The Journal of Neurophysiology Vol. 80 No. 1 July 1998, pp. 113-119
Copyright ©1998 The American Physiological Society

Substance P Enhances NMDA Channel Function in Hippocampal Dentate Gyrus Granule Cells

David N. Lieberman¹ and Istvan Mody²

¹ Neuroscience Graduate Program, Stanford University School of Medicine, Stanford 94305; and ² Departments of Neurology and Physiology, UCLA School of Medicine, Los Angeles, California 90095-1769

Lieberman, David N. and Istvan Mody. Substance P enhances NMDA channel function in hippocampal dentate gyrus granule cells. J. Neurophysiol. 80: 113-119, 1998. Substance P (SP)-containing afferents and the NK-1 tachykinin receptor to which SP binds are present in the dentate gyrus of the rat; however, direct actions of SP on principal cells have not been demonstrated in this brain region. We have examined the effect of SP on N-methyl-D-aspartate (NMDA) channels from acutely isolated dentate gyrus granule cells of adult rat hippocampus to assess the ability of SP to regulate glutamatergic input. SP produces a robust enhancement of single NMDA channel function that is mimicked by the NK-1-selective agonist Sar⁹, Met(O₂)¹¹-SP. The SP-induced prolongation of NMDA channel openings is prevented by the selective NK-1 receptor antagonist (+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine (CP-99,994). Calcium influx or activation of protein kinase C were not required for the SP-induced increase in NMDA channel open durations. The dramatic enhancement of excitatory amino acid-mediated excitability by SP places this neuropeptide in a key position to gate activation of hippocampal network activity.

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