Shunting inhibition modulates the input resistance of neurons, reducing the slope of the relationship between subthreshold voltage and injected current. However, the effect of inhibition on firing rates is controversial since in some studies inhibition offsets the suprathreshold input-output (I-O) relationship, while in others it changes the gain. Inhibition in granule cells (GCs) is controlled by Golgi cell firing rate and by glutamate spillover, which activates presynaptic mGluRs on Golgi cells, suppressing inhibition (Mitchell & Silver, 2000). We have investigated the modulation of GC I-O relationships by inhibition and presynaptic mGluRs.
Parasagittal slices of cerebellum (250 µm) were prepared from 25-day-old Sprague-Dawley rats, killed by decapitation. Whole-cell current-clamp recordings were made from GCs at 37 °C from a holding potential of -75 mV. Data are presented as means ± S.E.M. The mechanisms underlying gain modulation were studied using a single compartment conductance-based integrate-and-fire (I&F) model.
When GCs were driven by injected synaptic conductance waveforms, tonic inhibition reduced the gain of I-O relationships by 44 ± 6 % (n = 5) and offset the relationship by 16 ± 3 Hz (n = 5). However, during tonic excitation, the gain was unaltered by tonic inhibition (-8 ± 4% n = 6), whereas the relationship was shifted to the right (400 ± 50 pS; n = 6). These results show that tonic inhibition modulates the GC I-O relationship in different ways depending on whether excitation is synaptic or tonic.
Speeding the synaptic decay time constant and reducing the number of excitatory inputs, which both increase the coefficient of variation of the excitation train, increased gain changes in the I&F model. This suggests that the level of fluctuations in the excitatory waveform determines inhibition-mediated gain modulation.
Having shown that inhibition can reduce GC gain, we studied how suppression of inhibition by mGluRs affects the GC I-O relationship. Inclusion of mGluRs in the model increased the gain of synaptic I-O relationships during inhibition (Fig. 1A). The fractional increase in gain produced by mGluRs increased as a function of inhibition (Fig. 1B).
Our results suggest that inhibition and mGluR-mediated disinhibition can act as cellular mechanisms for gain control in granule cells.
This work was funded by The Wellcome Trust and the EC. R.A.S. is in receipt of a Wellcome Trust Senior Fellowship.