Trends in Neurosciences
Volume 28, Issue 11, November 2005, Pages 602-610
Journal home page for Trends in Neurosciences

Modulation of neocortical interneurons: extrinsic influences and exercises in self-control

https://doi.org/10.1016/j.tins.2005.08.007Get rights and content

Neocortical GABAergic interneurons are a highly heterogeneous 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 neurotransmitters released by afferents from subcortical nuclei, interneurons belonging to different classes are controlled 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 functions, such as perception and cognition. Networks of locally projecting GABAergic inhibitory interneurons sculpt the activities in cortical circuits through feedforward and feedback inhibition, and prevent runaway excitation 1, 2. Inhibitory interneurons are also important 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 phenomena [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 functionality 6, 7. In addition, transmitters and neuromodulatory substances released by cortical afferents can alter interneuronal excitability, a phenomenon we define here as ‘extrinsic modulation’. In addition, subclasses of interneurons exhibit forms of ‘self-control’ or ‘intrinsic modulation’ 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 interneuron subtypes, with emphasis on two new forms of intrinsic modulation, their underlying cellular mechanisms, and potential functional effects. We discuss how specific and selective modulation of GABAergic networks might differentially influence activity of excitatory pyramidal neurons, and thus the output of neocortical circuits.

Section snippets

Neocortical interneuron heterogeneity in cortical layer 5

Neocortical GABAergic interneurons represent highly heterogeneous groups of cells that can be classified according to their anatomy, electrophysiology and expression of Ca2+-binding proteins or neuropeptides 11, 12, 13, 14. Perhaps the most functionally relevant distinctions between subgroups 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

Extrinsic modulation of neocortical interneurons

The neocortex is the target of ascending neurotransmitter systems, including those containing ACh, 5-hydroxytryptamine (5-HT or serotonin), dopamine and noradrenaline. Modulation of interneurons by these transmitters is essential for many neocortical operations and defects in these neuromodulatory pathways can be associated with significant psychiatric pathologies, such as schizophrenia and depression [28]. Axons of these ascending transmitter systems diffusely innervate the neocortex. Some

Are selective actions on interneuronal subclasses a common feature of other ascending transmitter systems?

The actions of dopamine, 5-HT and noradrenaline in the neocortex provide additional support for the hypothesis that these transmitters differentially affect subgroups of neocortical interneurons.

Autaptic inhibition of FS interneurons

In addition to the effects of neurotransmitters released by activity of other cells (extrinsic modulation), GABAergic interneurons can regulate their own excitability through activity-dependent mechanisms. GABA itself, released during action potential discharges in an interneuron, can synaptically modulate activities of the same cell, a phenomenon known as autaptic transmission. The morphological evidence of putative autaptic contacts was initially found in pyramidal neurons of the neocortex

Are endocannabinoids extrinsic or intrinsic modulators?

Endocannabinoids are identified mainly in two endogenous lipids: anandamide, the ethanolamide of arachidonic acid, and 2-arachidonoyl-glycerol (2AG) 62, 63, a lipid intermediate in phospholipid turnover. Anandamide and 2AG are synthesized through different biochemical pathways, both within the plasma membrane and both using phospholipids as precursors. Interestingly, the biosynthesis of both anandamide and 2AG depends strongly on elevation of intracellular Ca2+ concentration 62, 63, 64, 65,

Concluding remarks

Perhaps the most elaborate cognitive and behavioral functions performed by the neocortex result from particular activity states of specific interneuron subtypes, whose number is likely to correlate with complexity of cortical networks [21]. In other words, neocortical interneurons are specific modulators of cortical activities, a function accomplished through precisely targeted GABAergic synaptic contacts onto pyramidal neurons, and heavily influenced by external modulators. Analysis so far

Acknowledgements

A large amount of work dealing with the properties of interneurons, especially those outside of neocortex, could not be cited here because of space limitations. We apologize to our colleagues for such necessary omissions. We thank Isabel Parada and Fran Shen for help and excellent assistance in all our studies. Our work is supported by NIH (NINDS) and Pimley Research Fund.

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