [K+]o without affecting their amplitude.Conclusions: 2DG reduced network excitability in elevated [K+]o without accompanying changes in membrane properties or mIPSC or mEPSC amplitudes, pointing to a presynaptic mechanism of action for its antiepileptic effects. The use-dependent effects of a reduction in mEPSC frequency and the reduction in isolated sIPSC frequency also support presynaptic actions. 2DG appears to have novel effects on presynaptic release as an antiepileptic mechanism. Supported by VA research and development.
Antiepileptic Drugs