How Inhibition Shapes Cortical Activity
2011; Cell Press; Volume: 72; Issue: 2 Linguagem: Inglês
10.1016/j.neuron.2011.09.027
ISSN1097-4199
AutoresJeffry S. Isaacson, Massimo Scanziani,
Tópico(s)Photoreceptor and optogenetics research
ResumoCortical processing reflects the interplay of synaptic excitation and synaptic inhibition. Rapidly accumulating evidence is highlighting the crucial role of inhibition in shaping spontaneous and sensory-evoked cortical activity and thus underscores how a better knowledge of inhibitory circuits is necessary for our understanding of cortical function. We discuss current views of how inhibition regulates the function of cortical neurons and point to a number of important open questions. Cortical processing reflects the interplay of synaptic excitation and synaptic inhibition. Rapidly accumulating evidence is highlighting the crucial role of inhibition in shaping spontaneous and sensory-evoked cortical activity and thus underscores how a better knowledge of inhibitory circuits is necessary for our understanding of cortical function. We discuss current views of how inhibition regulates the function of cortical neurons and point to a number of important open questions. Synaptic excitation and inhibition are inseparable events. Even the simplest sensory stimulus, like a whisker deflection (Okun and Lampl, 2008Okun M. Lampl I. Instantaneous correlation of excitation and inhibition during ongoing and sensory-evoked activities.Nat. Neurosci. 2008; 11: 535-537Crossref PubMed Scopus (150) Google Scholar, Swadlow, 2003Swadlow H.A. Fast-spike interneurons and feedforward inhibition in awake sensory neocortex.Cereb. Cortex. 2003; 13: 25-32Crossref PubMed Google Scholar, Wilent and Contreras, 2005Wilent W.B. Contreras D. Dynamics of excitation and inhibition underlying stimulus selectivity in rat somatosensory cortex.Nat. Neurosci. 2005; 8: 1364-1370Crossref PubMed Scopus (135) Google Scholar) a brief tone (Tan et al., 2004Tan A.Y. Zhang L.I. Merzenich M.M. Schreiner C.E. Tone-evoked excitatory and inhibitory synaptic conductances of primary auditory cortex neurons.J. Neurophysiol. 2004; 92: 630-643Crossref PubMed Scopus (163) Google Scholar, Wehr and Zador, 2003Wehr M. Zador A.M. Balanced inhibition underlies tuning and sharpens spike timing in auditory cortex.Nature. 2003; 426: 442-446Crossref PubMed Scopus (511) Google Scholar, Wu et al., 2008Wu G.K. Arbuckle R. Liu B.H. Tao H.W. Zhang L.I. Lateral sharpening of cortical frequency tuning by approximately balanced inhibition.Neuron. 2008; 58: 132-143Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar), an odor (Poo and Isaacson, 2009Poo C. Isaacson J.S. Odor representations in olfactory cortex: “sparse” coding, global inhibition, and oscillations.Neuron. 2009; 62: 850-861Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar), or an oriented bar in the visual field (Anderson et al., 2000Anderson J.S. Carandini M. Ferster D. Orientation tuning of input conductance, excitation, and inhibition in cat primary visual cortex.J. Neurophysiol. 2000; 84: 909-926PubMed Google Scholar, Monier et al., 2003Monier C. Chavane F. Baudot P. Graham L.J. Frégnac Y. Orientation and direction selectivity of synaptic inputs in visual cortical neurons: a diversity of combinations produces spike tuning.Neuron. 2003; 37: 663-680Abstract Full Text Full Text PDF PubMed Scopus (205) Google Scholar) lead to the concomitant occurrence of synaptic excitation and inhibition in sensory cortices. This co-occurrence of excitation and inhibition is not limited to activity generated by sensory stimuli. During spontaneous cortical activity (Okun and Lampl, 2008Okun M. Lampl I. Instantaneous correlation of excitation and inhibition during ongoing and sensory-evoked activities.Nat. Neurosci. 2008; 11: 535-537Crossref PubMed Scopus (150) Google Scholar), spontaneous cortical oscillations (Atallah and Scanziani, 2009Atallah B.V. Scanziani M. Instantaneous modulation of gamma oscillation frequency by balancing excitation with inhibition.Neuron. 2009; 62: 566-577Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar) or “up and down states” (Haider et al., 2006Haider B. Duque A. Hasenstaub A.R. McCormick D.A. Neocortical network activity in vivo is generated through a dynamic balance of excitation and inhibition.J. Neurosci. 2006; 26: 4535-4545Crossref PubMed Scopus (311) Google Scholar), for example, excitation and inhibition wax and wane together. What are the physiological consequences of this co-occurrence of excitation and inhibition; i.e., why should the cortex simultaneously push on the accelerator and on the brake? What cortical circuits regulate the relative magnitude of these two opposing forces and their spatial and temporal relation? The combination of these two synaptic conductances, by impacting the membrane potential and input resistance of the neuron, plays a fundamental role in regulating neuronal output. In other words, these two conductances together govern the computations performed by cortical neurons. Ultimately, the relative strength of these two conductances and their temporal relationship orchestrate cortical function in space and time. Inhibition in the cortex is generated by neurons that release the transmitter GABA. These neurons comprise approximately 20% of the cortical neuronal population (Meinecke and Peters, 1987Meinecke D.L. Peters A. GABA immunoreactive neurons in rat visual cortex.J. Comp. Neurol. 1987; 261: 388-404Crossref PubMed Google Scholar) and, in contrast to their counterpart, the excitatory glutamatergic principal cells, do not generally form long range projections with their axon; hence the name local circuit interneurons. The interactions between GABAergic interneurons and glutamatergic principal cells are reciprocal: interneurons inhibit principal cells and are excited by them. In fact the connectivity between these two neuronal classes is quite high: individual interneurons can inhibit >50% of principal cells located within ∼100 μm and receive excitatory input from a large fraction of them (Ali et al., 1999Ali A.B. Bannister A.P. Thomson A.M. IPSPs elicited in CA1 pyramidal cells by putative basket cells in slices of adult rat hippocampus.Eur. J. Neurosci. 1999; 11: 1741-1753Crossref PubMed Scopus (38) Google Scholar, Fino and Yuste, 2011Fino E. Yuste R. Dense inhibitory connectivity in neocortex.Neuron. 2011; 69: 1188-1203Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar, Glickfeld et al., 2008Glickfeld L.L. Atallah B.V. Scanziani M. Complementary modulation of somatic inhibition by opioids and cannabinoids.J. Neurosci. 2008; 28: 1824-1832Crossref PubMed Scopus (30) Google Scholar, Holmgren et al., 2003Holmgren C. Harkany T. Svennenfors B. Zilberter Y. Pyramidal cell communication within local networks in layer 2/3 of rat neocortex.J. Physiol. 2003; 551: 139-153Crossref PubMed Scopus (214) Google Scholar, Kapfer et al., 2007Kapfer C. Glickfeld L.L. Atallah B.V. Scanziani M. Supralinear increase of recurrent inhibition during sparse activity in the somatosensory cortex.Nat. Neurosci. 2007; 10: 743-753Crossref PubMed Scopus (161) Google Scholar, Packer and Yuste, 2011Packer A.M. Yuste R. Dense, unspecific connectivity of neocortical parvalbumin-positive interneurons: a canonical microcircuit for inhibition?.J. Neurosci. 2011; 31: 13260-13271Crossref PubMed Scopus (72) Google Scholar, Silberberg and Markram, 2007Silberberg G. Markram H. Disynaptic inhibition between neocortical pyramidal cells mediated by Martinotti cells.Neuron. 2007; 53: 735-746Abstract Full Text Full Text PDF PubMed Scopus (214) Google Scholar, Stokes and Isaacson, 2010Stokes C.C. Isaacson J.S. From dendrite to soma: dynamic routing of inhibition by complementary interneuron microcircuits in olfactory cortex.Neuron. 2010; 67: 452-465Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar, Yoshimura and Callaway, 2005Yoshimura Y. Callaway E.M. Fine-scale specificity of cortical networks depends on inhibitory cell type and connectivity.Nat. Neurosci. 2005; 8: 1552-1559Crossref PubMed Scopus (144) Google Scholar). Thus, not only are GABAergic interneurons excited in proportion to the level of local network activity, but they directly influence it through their inhibitory feedback. This simple connectivity pattern is ubiquitous in cortex and forms the basis for so-called feedback or recurrent inhibition (Figure 1A ). Of course, not all cortical excitation received by inhibitory interneurons is locally generated. Cortical cells receive excitatory inputs via long-range axons originating from subcortical nuclei, as well as from different cortical regions and different cortical layers. These excitatory afferent inputs diverge onto both principal cells and interneurons, generating feedforward inhibitory circuits (Figure 1B; Buzsáki, 1984Buzsáki G. Feed-forward inhibition in the hippocampal formation.Prog. Neurobiol. 1984; 22: 131-153Crossref PubMed Scopus (235) Google Scholar). Interestingly, the same afferent fibers make stronger excitatory connections onto interneurons than principal cells ensuring that even minimal levels of afferent input generate inhibition in cortical circuits (Cruikshank et al., 2007Cruikshank S.J. Lewis T.J. Connors B.W. Synaptic basis for intense thalamocortical activation of feedforward inhibitory cells in neocortex.Nat. Neurosci. 2007; 10: 462-468PubMed Google Scholar, Gabernet et al., 2005Gabernet L. Jadhav S.P. Feldman D.E. Carandini M. Scanziani M. Somatosensory integration controlled by dynamic thalamocortical feed-forward inhibition.Neuron. 2005; 48: 315-327Abstract Full Text Full Text PDF PubMed Scopus (221) Google Scholar, Glickfeld and Scanziani, 2006Glickfeld L.L. Scanziani M. Distinct timing in the activity of cannabinoid-sensitive and cannabinoid-insensitive basket cells.Nat. Neurosci. 2006; 9: 807-815Crossref PubMed Scopus (115) Google Scholar, Helmstaedter et al., 2008Helmstaedter M. Staiger J.F. Sakmann B. Feldmeyer D. Efficient recruitment of layer 2/3 interneurons by layer 4 input in single columns of rat somatosensory cortex.J. Neurosci. 2008; 28: 8273-8284Crossref PubMed Scopus (35) Google Scholar, Hull et al., 2009Hull C. Isaacson J.S. Scanziani M. Postsynaptic mechanisms govern the differential excitation of cortical neurons by thalamic inputs.J. Neurosci. 2009; 29: 9127-9136Crossref PubMed Scopus (59) Google Scholar, Stokes and Isaacson, 2010Stokes C.C. Isaacson J.S. From dendrite to soma: dynamic routing of inhibition by complementary interneuron microcircuits in olfactory cortex.Neuron. 2010; 67: 452-465Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar). Together, these two simple inhibitory circuits, feedback and feedforward, represent fundamental building blocks of cortical architecture and account for the fact that cortical excitation and inhibition are inseparable (van Vreeswijk and Sompolinsky, 1996van Vreeswijk C. Sompolinsky H. Chaos in neuronal networks with balanced excitatory and inhibitory activity.Science. 1996; 274: 1724-1726Crossref PubMed Scopus (519) Google Scholar). GABAergic interneurons will be recruited no matter whether excitation is generated locally or received from distant sites. In addition to principal cells, GABAergic interneurons also make inhibitory contacts onto each other and the connectivity between interneurons is highly reciprocal (Galarreta and Hestrin, 2002Galarreta M. Hestrin S. Electrical and chemical synapses among parvalbumin fast-spiking GABAergic interneurons in adult mouse neocortex.Proc. Natl. Acad. Sci. USA. 2002; 99: 12438-12443Crossref PubMed Scopus (180) Google Scholar, Gibson et al., 1999Gibson J.R. Beierlein M. Connors B.W. Two networks of electrically coupled inhibitory neurons in neocortex.Nature. 1999; 402: 75-79Crossref PubMed Scopus (856) Google Scholar, Tamas et al., 1998Tamas G. Somogyi P. Buhl E.H. Differentially interconnected networks of GABAergic interneurons in the visual cortex of the cat.J. Neurosci. 1998; 18: 4255-4270PubMed Google Scholar). This mutual connectivity between interneurons is also poised to shape spatial and temporal features of cortical inhibition. Cortical GABAergic interneurons are a heterogeneous bunch (reviewed in Ascoli et al., 2008Ascoli G.A. Alonso-Nanclares L. Anderson S.A. Barrionuevo G. Benavides-Piccione R. Burkhalter A. Buzsáki G. Cauli B. Defelipe J. Fairén A. et al.Petilla Interneuron Nomenclature GroupPetilla terminology: nomenclature of features of GABAergic interneurons of the cerebral cortex.Nat. Rev. Neurosci. 2008; 9: 557-568Crossref PubMed Scopus (420) Google Scholar, Freund and Buzsáki, 1996Freund T.F. Buzsáki G. Interneurons of the hippocampus.Hippocampus. 1996; 6: 347-470Crossref PubMed Google Scholar, Kawaguchi and Kondo, 2002Kawaguchi Y. Kondo S. Parvalbumin, somatostatin and cholecystokinin as chemical markers for specific GABAergic interneuron types in the rat frontal cortex.J. Neurocytol. 2002; 31: 277-287Crossref PubMed Scopus (219) Google Scholar, Kawaguchi and Kubota, 1998Kawaguchi Y. Kubota Y. Neurochemical features and synaptic connections of large physiologically-identified GABAergic cells in the rat frontal cortex.Neuroscience. 1998; 85: 677-701Crossref PubMed Scopus (152) Google Scholar, Klausberger and Somogyi, 2008Klausberger T. Somogyi P. Neuronal diversity and temporal dynamics: the unity of hippocampal circuit operations.Science. 2008; 321: 53-57Crossref PubMed Scopus (557) Google Scholar, Markram et al., 2004Markram H. Toledo-Rodriguez M. Wang Y. Gupta A. Silberberg G. Wu C. Interneurons of the neocortical inhibitory system.Nat. Rev. Neurosci. 2004; 5: 793-807Crossref PubMed Scopus (1030) Google Scholar, Monyer and Markram, 2004Monyer H. Markram H. Interneuron Diversity series: Molecular and genetic tools to study GABAergic interneuron diversity and function.Trends Neurosci. 2004; 27: 90-97Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar, Mott and Dingledine, 2003Mott D.D. Dingledine R. Interneuron diversity series: Interneuron research—challenges and strategies.Trends Neurosci. 2003; 26: 484-488Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar, Somogyi and Klausberger, 2005Somogyi P. Klausberger T. Defined types of cortical interneurone structure space and spike timing in the hippocampus.J. Physiol. 2005; 562: 9-26Crossref PubMed Scopus (467) Google Scholar, Somogyi et al., 1998Somogyi P. Tamás G. Lujan R. Buhl E.H. Salient features of synaptic organisation in the cerebral cortex.Brain Res. Brain Res. Rev. 1998; 26: 113-135Crossref PubMed Scopus (553) Google Scholar). One of the most striking features of this group of neurons is their morphological diversity, in particular with regard to their axonal arborization and, as a consequence, their postsynaptic targets. In fact, distinct classes of GABAergic interneurons inhibit particular compartments of principal neurons; “basket” cells, that target the somatic and perisomatic compartment, “chandelier” cells that selectively inhibit the axon initial segment, or “Martinotti” cells that preferentially target the apical dendritic tuft are just a few classic examples of this compartmentalization of inhibition. Morphological differences are however not the only properties that contribute to the diversity of cortical inhibitory neurons. Interneurons can be also subdivided based on intrinsic electrophysiological properties, synaptic characteristics, and protein expression patterns. Probably because of the many dimensions that can be used to describe an interneuron, no consensus yet exists with regard to their categorization. Strikingly, in contrast to the large amount of information that exists on the properties of the various types of cortical inhibitory neurons, knowledge of the specific role that each one plays in orchestrating cortical activity is still extremely limited. Thus, in this review, unless explicitly mentioned, we remain agnostic as to the specific interneuron subtypes mediating inhibition. The specific contribution of different subtypes of interneurons to cortical inhibition is still largely unknown, and is likely to strongly depend on the activity pattern of the network. An important open question is whether specific subtypes of interneurons have unique functional roles in cortical processing. Through the recruitment of interneurons via feedforward and/or feedback excitatory projections, inhibition generated in cortical networks is somehow proportional to local and/or incoming excitation. This proportionality has been observed in several sensory cortical regions where changes in the intensity or other features of a sensory stimulus lead to concomitant changes in the strength of both cortical excitation and inhibition (Figure 2A ; Anderson et al., 2000Anderson J.S. Carandini M. Ferster D. Orientation tuning of input conductance, excitation, and inhibition in cat primary visual cortex.J. Neurophysiol. 2000; 84: 909-926PubMed Google Scholar, Poo and Isaacson, 2009Poo C. Isaacson J.S. Odor representations in olfactory cortex: “sparse” coding, global inhibition, and oscillations.Neuron. 2009; 62: 850-861Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar, Wehr and Zador, 2003Wehr M. Zador A.M. Balanced inhibition underlies tuning and sharpens spike timing in auditory cortex.Nature. 2003; 426: 442-446Crossref PubMed Scopus (511) Google Scholar, Wilent and Contreras, 2004Wilent W.B. Contreras D. Synaptic responses to whisker deflections in rat barrel cortex as a function of cortical layer and stimulus intensity.J. Neurosci. 2004; 24: 3985-3998Crossref PubMed Scopus (78) Google Scholar, Zhang et al., 2003Zhang L.I. Tan A.Y. Schreiner C.E. Merzenich M.M. Topography and synaptic shaping of direction selectivity in primary auditory cortex.Nature. 2003; 424: 201-205Crossref PubMed Scopus (213) Google Scholar). In addition, during spontaneous cortical activity, increases in excitation are invariably accompanied by increases in inhibition (Figure 2B; Atallah and Scanziani, 2009Atallah B.V. Scanziani M. Instantaneous modulation of gamma oscillation frequency by balancing excitation with inhibition.Neuron. 2009; 62: 566-577Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar, Haider et al., 2006Haider B. Duque A. Hasenstaub A.R. McCormick D.A. Neocortical network activity in vivo is generated through a dynamic balance of excitation and inhibition.J. Neurosci. 2006; 26: 4535-4545Crossref PubMed Scopus (311) Google Scholar, Okun and Lampl, 2008Okun M. Lampl I. Instantaneous correlation of excitation and inhibition during ongoing and sensory-evoked activities.Nat. Neurosci. 2008; 11: 535-537Crossref PubMed Scopus (150) Google Scholar). Furthermore, acute experimental manipulations selectively decreasing either inhibition or excitation shift cortical activity to a hyperexcitable (epileptiform) or silent (comatose) state (Dudek and Sutula, 2007Dudek F.E. Sutula T.P. Epileptogenesis in the dentate gyrus: a critical perspective.Prog. Brain Res. 2007; 163: 755-773Crossref PubMed Scopus (118) Google Scholar). Thus, not only does excitation and inhibition increase and decrease together during physiological cortical activity (van Vreeswijk and Sompolinsky, 1996van Vreeswijk C. Sompolinsky H. Chaos in neuronal networks with balanced excitatory and inhibitory activity.Science. 1996; 274: 1724-1726Crossref PubMed Scopus (519) Google Scholar), but interference of this relationship appears to be highly disruptive. Highlighting the importance of a proper relationship between excitation and inhibition is the fact that changes in the weight of excitation or inhibition are accompanied by compensatory effects that preserve the excitability of cortical networks (Turrigiano, 2011Turrigiano G. Too many cooks? Intrinsic and synaptic homeostatic mechanisms in cortical circuit refinement.Annu. Rev. Neurosci. 2011; 34: 89-103Crossref PubMed Scopus (134) Google Scholar). These observations have led to the concept that the two opposing synaptic conductances balance each other out and that this balance is important for proper cortical function. “Balance” is a useful concept as it qualitatively captures some important properties of excitation and inhibition in the cortex, like the overall proportionality mentioned above and the fact that manipulating one conductance without the other can shift cortical activity to unphysiological extremes. However, it is also misleading if taken too literarily: first, it should not be understood as excitatory and inhibitory conductances being equal, i.e., canceling each other out. Excitation and inhibition are differentially distributed along the soma, dendrites and axon initial segment of neurons and thus their exact ratio is highly dependent on where it is measured. Furthermore, the concept of balance may lead to the naive view that the main role of cortical inhibition is to prevent epileptiform activity, a notion that is clearly too simplistic. Finally, and most important, despite the overall proportionality of excitation and inhibition, their exact ratio is highly dynamic, as will be detailed below. Cortical transmission is largely mediated by ionotropic neurotransmitter receptors that produce fast (<10 ms) synaptic conductances. Glutamate elicits fast excitation via the activation of cation permeable AMPA and NMDA receptor-mediated conductances, while GABA evokes fast inhibition via anion (Cl− and HCO3−) permeable GABAA receptor-mediated conductances. The possibility of varying the ratio between synaptic excitation and inhibition allows for the shifting of the membrane potential of a neuron toward any arbitrary value in-between the reversal potential of synaptic excitation (around 0 mV for AMPA and NMDA receptors) and synaptic inhibition (typically around −70 to −80 mV for GABAA receptors). Thus, by changing the ratio between synaptic excitation and inhibition, neuronal membranes can be rapidly brought to threshold for action-potential generation, just near threshold or far below threshold in a matter of a few milliseconds (Figure 3A ; Higley and Contreras, 2006Higley M.J. Contreras D. Balanced excitation and inhibition determine spike timing during frequency adaptation.J. Neurosci. 2006; 26: 448-457Crossref PubMed Scopus (123) Google Scholar). Furthermore, even a specific ratio between excitation and inhibition can lead to different membrane potentials depending on the absolute magnitude of the two opposing conductances. In fact, since synaptic excitation and inhibition are not the only conductances of a neuron, their contribution to the membrane potential will depend on their magnitude relative to other conductances. Accordingly, the larger their magnitude, the closer the membrane potential of the neuron will approach the equilibrium potential set by the combination of synaptic excitation and inhibition. Finally, because the impact on membrane potential of any current flowing through the membrane is affected in a divisive manner by the conductance of the membrane (Ohm's law), the activation of GABAA receptors, simply by increasing the conductance, can significantly reduce the excitability of a neuron, an effect referred to as “shunting inhibition.” This might represent the major inhibitory effect of GABAA receptor activation in those specific cases in which the resting membrane potential is equal to or even more negative than the reversal potential of GABAA receptor-mediated currents. In other words, activation of GABAA receptors may not change the membrane potential or even generate a depolarization and still reduce neuronal excitability. Membrane pumps, by setting intracellular Cl− concentration, play a critical role in regulating the reversal potential of GABAA receptor-mediated currents (Blaesse et al., 2009Blaesse P. Airaksinen M.S. Rivera C. Kaila K. Cation-chloride cotransporters and neuronal function.Neuron. 2009; 61: 820-838Abstract Full Text Full Text PDF PubMed Scopus (279) Google Scholar). In certain instances, for example in immature neurons (Ben-Ari et al., 2007Ben-Ari Y. Gaiarsa J.L. Tyzio R. Khazipov R. GABA: a pioneer transmitter that excites immature neurons and generates primitive oscillations.Physiol. Rev. 2007; 87: 1215-1284Crossref PubMed Scopus (465) Google Scholar) or in specialized neuronal compartments (Gulledge and Stuart, 2003Gulledge A.T. Stuart G.J. Excitatory actions of GABA in the cortex.Neuron. 2003; 37: 299-309Abstract Full Text Full Text PDF PubMed Scopus (226) Google Scholar, Szabadics et al., 2006Szabadics J. Varga C. Molnár G. Oláh S. Barzó P. Tamás G. Excitatory effect of GABAergic axo-axonic cells in cortical microcircuits.Science. 2006; 311: 233-235Crossref PubMed Scopus (272) Google Scholar, Woodruff et al., 2009Woodruff A. Xu Q. Anderson S.A. Yuste R. Depolarizing effect of neocortical chandelier neurons.Front. Neural Circuits. 2009; 3: 15Crossref PubMed Scopus (64) Google Scholar), the reversal potential for Cl− is so depolarized that it may lead to an excitatory action of GABAA receptors. Although intriguing, still too little is known about how excitatory actions of GABA might impact processing in adult cortex to be discussed here. In addition to fast GABAA receptor-mediated conductances, GABA activates G protein-coupled GABAB receptors that cause slow (100–500 ms) postsynaptic inhibition by opening inwardly rectifying K+ (GIRK) channels (Lüscher et al., 1997Lüscher C. Jan L.Y. Stoffel M. Malenka R.C. Nicoll R.A. G protein-coupled inwardly rectifying K+ channels (GIRKs) mediate postsynaptic but not presynaptic transmitter actions in hippocampal neurons.Neuron. 1997; 19: 687-695Abstract Full Text Full Text PDF PubMed Scopus (396) Google Scholar). It has been suggested that synaptically released GABA from a large number of coactive interneurons must be pooled or accumulated to activate GABAB receptors (Isaacson et al., 1993Isaacson J.S. Solís J.M. Nicoll R.A. Local and diffuse synaptic actions of GABA in the hippocampus.Neuron. 1993; 10: 165-175Abstract Full Text PDF PubMed Scopus (442) Google Scholar, Scanziani, 2000Scanziani M. GABA spillover activates postsynaptic GABA(B) receptors to control rhythmic hippocampal activity.Neuron. 2000; 25: 673-681Abstract Full Text Full Text PDF PubMed Google Scholar). Postsynaptic GABAB receptors also inhibit voltage-gated calcium channels, thereby, for example, reducing dendritic excitability (Pérez-Garci et al., 2006Pérez-Garci E. Gassmann M. Bettler B. Larkum M.E. The GABAB1b isoform mediates long-lasting inhibition of dendritic Ca2+ spikes in layer 5 somatosensory pyramidal neurons.Neuron. 2006; 50: 603-616Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar). Furthermore, GABAB receptors are present on both glutamatergic and GABAergic nerve terminals where their activation causes presynaptic inhibition of transmitter release (Bowery, 1993Bowery N.G. GABAB receptor pharmacology.Annu. Rev. Pharmacol. Toxicol. 1993; 33: 109-147Crossref PubMed Google Scholar). Curiously, while inhibitory actions of GABAB receptors have been well characterized in brain slices, few in vivo studies have probed the role of slow GABAB receptor mediated transmission in cortical function. Although transgenic mice lacking functional GABAB receptors are prone to spontaneous epileptic seizures (Schuler et al., 2001Schuler V. Lüscher C. Blanchet C. Klix N. Sansig G. Klebs K. Schmutz M. Heid J. Gentry C. Urban L. et al.Epilepsy, hyperalgesia, impaired memory, and loss of pre- and postsynaptic GABA(B) responses in mice lacking GABA(B(1)).Neuron. 2001; 31: 47-58Abstract Full Text Full Text PDF PubMed Scopus (304) Google Scholar), the contribution of GABAB receptor signaling to spontaneous or sensory-evoked cortical activity is unclear. Within individual neurons the ratio between incoming excitation and inhibition can change rapidly, on a millisecond basis. In principal neurons of the auditory cortex, for example, brief tones lead to an increase in synaptic excitation that is followed within a couple of milliseconds by a surge in inhibition (Wehr and Zador, 2003Wehr M. Zador A.M. Balanced inhibition underlies tuning and sharpens spike timing in auditory cortex.Nature. 2003; 426: 442-446Crossref PubMed Scopus (511) Google Scholar, Wu et al., 2008Wu G.K. Arbuckle R. Liu B.H. Tao H.W. Zhang L.I. Lateral sharpening of cortical frequency tuning by approximately balanced inhibition.Neuron. 2008; 58: 132-143Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar). Similarly, whisker deflections lead to a rapid sequence of excitation followed by inhibition in neurons of the somatosensory “barrel” cortex (Figure 3A; Swadlow, 2002Swadlow H.A. Thalamocortical control of feed-forward inhibition in awake somatosensory ‘barrel’ cortex.Philos. Trans. R. Soc. Lond. B Biol. Sci. 2002; 357: 1717-1727Crossref PubMed Scopus (48) Google Scholar, Wilent and Contreras, 2005Wilent W.B. Contreras D. Dynamics of excitation and inhibition underlying stimulus selectivity in rat somatosensory cortex.Nat. Neurosci. 2005; 8: 1364-1370Crossref PubMed Scopus (135) Google Scholar). Also in the visual cortex, visual stimulation with a light flash triggers excitatory and inhibitory conductances that are staggered by a few milliseconds (Liu et al., 2010Liu B.H. Li P. Sun Y.J. Li Y.T. Zhang L.I. Tao H.W. Intervening inhibition underlies simple-cell receptive field structure in visual cortex.Nat. Neurosci. 2010; 13: 89-96Crossref PubMed Scopus (39) Google Scholar). Hence, in these cortical areas, in response to impulse-like sensory stimuli, the ratio between excitation and inhibition is initially tilted toward excitation, and subsequently shifts toward inhibition. These rapid changes in the ratio between excitation and inhibition can have important consequences in tuning cortical neurons to specific stimuli and in shaping their activity pattern in time (see below). Both feedforward and feedback inhibitory circuits can generate these rapid sequences of excitation and inhibition. In feedforward circuits, since afferent inputs contact both principal cells and interneurons, the onset of excitation recorded
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