HYPERPOLARIZATION-ACTIVATED CATION CURRENT (I(H)) IN NEURONS OF THE MEDIAL NUCLEUS OF THE TRAPEZOID BODY - VOLTAGE-CLAMP ANALYSIS AND ENHANCEMENT BY NOREPINEPHRINE AND CAMP SUGGEST A MODULATORY MECHANISM IN THE AUDITORY BRAIN-STEM

1. Principal cells in the medial nucleus of the trapezoid body (MNTB) are part of a circuit in the superior olivary complex (SOC) that proce sses binaural information important for sound localization. MNTB cells have two voltage-dependent currents active near rest that contribute to these cells' highly nonlinear membrane properties and shape their r esponses to synaptic input. One of these currents, a low-threshold, 4- aminopyridine (4-AP)-sensitive K+ current, has been studied previously under current clamp. Using the single-electrode voltage-clamp techniq ue, we have investigated the other of these currents, a hyperpolarizat ion-activated, mixed cation current (I(h)), in brain slices of the rat SOC. 2. I(h) is responsible for a prominent ''sag'' in the voltage re sponse to a steady hyperpolarizing current recorded under current clam p in MNTB cells. In voltage-clamp recordings, hyperpolarizing voltage steps from the resting potential elicited a large inward current that activated and deactivated with biexponential kinetics. Activation time constants were voltage dependent, with tau1 and tau2 = 246 and 1620 m s at -75 mV and 107 and 560 ms at -100 mV. 3. I(h) was blocked by 1-5 mM cesium and had a reversal potential of -43 mV. Steady-state activat ion curves derived from tail currents yielded a half-activation voltag e of -75.7 mV and slope factor of 5.7 mV, corresponding to < 10% activ ation of I(h) at rest. 4. Application of norepinephrine (15-20 muM) or 8-bromoadenosine 3',5'-cyclic monophosphate (8-Br-cAMP) (1 mM) caused a depolarizing shift in the steady-state activation curve and decreas ed the activation time constants. The shift in the activation curve re sulted in a large increase in the activation of I(h) at rest, an inwar d shift in the holding current, and an increase in the resting membran e conductance. In current-clamp recordings, this increase in the resti ng activation level of I(h) resulted in membrane depolarization of 2-3 mV in the absence of 4-AP, and 5-10 mV in the presence of 4-AP, an in crease in the input conductance, and a reduction in the voltage sag in response to hyperpolarizing currents. 5. The resulting change in the resting point of MNTB cells exposed to norepinephrine or 8-Br-cAMP is likely to alter the responses of these cells to synaptic input, both v ia the direct effect on the resting membrane conductance and by changi ng the activation of the low-threshold, 4-AP-sensitive potassium curre nt. Thus, activation of I(h) by noradrenergic inputs, as well as other inputs linked to 8-Br-cAMP production, is a potential mechanism for m odulating the acoustic signal processing capabilities of MNTB cells.