The Journal of Neurophysiology Vol. 81 No. 6 June 1999, pp. 2814-2822
Copyright ©1999 by the American Physiological Society

Blockade of GABA_A Receptors Facilitates Induction of NMDA Receptor-Independent Long-Term Potentiation

Department of Physiology, Marshall University School of Medicine, Huntington, West Virginia 25755-9340

Grover, Lawrence M. and Chen Yan. Blockade of GABA_A Receptors Facilitates Induction of NMDA Receptor-Independent Long-Term Potentiation. J. Neurophysiol. 81: 2814-2822, 1999.Blockade of GABA_A receptors facilitates induction of NMDA receptor-independent long-term potentiation. An N-methyl-D-aspartate (NMDA)-independent form of long-term potentiation (LTP), which depends on postsynaptic, voltage-dependent calcium channels (VDCCs), has been demonstrated in area CA1 of hippocampus. GABA acting at GABA_A receptors limits postsynaptic depolarization during LTP induction. Blockade of GABA_A receptors should therefore enhance activation of postsynaptic VDCCs and facilitate the induction of this NMDA receptor-independent, VDCC-dependent LTP. In agreement with this hypothesis, pharmacological blockade of GABA_A receptors in the in vitro rat hippocampal slice increased the magnitude of LTP resulting from a normally effective, high-frequency (200 Hz) tetanic stimulation protocol. In addition, GABA_A receptor blockade allowed a lower frequency (25 Hz) and normally ineffective tetanic stimulation protocol to induce this form of LTP. Intracellular recordings from CA1 pyramidal cells revealed that blocking GABA_A receptors during tetanic stimulation allowed greater postsynaptic depolarization, increased the number of postsynaptic action potentials fired during the tetanization, and also increased the duration of synaptically evoked action potentials. To mimic the increased action potential firing observed when GABA_A receptors were blocked, we paired 25-Hz antidromic stimulation with 25-Hz orthodromic stimulation. Paired antidromic + orthodromic 25-Hz stimulation induced NMDA receptor-independent LTP, whereas neither antidromic nor orthodromic stimulation alone induced LTP. Increased action potential firing can therefore at least partially account for the facilitation of NMDA receptor-independent LTP caused by blockade of GABA_A receptors. This conclusion is consistent with prior studies demonstrating that action potentials are particularly effective stimuli for the gating of VDCCs in CA1 pyramidal cell dendrites.