Modulation of neocortical interneurons: extrinsic influences and exercises in self-control Alberto Bacci, John R. Huguenard and David A. Prince Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA Neocortical GABAergic interneurons are a highly hetero- geneous cell population that forms complex functional networks and has key roles in information processing within the cerebral cortex. Mechanisms that control the output of these cells are therefore crucial in regulating excitability within the neocortex during normal and pathophysiological activities. In addition to subtype- specific modulation of GABAergic cells by neurotrans- mitters released by afferents from subcortical nuclei, interneurons belonging to different classes are con- trolled by distinct self-modulatory mechanisms, each unique and powerful. In this article, we review the diverse responses of neocortical interneurons to extrinsic and intrinsic neuromodulators. We discuss how specificity of responses might differentially influence inhibition in somatodendritic compartments of pyramidal neurons and affect the balance of activities in neocortical circuits. Introduction The neocortex is where sensory information is filtered, processed and stored to enable complex behavioral func- tions, such as perception and cognition. Networks of locally projecting GABAergic inhibitory interneurons sculpt the activities in cortical circuits through feed- forward and feedback inhibition, and prevent runaway excitation [1,2]. Inhibitory interneurons are also import- ant in the generation of rhythmic activity in large neuronal populations [3,4]. This oscillatory activity is thought to be associated with physiological cortical functions, underlying several cognitive tasks and specific behaviors [3,4], in addition to pathophysiological phenom- ena [5]. Thus, the control or modulation of interneuronal activities is crucial in the function of neocortical circuits. Several ascending neurotransmitter systems project to the neocortex, where they specifically or preferentially target GABAergic interneurons, thus affecting their func- tionality [6,7]. In addition, transmitters and neuromodu- latory substances released by cortical afferents can alter interneuronal excitability, a phenomenon we define here as ‘extrinsic modulation’. In addition, subclasses of inter- neurons exhibit forms of ‘self-control’ or ‘intrinsic modu- lation’ that arise as a consequence of their own activity [8,9]. Note that this terminology differs from that used by Katz and Frost to describe effects of modulators on neural circuit function [10]. Here, we review aspects of intrinsic versus extrinsic modulation of two major cortical inter- neuron subtypes, with emphasis on two new forms of intrinsic modulation, their underlying cellular mechan- isms, and potential functional effects. We discuss how specific and selective modulation of GABAergic networks might differentially influence activity of excitatory pyra- midal neurons, and thus the output of neocortical circuits. Neocortical interneuron heterogeneity in cortical layer 5 Neocortical GABAergic interneurons represent highly heterogeneous groups of cells that can be classified accord- ing to their anatomy, electrophysiology and expression of Ca 2C -binding proteins or neuropeptides [11–14]. Perhaps the most functionally relevant distinctions between sub- groups are the patterns of connections that they make onto pyramidal cells (discussed later in this section), suggesting that different subgroups have distinct roles in the control of cortical activities. In layer 5, the major class of GABAergic interneurons consists of parvalbumin-positive, fast-spiking (FS) cells [12] that include multipolar basket cells and chandelier cells [12]. These neurons generate fast, non-accommodat- ing firing in response to depolarizing direct-current injections [12,13] and they do not express the neuropep- tides somatostatin (SST), cholecystokinin (CCK) or vaso- active intestinal polypeptide (VIP) [9,12]. Low-threshold spiking (LTS) interneurons represent another prominent cell type in layer 5. These cells tend to generate bursts of spikes following hyperpolarizing current steps and gene- rally have a much lower firing frequency and more pro- nounced spike frequency accommodation than FS cells [13]. The LTS interneuronal subclass includes cells expressing CCK [9], VIP [11,15] and SST [16], sometimes in combination. Important clues to specific roles of subtypes of GABAergic cells derive from their different axonal arborizations [12,13,17] and the sites of synaptic connec- tions that they form with pyramidal neurons. LTS inter- neurons tend to contact the dendrites of neocortical pyramidal cells [18] (Figure 1a), suggesting that they control the efficacy of glutamatergic excitatory inputs [4]. By contrast, FS basket and chandelier cells target the soma (Figure 1b) and axonal hillock of pyramidal neurons, respectively [19,20] – ideal locations for controlling the Corresponding author: Prince, D.A. (daprince@stanford.edu). Available online 31 August 2005 Review TRENDS in Neurosciences Vol.28 No.11 November 2005 www.sciencedirect.com 0166-2236/$ - see front matter Q 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.tins.2005.08.007