Art.-Zador (E)

Cortical neurons in the waking brain fire highly irregular spike trains that have more in common with the ticking of a Geiger counter than of a clock. What is the source of this irregular firing? Softky and Koch1 noted a theoretical conundrum posed by the irregularity of cortical neurons firing at a constant average rate in vivo. If each cortical neuron were providing independent input to the other similar cortical neurons it contacts, then the input to any neuron would just be a shower of statistically independent excitatory postsynaptic potentials (EPSPs) with a constant mean rate. Yet such an input, when tested on a theoretical model of a cortical neuron, gave rise to a firing variability much less than that observed in vivo. What, then, is the source of the unexpectedly large variability in spike timing that characterizes in vivo firing behavior? Is the high variability due to some subtle interplay between the noise resulting from randomly timed synaptic inputs and the nonlinear spike-generating mechanism, or instead due to unexpectedly large fluctuations in the synaptic input itself? Although most earlier workers have argued that the large variability arises from the interaction between this noisy synaptic input and the spike-generating mechanism, we will conclude that large fluctuations in the synaptic drive, such as might arise from the synchronous arrival of inputs from many neurons, are necessary to account for the high in vivo variability. The neuronal spike generator converts input current into output spike trains with high fidelity2,3. Irregular firing must, then, reflect fluctuations in the currents that drive the spike generator, rather than some intrinsic noise in the spike-generating mechanism itself4. Most previous attempts to identify the source of irregular firing have focused on the details of the spike-generating mechanism and on the importance of the inhibitory synaptic noise5–7 (Tsodyks et al., Soc. Neurosci. Abstr., 20, 1527, 1994). These workers have concluded that unstructured synaptic noise processed by a model spike generator can produce the unexpected variability in spike timing. However, most of these proposals have relied on theoretical models of the neuronal spike generator (but see ref. 8), and thus one may question the extent to which such models can be relied upon to provide a sufficiently realistic representation of spike generation. We therefore set out to determine experimentally whether the high variability observed in vivo could arise from the superposition of independent excitatory and inhibitory inputs. Because reconciliation of the in vivo variability with the synaptic drive depends critically on the details of the spike generation mechanism, we have used a direct approach rather than rely on theoretical models of the spike generator. We have injected ‘synthetic’ synaptic currents through a somatic electrode to drive neurons in neocortical slices to fire. With this method, we can assess the output variability in response to any input ensemble. We have complemented this approach by testing the response to miniature excitatory postsynaptic currents (EPSCs) whose rate of release was elevated at many synapses independently through the local application of hypertonic solution. We find that when neocortical neurons are driven by a population of independent inputs, the spike variability is consistently lower than that observed in vivo. We thus cannot confirm the earlier conclusions that unstructured synaptic noise interacting with the spike-generating mechanism can account for the unexpectedly large variability of neuronal activity in the neocortex. However, when a population of transiently synchronous inputs is added to the background of independent inputs, the observed firing variability is within the range observed in vivo. The high variability observed in vivo is therefore inconsistent with the activity of independent excitatory and inhibitory inputs, but could arise from large rapid fluctuations in the synaptic drive, such as would result from the nearly synchronous firing of subpopulations of afferents.