Functional Interaction Between NMDA And GABA A Receptors In Neurons Of Rat Inferior Colliculus

BACKGROUND: Membrane ion channels of different types often do not function independently but cross-talk to each other, i.e., activation of one channel would inhibit or potentiate the other. The cross-talk between ion channels plays an important role in neuronal excitability and processing of neural signals. The N-methyl-D-aspartate receptor (NMDA receptor) and theγ-aminobutyric acid type A receptor (GABA_A receptor) are the major excitatory and inhibitory receptors in the central nervous system, respectively. However, the cross-talk between the two channels has not been thoroughly studied. In particular, the characteristics of the cross-talk between the two channels in the central auditory system are not known. The inferior colliculus (IC) is a major information integration center of the central auditory pathways in mammals, in which the NMDA and GABA_A receptors are abundantly expressed. The purpose of the present study was to investigate the funcational interaction between NMDA and GABA_A receptors in the IC.METHODS: The cross-talk between NMDA and GABA_A receptors in cultured IC neurons from new born Wistar rats was investigated with whole-cell patch-clamp techniques. The membrane current induced by aspartate (IAsp) and that by GABA (IGABA) were recorded through a voltage-clamp mode with the membrane potential of the recorded cell held at -60 mV. Drugs used in the present study were applied with a rapid application technique termed"Y-tube"method.RESULTS: (1) The current induced by Asp at 100μM was suppressed by the pre-perfusion of GABA at 100μM, indicating cross-inhibition of NMDA receptors by activation of GABA_A receptors. The cross-inhibtion could be blocked by application of bicuculline (10μM), a selective GABA_A receptor antagonist; (2) the current induced by GABA at 100μM was not suppressed by the pre-perfusion of 100μM Asp, but that induced by GABA at 3μM was, indicating concentration-dependent cross-inhibition of GABA_A receptors by activation of NMDA receptors. The cross-inhibtion could be blocked by application of D-2-amino-5-phosphonovalerate (100μM), a selective NMDA receptor antagonist; (3) The inhibition of IGABA by Asp was not affected by blockage of voltage-dependent Ca²⁺ channels (VDCCs) with CdCl₂; however, the inhibition was blocked when the Ca²⁺ in the external solution was substituted by Ba²⁺ or when 10 mM BAPTA-a membrane-permeable Ca²⁺ chelator was added into the pipette solution, suggesting that the inhibition was mediatd by the Ca²⁺influx specifically through NMDA receptor channels, rather than VDCC_s; (4) KN-62, a potent inhibitor of Ca²⁺/calmodulin-dependent protein kinaseâ…¡(CaMKâ…¡), reduced the inhibition of I_GABA by Asp, indicating the involvement of CaMKâ…¡in the cross-inhibition.CONCLUSIONS: There exists a functional interaction between NMDA and GABAA receptors in cultured neurons of the IC in rats. The cross-inhibition between the two types of channels is mediated by Ca²⁺ entry through NMDA receptor channels, rather than VGCC_s, and activation of CaMKâ…¡is involved in the downstream of the signaling pathway. The cross-talk between NMDA and GABAA receptors suggests complexity of information processing in the central auditory system.