Portal de Periódicos da CAPES

Neuronal Dynamics and Neuropsychiatric Disorders: Toward a Translational Paradigm for Dysfunctional Large-Scale Networks

2012; Cell Press; Volume: 75; Issue: 6 Linguagem: Inglês

10.1016/j.neuron.2012.09.004

1097-4199

Peter J. Uhlhaas, Wolf Singer,

Neuroscience and Neuropharmacology Research

In recent years, numerous studies have tested the relevance of neural oscillations in neuropsychiatric conditions, highlighting the potential role of changes in temporal coordination as a pathophysiological mechanism in brain disorders. In the current review, we provide an update on this hypothesis because of the growing evidence that temporal coordination is essential for the context and goal-dependent, dynamic formation of large-scale cortical networks. We shall focus on issues that we consider particularly promising for a translational research program aimed at furthering our understanding of the origins of neuropsychiatric disorders and the development of effective therapies. We will focus on schizophrenia and autism spectrum disorders (ASDs) to highlight important issues and challenges for the implementation of such an approach. Specifically, we will argue that deficits in temporal coordination lead to a disruption of functional large-scale networks, which in turn can account for several specific dysfunctions associated with these disorders. In recent years, numerous studies have tested the relevance of neural oscillations in neuropsychiatric conditions, highlighting the potential role of changes in temporal coordination as a pathophysiological mechanism in brain disorders. In the current review, we provide an update on this hypothesis because of the growing evidence that temporal coordination is essential for the context and goal-dependent, dynamic formation of large-scale cortical networks. We shall focus on issues that we consider particularly promising for a translational research program aimed at furthering our understanding of the origins of neuropsychiatric disorders and the development of effective therapies. We will focus on schizophrenia and autism spectrum disorders (ASDs) to highlight important issues and challenges for the implementation of such an approach. Specifically, we will argue that deficits in temporal coordination lead to a disruption of functional large-scale networks, which in turn can account for several specific dysfunctions associated with these disorders. The understanding of the origins of neuropsychiatric disorders, such as schizophrenia, affective disorders (depression and bipolar disorder), Alzheimer’s disease (AD), and autism spectrum disorders (ASDs), represents one of the most urgent and challenging areas of current scientific enquiry. In Europe alone, 38% of the general population fall into one of these categories, thus creating an enormous need for medical and psychosocial intervention (Wittchen et al., 2011Wittchen H.U. Jacobi F. Rehm J. Gustavsson A. Svensson M. Jönsson B. Olesen J. Allgulander C. Alonso J. Faravelli C. et al.The size and burden of mental disorders and other disorders of the brain in Europe 2010.Eur. Neuropsychopharmacol. 2011; 21: 655-679Abstract Full Text Full Text PDF PubMed Scopus (455) Google Scholar). Globally, disorders affecting the central nervous system constitute 13% of the total burden of disease (Collins et al., 2011Collins P.Y. Patel V. Joestl S.S. March D. Insel T.R. Daar A.S. Anderson W. Dhansay M.A. Phillips A. Shurin S. et al.Scientific Advisory Board and the Executive Committee of the Grand Challenges on Global Mental HealthGrand challenges in global mental health.Nature. 2011; 475: 27-30Crossref PubMed Scopus (303) Google Scholar). Despite the prevalence of neuropsychiatric disorders and the rapid advances in the basic neurosciences, there is only little progress in understanding the pathophysiology and the development of effective therapies. In schizophrenia, for example, recent studies have shown that since the introduction of second-generation antipsychotics, treatment efficacy has only marginally improved over traditional dopamine D-2 antagonists, which were introduced 50 years ago (Lieberman et al., 2005Lieberman J.A. Stroup T.S. McEvoy J.P. Swartz M.S. Rosenheck R.A. Perkins D.O. Keefe R.S. Davis S.M. Davis C.E. Lebowitz B.D. et al.Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) InvestigatorsEffectiveness of antipsychotic drugs in patients with chronic schizophrenia.N. Engl. J. Med. 2005; 353: 1209-1223Crossref PubMed Scopus (3144) Google Scholar). Moreover, recent studies have raised the possibility that chronic antipsychotic treatment could be associated with loss of brain tissue (Ho et al., 2011Ho B.C. Andreasen N.C. Ziebell S. Pierson R. Magnotta V. Long-term antipsychotic treatment and brain volumes: a longitudinal study of first-episode schizophrenia.Arch. Gen. Psychiatry. 2011; 68: 128-137Crossref PubMed Scopus (239) Google Scholar). As a result, schizophrenia largely remains a chronic and debilitating condition which in up to 80% of cases leads to lifelong social and occupational impairments with an average reduced life expectancy of ∼20 years due to medical complications (Tiihonen et al., 2009Tiihonen J. Lönnqvist J. Wahlbeck K. Klaukka T. Niskanen L. Tanskanen A. Haukka J. 11-year follow-up of mortality in patients with schizophrenia: a population-based cohort study (FIN11 study).Lancet. 2009; 374: 620-627Abstract Full Text Full Text PDF PubMed Scopus (384) Google Scholar). These data clearly highlight the need to reconsider approaches toward studying and treating mental disorders in order to improve therapies and outcome and eventually provide tools aimed at prevention of disorders. Strategies for the identification and development of new drugs have so far relied essentially on serendipitous discovery, which is then followed by clinical testing. Over the last decade, however, we have witnessed a paradigm shift that emphasizes the importance of applying findings from the basic sciences to formulate and test hypotheses on disease mechanisms. Insel, 2009Insel T.R. Translating scientific opportunity into public health impact: a strategic plan for research on mental illness.Arch. Gen. Psychiatry. 2009; 66: 128-133Crossref PubMed Scopus (174) Google Scholar, for example, has advocated a “reverse translational” paradigm that involves identification of risk genes and then to study in transgenic animals whether and how the abnormal gene patterns alter brain development and function (Figure 1). For a number of reasons, we believe that this approach needs to be complemented by the development of a paradigm, which stresses the importance of neuronal dynamics and temporal coding. This is because novel measures of the brain’s structural and functional organization have highlighted the fact that cognitive and executive functions emerge from the coordinated activity of large-scale networks that are dynamically configured on the backbone of the fixed anatomical connections. The brain’s connectome has small-world properties (Bullmore and Sporns, 2009Bullmore E. Sporns O. Complex brain networks: graph theoretical analysis of structural and functional systems.Nat. Rev. Neurosci. 2009; 10: 186-198Crossref PubMed Scopus (1694) Google Scholar), which implies that even neuronal groups distributed across distant cortical areas can communicate with one another either directly or via only a small number of intervening nodes. The hypothesis that we would like to propose is that the formation of functional networks requires dynamic routing and coordination and that this is achieved by modulating the degree of coherence among the temporally structured responses of widely distributed neurons. If these dynamics are disrupted, according to the hypothesis, pathological states emerge that give rise to neuropsychiatric syndromes. In this review, we shall therefore focus on recently obtained evidence supporting the possibility that disturbances in the temporal dynamics in large-scale networks might be causally involved in neuropsychiatric disorders, such as schizophrenia and ASD. In addition, we summarize evidence that emphasizes the strong dependence of temporal variables, such as oscillations and synchrony, on the subtle balance between excitation and inhibition (E/I balance). Moreover, we will highlight other likely causes for abnormal neural dynamics, such as developmental modifications of circuitry and transmitter systems, and provide recommendations for the design of novel treatments. Until recently, efforts to understand the neural basis of cognitive processes have focused on the analysis of individual brain regions and circuits. This paradigm has been highly successful but failed to address several central issues, such as the putative importance of interactions between distributed neuronal ensembles and the role of large-scale temporal coordination in cognitive and executive processes. Beginning with the discovery of stimulus- and context-dependent changes in neural synchrony (Gray et al., 1989Gray C.M. König P. Engel A.K. Singer W. Oscillatory responses in cat visual cortex exhibit inter-columnar synchronization which reflects global stimulus properties.Nature. 1989; 338: 334-337Crossref PubMed Google Scholar), evidence has been accumulated suggesting that the brain is a self-organizing complex system in which numerous, densely interconnected but functionally specialized areas cooperate in ever-changing, context- and task-dependent constellations. One reflection of such dynamic interactions are changes in the coherence of oscillatory activity in different frequency bands. Evidence obtained over the last two decades suggests that the precise synchronization of neural responses serves the dynamic coordination of distributed neural responses in both local and extended networks and is related to a wide range of cognitive and executive processes (Buzsáki and Draguhn, 2004Buzsáki G. Draguhn A. Neuronal oscillations in cortical networks.Science. 2004; 304: 1926-1929Crossref PubMed Scopus (1484) Google Scholar; Uhlhaas et al., 2009aUhlhaas P.J. Pipa G. Lima B. Melloni L. Neuenschwander S. Nikolić D. Singer W. Neural synchrony in cortical networks: history, concept and current status.Front Integr Neurosci. 2009; 3: 17Crossref PubMed Scopus (190) Google Scholar; Varela et al., 2001Varela F. Lachaux J.P. Rodriguez E. Martinerie J. The brainweb: phase synchronization and large-scale integration.Nat. Rev. Neurosci. 2001; 2: 229-239Crossref PubMed Scopus (1825) Google Scholar). Important and distinct variables of these dynamic processes are the power and frequency of oscillatory activity in local circuits and the long-range synchronization of these temporally structured activities across brain areas (Varela et al., 2001Varela F. Lachaux J.P. Rodriguez E. Martinerie J. The brainweb: phase synchronization and large-scale integration.Nat. Rev. Neurosci. 2001; 2: 229-239Crossref PubMed Scopus (1825) Google Scholar). Engel and colleagues (Siegel et al., 2012Siegel M. Donner T.H. Engel A.K. Spectral fingerprints of large-scale neuronal interactions.Nat. Rev. Neurosci. 2012; 13: 121-134PubMed Google Scholar) have proposed that local oscillatory processes, in particular at gamma-band frequencies, serve the generic cortical computations underlying local encoding of information while long-range synchronization in various frequency bands serves the effective coupling between more remote brain regions (Fries, 2005Fries P. A mechanism for cognitive dynamics: neuronal communication through neuronal coherence.Trends Cogn. Sci. 2005; 9: 474-480Abstract Full Text Full Text PDF PubMed Scopus (908) Google Scholar). Previous theoretical and empirical studies have indeed shown that functional interactions between brain regions are particularly crucial for cognitive processes and can occur in the absence of changes in local activity parameters, such as discharge rate and oscillation amplitude (Hipp et al., 2011Hipp J.F. Engel A.K. Siegel M. Oscillatory synchronization in large-scale cortical networks predicts perception.Neuron. 2011; 69: 387-396Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar; Lima et al., 2011Lima B. Singer W. Neuenschwander S. Gamma responses correlate with temporal expectation in monkey primary visual cortex.J. Neurosci. 2011; 31: 15919-15931Crossref PubMed Scopus (22) Google Scholar). Recent advances in EEG and MEG approaches have now allowed the noninvasive mapping of changes in the large-scale networks during perceptual and higher cognitive processes (Figure 2). Support for the distinction between local oscillatory versus long-range synchronization processes comes from studies that have examined the frequencies at which neuronal ensembles oscillate. Local processes tend to be associated with increased oscillations at gamma-band frequencies (25–200 Hz) while long-range interactions tend to involve a larger spectrum of frequency bands comprising theta (4–7 Hz), alpha (8–12 Hz), and beta (13–25 Hz) frequencies (von Stein and Sarnthein, 2000von Stein A. Sarnthein J. Different frequencies for different scales of cortical integration: from local gamma to long range alpha/theta synchronization.Int. J. Psychophysiol. 2000; 38: 301-313Crossref PubMed Scopus (547) Google Scholar). One reason could be that larger networks cannot support synchronization with very high temporal precision as a result of long conduction times. This is because lower frequencies put fewer constraints on the precision of timing since the phases of increased and reduced excitability are longer (Kopell et al., 2000Kopell N. Ermentrout G.B. Whittington M.A. Traub R.D. Gamma rhythms and beta rhythms have different synchronization properties.Proc. Natl. Acad. Sci. USA. 2000; 97: 1867-1872Crossref PubMed Scopus (430) Google Scholar). Recent theoretical (Vicente et al., 2008Vicente R. Gollo L.L. Mirasso C.R. Fischer I. Pipa G. Dynamical relaying can yield zero time lag neuronal synchrony despite long conduction delays.Proc. Natl. Acad. Sci. USA. 2008; 105: 17157-17162Crossref PubMed Scopus (113) Google Scholar) and empirical work (Buschman and Miller, 2007Buschman T.J. Miller E.K. Top-down versus bottom-up control of attention in the prefrontal and posterior parietal cortices.Science. 2007; 315: 1860-1862Crossref PubMed Scopus (621) Google Scholar), however, indicates that long-range synchronization can also occur at substantially higher frequencies (>30 Hz) and that even zero phase-lag synchronization is compatible with conduction delays. It is therefore conceivable that the nesting of local high-frequency oscillations in more global, lower-frequency oscillations serves the binding of local processes into more integrated global assemblies. This possibility is supported by the growing evidence on the existence of cross-frequency coupling, the amplitude, frequency or phase of high-frequency oscillations being modulated by slower oscillatory processes (Canolty et al., 2006Canolty R.T. Edwards E. Dalal S.S. Soltani M. Nagarajan S.S. Kirsch H.E. Berger M.S. Barbaro N.M. Knight R.T. High gamma power is phase-locked to theta oscillations in human neocortex.Science. 2006; 313: 1626-1628Crossref PubMed Scopus (670) Google Scholar; Canolty and Knight, 2010Canolty R.T. Knight R.T. The functional role of cross-frequency coupling.Trends Cogn. Sci. 2010; 14: 506-515Abstract Full Text Full Text PDF PubMed Scopus (209) Google Scholar; Jensen and Colgin, 2007Jensen O. Colgin L.L. Cross-frequency coupling between neuronal oscillations.Trends Cogn. Sci. 2007; 11: 267-269Abstract Full Text Full Text PDF PubMed Scopus (206) Google Scholar; Palva et al., 2005Palva J.M. Palva S. Kaila K. Phase synchrony among neuronal oscillations in the human cortex.J. Neurosci. 2005; 25: 3962-3972Crossref PubMed Scopus (244) Google Scholar). Neuron clusters can participate in several networks oscillating at different frequencies by engaging in partial coherence with both of them. This concatenation of rhythms has been observed in the hippocampus for gamma- and theta-band oscillations (Wang and Buzsáki, 1996Wang X.J. Buzsáki G. Gamma oscillation by synaptic inhibition in a hippocampal interneuronal network model.J. Neurosci. 1996; 16: 6402-6413PubMed Google Scholar), between different cortical laminae (Roopun et al., 2008Roopun A.K. Kramer M.A. Carracedo L.M. Kaiser M. Davies C.H. Traub R.D. Kopell N.J. Whittington M.A. Period concatenation underlies interactions between gamma and beta rhythms in neocortex.Front Cell Neurosci. 2008; 2: 1Crossref PubMed Scopus (45) Google Scholar) and for both low- and high-frequency activity (Canolty et al., 2006Canolty R.T. Edwards E. Dalal S.S. Soltani M. Nagarajan S.S. Kirsch H.E. Berger M.S. Barbaro N.M. Knight R.T. High gamma power is phase-locked to theta oscillations in human neocortex.Science. 2006; 313: 1626-1628Crossref PubMed Scopus (670) Google Scholar; Jensen and Colgin, 2007Jensen O. Colgin L.L. Cross-frequency coupling between neuronal oscillations.Trends Cogn. Sci. 2007; 11: 267-269Abstract Full Text Full Text PDF PubMed Scopus (206) Google Scholar; Palva et al., 2005Palva J.M. Palva S. Kaila K. Phase synchrony among neuronal oscillations in the human cortex.J. Neurosci. 2005; 25: 3962-3972Crossref PubMed Scopus (244) Google Scholar). Much work has been devoted to the analysis of synaptic mechanisms and circuits that support the generation of oscillatory activity and its synchronization over short and long distances, respectively, which makes it possible to relate abnormalities of these dynamic phenomena to specific neuronal processes (Sohal et al., 2009Sohal V.S. Zhang F. Yizhar O. Deisseroth K. Parvalbumin neurons and gamma rhythms enhance cortical circuit performance.Nature. 2009; 459: 698-702Crossref PubMed Scopus (578) Google Scholar; Traub et al., 2004Traub R.D. Bibbig A. LeBeau F.E. Buhl E.H. Whittington M.A. Cellular mechanisms of neuronal population oscillations in the hippocampus in vitro.Annu. Rev. Neurosci. 2004; 27: 247-278Crossref PubMed Scopus (182) Google Scholar; Vicente et al., 2008Vicente R. Gollo L.L. Mirasso C.R. Fischer I. Pipa G. Dynamical relaying can yield zero time lag neuronal synchrony despite long conduction delays.Proc. Natl. Acad. Sci. USA. 2008; 105: 17157-17162Crossref PubMed Scopus (113) Google Scholar; Wang and Buzsáki, 1996Wang X.J. Buzsáki G. Gamma oscillation by synaptic inhibition in a hippocampal interneuronal network model.J. Neurosci. 1996; 16: 6402-6413PubMed Google Scholar). During an oscillation cycle, neurons pass through a phase of enhanced and a phase of reduced excitability. During the former, the depolarizing phase, neurons become increasingly sensitive to excitatory input and emit spikes. During the following hyperpolarizing phase, they are exposed to massive inhibition by synchronously bursting inhibitory interneurons, emit no spikes, and are little susceptible to excitatory inputs (Wang and Buzsáki, 1996Wang X.J. Buzsáki G. Gamma oscillation by synaptic inhibition in a hippocampal interneuronal network model.J. Neurosci. 1996; 16: 6402-6413PubMed Google Scholar; Whittington et al., 1995Whittington M.A. Traub R.D. Jefferys J.G. Synchronized oscillations in interneuron networks driven by metabotropic glutamate receptor activation.Nature. 1995; 373: 612-615Crossref PubMed Google Scholar). Thus, by adjusting oscillation frequency and phase of anatomically connected cell clusters, effective coupling between these clusters can be enhanced by assuring that the respective excitatory inputs are synchronized and arrive at the peak of susceptibility while coupling can be virtually abolished if phase relations among the oscillating clusters are such that excitatory volleys arrive during the phase of low susceptibility (Fries, 2005Fries P. A mechanism for cognitive dynamics: neuronal communication through neuronal coherence.Trends Cogn. Sci. 2005; 9: 474-480Abstract Full Text Full Text PDF PubMed Scopus (908) Google Scholar; Womelsdorf et al., 2007Womelsdorf T. Schoffelen J.M. Oostenveld R. Singer W. Desimone R. Engel A.K. Fries P. Modulation of neuronal interactions through neuronal synchronization.Science. 2007; 316: 1609-1612Crossref PubMed Scopus (439) Google Scholar). Experimental and theoretical evidence indicates that the networks of mutually interacting GABAergic interneurons are crucially involved as pacemakers in the generation of high-frequency oscillations in local circuits (Traub et al., 2004Traub R.D. Bibbig A. LeBeau F.E. Buhl E.H. Whittington M.A. Cellular mechanisms of neuronal population oscillations in the hippocampus in vitro.Annu. Rev. Neurosci. 2004; 27: 247-278Crossref PubMed Scopus (182) Google Scholar; Wang and Buzsáki, 1996Wang X.J. Buzsáki G. Gamma oscillation by synaptic inhibition in a hippocampal interneuronal network model.J. Neurosci. 1996; 16: 6402-6413PubMed Google Scholar). GABAergic interneurons, especially those expressing the calcium binding protein parvalbumin (PV), play a particularly important role in the generation of high-frequency oscillations because of their fast-spiking characteristics and the short time constants of synaptic interactions mediated by these cells (Bartos et al., 2007Bartos M. Vida I. Jonas P. Synaptic mechanisms of synchronized gamma oscillations in inhibitory interneuron networks.Nat. Rev. Neurosci. 2007; 8: 45-56Crossref PubMed Scopus (612) Google Scholar). In a landmark paper, Sohal et al., 2009Sohal V.S. Zhang F. Yizhar O. Deisseroth K. Parvalbumin neurons and gamma rhythms enhance cortical circuit performance.Nature. 2009; 459: 698-702Crossref PubMed Scopus (578) Google Scholar probed the influence of up- and downregulation of PV interneurons on gamma-band oscillations in mice. Inhibition of PV interneurons led to an immediate suppression of 30–80 Hz oscillations while 10–30 Hz oscillations increased in power. In contrast, increasing PV-interneuron-mediated feedback inhibition by boosting principal cell activity enhanced gamma-band power (Cardin et al., 2009Cardin J.A. Carlén M. Meletis K. Knoblich U. Zhang F. Deisseroth K. Tsai L.H. Moore C.I. Driving fast-spiking cells induces gamma rhythm and controls sensory responses.Nature. 2009; 459: 663-667Crossref PubMed Scopus (610) Google Scholar). Recent studies have also examined the specific role of glutamatergic inputs to PV interneurons for the generation of coordinated network activity. Carlén et al., 2012Carlén M. Meletis K. Siegle J.H. Cardin J.A. Futai K. Vierling-Claassen D. Ruhlmann C. Jones S.R. Deisseroth K. Sheng M. et al.A critical role for NMDA receptors in parvalbumin interneurons for gamma rhythm induction and behavior.Mol. Psychiatry. 2012; 17: 537-548Crossref PubMed Scopus (85) Google Scholar examined the effect of deleting NMDA NR1 receptors on PV interneurons applying an optogenetic approach. Mice with a reduced expression of NR1 subunits were characterized by increased spontaneous 36–44 Hz activity in somatosensory cortex compared to control animals while showing reduced gamma-band activity during sensory stimulation which was accompanied by dysfunctions in habituation, working memory, and associative learning. Optic stimulation of PV interneurons revealed diminished spike synchronization as well as increased spike latency and variance in spike timing. Similarly, Belforte et al., 2010Belforte J.E. Zsiros V. Sklar E.R. Jiang Z. Yu G. Li Y. Quinlan E.M. Nakazawa K. Postnatal NMDA receptor ablation in corticolimbic interneurons confers schizophrenia-like phenotypes.Nat. Neurosci. 2010; 13: 76-83Crossref PubMed Scopus (241) Google Scholar showed that NR1 deletion in GABAergic interneurons resulted in increased firing of pyramidal cells and reduced synchronization of neuronal responses in slices, suggesting that NMDA-receptor hypofunctioning is associated with impaired temporal coordination of neuronal activity. Further evidence that AMPA- and NMDA-receptor-mediated activation of PV interneurons is essential for the generation of oscillatory activity and its synchronization has been obtained in the hippocampus. Reduction of the GLuR-D receptor leads to a decrease of AMPA-mediated currents in PV interneurons and reduced power of oscillations in the 20–80 Hz range, which is accompanied by a deficit in working memory (Fuchs et al., 2007Fuchs E.C. Zivkovic A.R. Cunningham M.O. Middleton S. Lebeau F.E. Bannerman D.M. Rozov A. Whittington M.A. Traub R.D. Rawlins J.N. Monyer H. Recruitment of parvalbumin-positive interneurons determines hippocampal function and associated behavior.Neuron. 2007; 53: 591-604Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar). In addition, selective ablation of the NMDA NR1 subunit in PV interneurons is associated with a significant reduction of power, stability, and rhythmicity of theta oscillations and an enhancement of gamma oscillations in CA1 (Korotkova et al., 2010Korotkova T. Fuchs E.C. Ponomarenko A. von Engelhardt J. Monyer H. NMDA receptor ablation on parvalbumin-positive interneurons impairs hippocampal synchrony, spatial representations, and working memory.Neuron. 2010; 68: 557-569Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar). While the reciprocal connections between excitatory and inhibitory neurons determine the strength and duration of the oscillations and mediate local synchronization, long-range synchronization of spatially segregated cell groups has been attributed mainly to the action of excitatory pathways that target both excitatory and inhibitory neurons (Fuchs et al., 2001Fuchs E.C. Doheny H. Faulkner H. Caputi A. Traub R.D. Bibbig A. Kopell N. Whittington M.A. Monyer H. Genetically altered AMPA-type glutamate receptor kinetics in interneurons disrupt long-range synchrony of gamma oscillation.Proc. Natl. Acad. Sci. USA. 2001; 98: 3571-3576Crossref PubMed Scopus (51) Google Scholar; Kopell et al., 2000Kopell N. Ermentrout G.B. Whittington M.A. Traub R.D. Gamma rhythms and beta rhythms have different synchronization properties.Proc. Natl. Acad. Sci. USA. 2000; 97: 1867-1872Crossref PubMed Scopus (430) Google Scholar). Specifically, modeling and experimental evidence suggests that generation of long-range synchronization is dependent on AMPA-type glutamate receptor (Fuchs et al., 2001Fuchs E.C. Doheny H. Faulkner H. Caputi A. Traub R.D. Bibbig A. Kopell N. Whittington M.A. Monyer H. Genetically altered AMPA-type glutamate receptor kinetics in interneurons disrupt long-range synchrony of gamma oscillation.Proc. Natl. Acad. Sci. USA. 2001; 98: 3571-3576Crossref PubMed Scopus (51) Google Scholar). Another and probably very important substrate for interregional synchronization are long-range inhibitory projections that originate from GABAergic cells and terminate selectively on inhibitory interneurons in the respective target areas. Such long-range inhibitory projections have been shown between the basal forebrain and the cortical mantel (Manns et al., 2000Manns I.D. Alonso A. Jones B.E. Discharge properties of juxtacellularly labeled and immunohistochemically identified cholinergic basal forebrain neurons recorded in association with the electroencephalogram in anesthetized rats.J. Neurosci. 2000; 20: 1505-1518PubMed Google Scholar) between the two hemispheres (Buhl and Singer, 1989Buhl E.H. Singer W. The callosal projection in cat visual cortex as revealed by a combination of retrograde tracing and intracellular injection.Exp. Brain Res. 1989; 75: 470-476Crossref PubMed Google Scholar; Melzer et al., 2012Melzer S. Michael M. Caputi A. Eliava M. Fuchs E.C. Whittington M.A. Monyer H. Long-range-projecting GABAergic neurons modulate inhibition in hippocampus and entorhinal cortex.Science. 2012; 335: 1506-1510Crossref PubMed Scopus (50) Google Scholar), between septum and hippocampus (Jinno et al., 2007Jinno S. Klausberger T. Marton L.F. Dalezios Y. Roberts J.D. Fuentealba P. Bushong E.A. Henze D. Buzsáki G. Somogyi P. Neuronal diversity in GABAergic long-range projections from the hippocampus.J. Neurosci. 2007; 27: 8790-8804Crossref PubMed Scopus (95) Google Scholar), and between hippocampus and entorhinal cortex (Melzer et al., 2012Melzer S. Michael M. Caputi A. Eliava M. Fuchs E.C. Whittington M.A. Monyer H. Long-range-projecting GABAergic neurons modulate inhibition in hippocampus and entorhinal cortex.Science. 2012; 335: 1506-1510Crossref PubMed Scopus (50) Google Scholar). Given the pace-maker function of inhibitory networks, such direct coupling could provide a very efficient mechanism for the temporal coordination of distributed processes. In addition to GABAergic and glutamatergic circuit dynamics, modulatory systems play an important role in the gating of oscillations and synchrony. Thus, gamma oscillations and their synchronization depend critically on the activation of muscarinic acetylcholine receptors (Rodriguez et al., 2004Rodriguez R. Kallenbach U. Singer W. Munk M.H. Short- and long-term effects of cholinergic modulation on gamma oscillations and response synchronization in the visual cortex.J. Neurosci. 2004; 24: 10369-10378Crossref PubMed Scopus (127) Google Scholar). Evidence is also available that dopamine and 5-HT modulate the prevalence of oscillations in different frequency bands (Demiralp et al., 2007Demiralp T. Herrmann C.S. Erdal M.E. Ergenoglu T. Keskin Y.H. Ergen M. Beydagi H. DRD4 and DAT1 polymorphisms modulate human gamma band responses.Cereb. Cortex. 2007; 17: 1007-1019Crossref PubMed Scopus (58) Google Scholar; Dzirasa et al., 2009Dzirasa K. Ramsey A.J. Takahashi D.Y. Stapleton J. Potes J.M. Williams J.K. Gainetdinov R.R. Sameshima K. Caron M.G. Nicolelis M.A. Hyperdopaminergia and NMDA receptor hypofunction disrupt neural phase signaling.J. Neurosci. 2009; 29: 8215-8224Crossref PubMed Scopus (40) Google Scholar; Krause and Jia, 2005Krause M. Jia Y. Serotonergic modulation of carbachol-induced rhythmic activity in hippocampal slices.Neuropharmacology. 2005; 48: 381-390Crossref PubMed Scopus (17) Google Scholar; Wójtowicz et al., 2009Wójtowicz A.M. van den Boom L. Chakrabarty A. Maggio N. Haq R.U. Behrens C.J. Heinemann U. Monoamines block kainate- and carbachol-induced gamma-oscillations but augment stimulus-induced gamma-oscillations in rat hippocampus in vitro.Hi