Title: Asynchronous Inhibition in Neocortical Microcircuits
Description: Neurons are constantly integrating information from external and internal sources, causing them to spike at particular times. The exact timing of spikes is determined by a neuron's intrinsic properties, as well as the interplay between local excitatory and inhibitory inputs. Although inhibitory interneurons have been extensively studied, their contribution to neuronal integration and spike timing remains poorly understood. To elucidate the functional role of GABAergic interneurons during cortical activity, we combined molecular identification of interneurons, two photon imaging and electrophysiological recordings in mouse thalamocortical slices. In this preparation, cortical UP states, a network state characterized by prolonged periods of depolarization and synchronized spiking, can be evoked by thalamic stimulation and can also occur spontaneously. To assay the role of inhibition, we first characterized the firing properties of Parvalbumin (PV) and Somatostatin (SOM) interneurons during UP states activity, and found a higher probability and rate of spiking in these two subtypes compared to excitatory cells.

These subtypes did not display differential timing of activation during the evoked response. Furthermore, calcium imaging showed low correlations among PV and SOM interneurons, indicating that neurons sharing these neurochemical markers do not coordinate their firing. Intracellular recordings confirmed that nearby interneurons, known to be electrically coupled, do not display more synchronous spiking than excitatory cells, suggesting that this coupling may not function to synchronize the activity of interneurons on fast time scales¬¬¬. After characterizing inhibitory interneuron outputs, we next studied the timing and correlation of inhibitory inputs, which we isolated from excitatory inputs by voltage clamping at the reversal for excitation (0mV) or inhibition (-70mV). In both thalamically triggered and spontaneous activations, IPSCs between cell pairs were remarkably well correlated, with correlation coefficients reaching over .9 in some cases. This high degree of correlation has previously been assumed to be due to interneuron synchrony, but our population imaging and paired recordings did not support this view.

In addition, we found that the connection rate between interneurons is very high (~80%), and quantal analysis revealed that each IPSC recorded in neighboring cells during an UP state could be due to a single presynaptic interneuron. Therefore, we explain the high IPSCs correlations in nearby pyramidal cells are emerging from the common input from individual interneurons, rather than from synchronization of interneuron activity across the population. In a final set of experiments, we found that a partial pharmacological block of inhibitory signaling increased EPSC correlations. Our data support a model in which inhibitory neurons do not fire in a correlated fashion but have strong, dense connections to pyramidal neurons that serve to prevent local excitatory synchrony during UP states. This would mean that inhibition may not, as previously thought, serve to synchronize the firing of excitatory cells, but have precisely the opposite effect, decorrelating their activity by breaking down their coordinated firing.

This is consistent with the hypothesis that pyramidal cells are carrying out an essentially integrative function in the circuit and that interneurons expand the temporal dynamic range of this integration.