No abstract

Gamma oscillations synchronized between distant neuronal populations may be critical for binding together brain regions devoted to common processing tasks. Network modeling predicts that such synchrony depends in part on the fast time course of excitatory postsynaptic potentials (EPSPs) in interneurons, and that even moderate slowing of this time course will disrupt synchrony. We generated mice with slowed interneuron EPSPs by gene targeting, in which the gene encoding the 67-kDa form of glutamic acid decarboxylase (GAD67) was altered to drive expression of the ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor subunit GluR-B. GluR-B is a determinant of the relatively slow EPSPs in excitatory neurons and is normally expressed at low levels in ␥-aminobutyric acid (GABA)ergic interneurons, but at high levels in the GAD-GluR-B mice. In both wild-type and GAD-GluR-B mice, tetanic stimuli evoked gamma oscillations that were indistinguishable in local field potential recordings. Remarkably, however, oscillation synchrony between spatially separated sites was severely disrupted in the mutant, in association with changes in interneuron firing patterns. The congruence between mouse and model suggests that the rapid time course of AMPA receptor-mediated EPSPs in interneurons might serve to allow gamma oscillations to synchronize over distance.G amma-frequency (30-to 90-Hz) neuronal oscillations, occurring in a non-time-locked fashion in response to visual stimuli, have been proposed to encode global features of spatially extended stimuli (1). A crucial physiological question concerns how synchrony arises, given the expected slow axonal conduction times in the cortex, estimated to be as low as 0.10-0.15 mm͞ms (2, 3).Network simulations (containing model pyramidal cells, interneurons, and axon conduction delays) predict that tight synchrony between distant sites could arise as an emergent property-without a central pacemaker-when interneurons fire in doublets (4-7). Precise timing of the doublet intervaldetermined in part by ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-receptor mediated excitation from pyramidal cells, especially cells at a distance from the postsynaptic interneuron-provides a signal encoding phase lags between separated neurons; this signal would provide feedback to nearby pyramidal cells, in the form of synaptic inhibition, which would tend to correct for phase differences (ref. 8; Appendix, which is published as supplemental data on the PNAS web site, www.pnas.org).Here we use a combination of simulation, transgenic, and electrophysiological techniques to show that interneuron doublets are necessary for two-site synchrony to occur and that they critically depend on excitatory postsynaptic potential (EPSP) kinetics in interneurons. Experimental ProceduresSimulations. Network simulations of gamma oscillations were performed by using the program described in Traub et al. (5).Briefly, the network consisted of a 96 ϫ 32 cell array of pyramidal neurons, and a superimp...