Inhibitory interneurons and network oscillations.

N euronal networks in the brain oscillate in various frequency bands, and such oscillations can be detected by observing local field potential or EEG activity (1). Oscillations in the gamma frequency band (30–80 Hz) have drawn special attention because of their link to a variety of cognitive processes including sensory binding (2), attention selection (3), and memory (4, 5). Of particular physiological interest are questions of how gamma oscillations are generated and synchronized across brain regions. The study by Middleton et al. in this issue of PNAS (6) provides novel insights into these questions: it identifies 2 subcircuits within the entorhinal cortex (EC) that are capable of generating gamma oscillations at different frequencies. Moreover, it presents data implying that these generators recruit different neuronal pathways in their communication with the hippocampus. Their study points out for the first time the specialized role of inhibitory interneuron types in generating oscillatory patterns at different frequencies. Given that both the hippocampo–EC system and gamma oscillations are linked to memory processing, the temporal interactions between the EC and the hippocampus at these distinct gamma frequencies could be involved in different aspects of mnemonic processes. The report by Middleton et al. (6) examines the mechanism behind how gamma oscillations are generated in the EC with an emphasis on the effect of the NMDA receptor activation: a key glutamatergic receptor for synaptic plasticity and memory formation. Using an in vitro preparation of the EC, they demonstrate that gamma oscillations slow down when NMDA receptors (NMDARs) are blocked by ketamine (an NMDAR antagonist). They then show that NMDA-dependent (fast, 40 Hz) and NMDA-independent (slow, 30 Hz) gamma rhythms are generated by functionally distinct subcircuits (Fig. 1). Both subcircuits consist of EC excitatory principal cells and inhibitory interneurons whose reciprocal interactions lead to oscillations. However, Middleton et al. find that these subcircuits include 2 distinct types of interneurons. The interneurons participating in the first subcircuit are the basket cells whose cell bodies are located in the layer II of the EC. NMDAR activation leads to a prominent tonic excitation of these basket cells that interact with principal cells to generate 40-Hz gamma rhythm (Fig. 1 A). These basket cells, however, have another function: they suppress the activity of interneurons in the second subcircuit. The cell bodies of these latter interneurons are located in layer III of the EC and are called ‘‘goblet’’ cells, newly-discovered by the Middleton et al. study (6). In the absence of NMDARmediated excitation in the EC, the decreased spiking activity of the basket interneurons reduces the inhibition they exert on goblet cells. The release of goblet cells from inhibition allows them to participate in the reciprocal interaction with principal cells (Fig. 1B), leading to the generation of the second gamma rhythm at a lower frequency ( 30 Hz). Based on the results of the experiments, a biophysical model was created that confirmed that these 2 types of gamma oscillations can be generated by using the microcircuit architecture described above. Finally, the Middleton et al. study (6) shows that hippocampal regions in vitro have a selective preference for slow or fast gamma oscillations: whereas the CA1 region preferentially oscillates with 40-Hz oscillations, the CA3 region prefers slower 30-Hz oscillations. Hence NMDA-dependent EC gamma oscillations may preferentially synchronize with the CA1 region, whereas NMDA-independent EC gamma oscillations may recruit coherent oscillations with the CA3 region. The surprising finding in the Middleton et al. study (6) is that 2 gamma patterns are generated locally by 2 different types of interneurons. Previous work in vivo has demonstrated that hippocampal GABAergic interneuron types exhibit differentiable firing patterns in relation to network oscillations, indicating that they have specialized roles in controlling various oscillations in the brain (7). Similarly, previous work in vitro has demonstrated that both interneuron– interneuron and pyramidal cell– interneuron interactions can generate the gamma rhythm in the hippocampus,