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1. Using whole cell recording techniques, we studied subthreshold and suprathreshold voltage responses to oscillatory current inputs in neurons from the sensorimotor cortex of juvenile rats. 2. Based on firing patterns, neurons were classified as regular spiking (RS), intrinsic bursting (IB), and fast spiking (FS). The subthreshold voltage-current relationships of RS and IB neurons were rectifying whereas FS neurons were almost ohmic near rest. 3. Frequency response curves (FRCs) for neurons were determined by analyzing the frequency content of inputs and outputs. The FRCs of most neurons were voltage dependent at frequencies below, but not above, 20 Hz. Approximately 60% of RS and IB neurons had a membrane resonance at their resting potential. Resonant frequencies were between 0.7 and 2.5 Hz (24-26 degrees C) near -70 mV and usually increased with hyperpolarization and decreased with depolarization. The remaining RS and IB neurons and all FS neurons were nonresonant. 4. Resonant neurons near rest had a selective coupling between oscillatory inputs and firing. These neurons selectively fired action potentials when the frequency of the swept-sine-wave (ZAP) current input was near the resonant frequency. However, when these neurons were depolarized to -60 mV, spike firing was associated with many input frequencies rather than selectively near the resonant frequency. 5. We examined three subthreshold currents that could cause low-frequency resonance: IH, a slow, hyperpolarization-activated cation current that was blocked by external Cs+ but not Ba2+; IIR, an instantaneously activating, inwardly rectifying K+ current that was blocked by both Cs+ and Ba2+; and INaP, an quickly activating, inwardly rectifying persistent Na+ current that was blocked by tetrodotoxin (TTX). Voltage-clamp experiments defined the relative steady state activation ranges of these currents. IIR (activates below -80 mV) and INaP (activates above -65 mV) are unlikely to interact with each other because their activation ranges never overlap. However, both currents may interact with IH, which activated variably at potentials between -50 and -90 mV in different neurons. 6. We found that IH produces subthreshold response. Consistent with this, subthreshold resonance was blocked by external Cs+ but not Ba2+ or TTX. Application of Ba2+ enlarged FRCs and resonance at potentials below -80 mV, indicating that IK,ir normally attenuates resonance. Application of TTX greatly diminished resonance at potentials more depolarized than -65 mV, indicating that INaP normally amplifies resonance at these potentials. 7. The ZAP current input may be viewed as a model of oscillatory currents that arise in neocortical neurons during synchronized activity in the brain. We propose that the frequency selectivity endowed on neurons by IH may contribute to their participation in synchronized firing. The voltage dependence of the frequency-selective coupling between oscillatory inputs and spikes may indicate a novel mechanism for controlling the extent of low-frequency synch...

1. We obtained whole cell data from sensorimotor cortical neurons of in vitro slices (juvenile rats) and observed a low-frequency resonance (1-2 Hz) in their voltage responses. We constructed models of subthreshold membrane currents to determine whether a hyperpolarization-activated cation current (IH) is sufficient to account for this resonance. 2. Parameter values for a basic IH (BH) model were estimated from voltage-clamp experiments at room temperature. The BH model formed a component of a reduced membrane (RM) model. On numerical integration, the RM model exhibited voltage sags and rebounds to injected current pulses; maximal voltage responses to injected oscillatory currents occurred near 2 Hz. 3. We compared the experimentally measured frequency-response curves (FRCs) at room temperature with the theoretical FRCs derived from the RM model. The theoretical FRCs exhibited resonant humps with peaks between 1 and 2 Hz. At 36 degrees C, the theoretical FRCs peaked near 10 Hz. The characteristics of theoretical and observed FRCs were in close agreement, demonstrating that IH is sufficient to cause resonance. Thus we classified IH as a resonator current. 4. We developed a technique, the reactive current clamp (RCC), to inject a computer-calculated current corresponding to a membrane ionic current in response to the membrane potential of the neuron. This enabled us to study the interaction of an artificial ionic current with living neurons (electronic pharmacology or EP-method). Using the RCC, a simplified version of the BH model was used to cancel an endogenous IH (electronic antagonism) and to introduce an artificial IH (electronic expression) when an endogenous IH was absent. Antagonism of IH eliminated sags and rebounds, whereas expression of IH endowed neurons with resonance and the frequency-selective firing that accompanies resonance in neurons with an endogenous IH. Previous investigations have relied on the specificity of pharmacological agents to block ionic channels, e.g., Cs+ to block IH. However, Cs+ additionally affects other currents. This represents the first time an in vitro modeling technique (RCC) has been used to antagonize a specific endogenous current, IH. 5. A simplified RM model yielded values of the resonant frequency and Q (an index of the sharpness of resonance), which rose almost linearly between -55 and -80 mV. Resonant frequencies could be much higher than fH = (2 pi tau H) - 1 where tau H is the activation time constant for IH. 6. In the FRCs, resonance appeared as a hump at intermediate frequencies because of low- and high-frequency attenuations due to IH and membrane capacitance, respectively. Changing the parameters of IH altered the low-frequency attenuation and, hence, the resonance. Changes in the leak conductance affected both the low- and high-frequency attenuations. 7. We modeled an inwardly rectifying K+ current (IIR) and a persistent Na+ current (INaP) to study their effects on resonance. Neither current produced resonance in the absence of IH. We found that IIR attenuated...

We examined the maturation of GABAA receptor synapses in cortical pyramidal neurons cultured from embryonic rats. The decay kinetics of GABAA receptor‐mediated miniature postsynaptic currents (mPSCs) were compared with those of responses evoked by GABA in excised membrane patches. Fast perfusion of 1 or 10 mM GABA on membrane patches evoked currents with different desensitizing time courses in young and old neurons. For neurons older than 4 days in vitro (DIV), GABAA currents had a fast component of desensitization (median ≈ 3 ms) seldom seen in patches from younger neurons. In contrast, mPSCs exhibited a substantial fast component of decay at 2–4 DIV that became more prominent with further development although the median value of its time constant remained unchanged. The selective α3 subunit positive modulator SB‐205384 had no effect on mPSCs at any time in vitro but potentiated extrasynaptic activity. This suggests that synapse maturation does not proceed by a gradual exchange of early embryonic GABAA receptor subforms for adult forms. At all ages, the kinetic properties of mPSCs were heterogeneous. This heterogeneity extended to the level of mPSCs from single neurons and may be a normal aspect of synaptic functioning. These results suggest that inhibitory synapses in developing neurons are capable of selectively capturing GABAA receptors having fast desensitization kinetics. This functional preference probably reflects the developmental turning point from an inwardly looking trophic capacity of embryonic GABAA receptors to a role concerned with information processing.

1. We constructed a mathematical model of the subthreshold electrical behavior of neurons in the nucleus mediodorsalis thalami (MDT) to elucidate the basis of a Ni(2+)-sensitive low-frequency (2-4 Hz) resonance found previously in these neurons. 2. A model that included the low- and high-threshold Ca2+ currents (IT and IL), a Ca(2+)-activated K+ current (IC), a rapidly inactivating K+ current (IA), a voltage-dependent K+ current which we call IKx, and a voltage-independent leak current (Il), successfully simulated the low-threshold spike observed in MDT neurons. This model (the MDT model) and a minimal version of the model containing only IT and I1 (the minimal MDT model) were used in the analysis. 3. An impedance function was derived for a linearized version of the MDT model. This showed that the model predicts a low-frequency (2-4 Hz) resonance in the voltage response to "small" oscillatory current inputs (producing voltage changes of < 10 mV) when the membrane potential is between -60 and -85 mV. 4. Further examination of the impedances for the MDT and minimal MDT models shows that IT underlies the frequency- and voltage-dependent resonance. The slow inactivation of IT results in an attenuation of voltage responses to low frequencies, resulting in a band-pass behavior. The fast activation of IT amplifies the resonance and modulates the peak frequency but does not, in itself, cause resonance. 5. When voltage responses are small (< 10 mV), the strength and voltage-dependence of resonance of the minimal MDT model are determined by the steady-state window conductance, gw, due to IT. This steady-state conductance arises where the steady-state activation, m(infinity2)(V), and inactivation, h(infinity) (V), curves overlap. Parallel shifts in the inactivation curve can eliminate or enhance resonance with little effect on the IT-dependent low-threshold spike evoked after hyperpolarizing current pulses. When the peak magnitude of gw was large, the minimal MDT model showed spontaneous oscillations at 3 Hz with amplitudes > 30 mV. 6. Large oscillatory current inputs evoked significantly nonlinear voltage responses in the minimal MDT model, but the 2- to 4-Hz frequency selectivity (predicted from the linearized impedance) remained. 7. We conclude that the properties of the low-threshold Ca2+ current, IT, are sufficient to explain the Ni(2+)-sensitive 2- to 4-Hz resonance seen in MDT neurons.(ABSTRACT TRUNCATED AT 400 WORDS)