Motifs in health and disease: the promise of circuit interrogation by optogenetics

Abstract

Identifying the dominant dynamical motifs in cortical circuits and determining their functional relevance is of the utmost importance to understand the underlying mechanisms of psychiatric diseases and to develop effective therapies. Optogenetics can be used to interrogate cortical circuits to determine the dominant motif and thereby identify the relevant biophysical time scales that set the oscillation frequency. We review how computational models of cortical networks can help guide optogenetics experiments. We focus our attention on the pyramidal interneuron gamma motif, which is comprised of reciprocally connected excitatory and inhibitory neurons, and determine how the different biophysical time scales of the circuit components are reflected in the resonance of the power in the local field potential at the frequency of stimulation as a function of that frequency. Cardin et al. [J.A. Cardin et al. (2009)Nature, 459, 663-667] find that periodic stimulation of inhibitory cells leads to a resonance at gamma frequencies (30-80 Hz), but that stimulation of excitatory cells does not lead to a resonance. We can account for these results when the pyramidal cells are endowed with an intrinsic frequency preference due to a slow hyperpolarizing current. Furthermore, when fast α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-mediated excitatory currents are replaced by slow N-methyl-d-aspartate (NMDA)-mediated ones in inhibitory cells, the gamma frequency resonance is reduced; however, when the same replacement is made in excitatory cells, gamma oscillations are enhanced. The results are relevant to schizophrenia, because there is evidence that NMDA receptors on parvalbumin-positive cells are primarily affected and that the regulation of gamma oscillations is impaired.