Excitatory/Inhibitory Balance and Circuit Homeostasis in Autism Spectrum Disorders
2015; Cell Press; Volume: 87; Issue: 4 Linguagem: Inglês
10.1016/j.neuron.2015.07.033
ISSN1097-4199
Autores Tópico(s)Congenital heart defects research
ResumoAutism spectrum disorders (ASDs) and related neurological disorders are associated with mutations in many genes affecting the ratio between neuronal excitation and inhibition. However, understanding the impact of these mutations on network activity is complicated by the plasticity of these networks, making it difficult in many cases to separate initial deficits from homeostatic compensation. Here we explore the contrasting evidence for primary defects in inhibition or excitation in ASDs and attempt to integrate the findings in terms of the brain’s ability to maintain functional homeostasis. Autism spectrum disorders (ASDs) and related neurological disorders are associated with mutations in many genes affecting the ratio between neuronal excitation and inhibition. However, understanding the impact of these mutations on network activity is complicated by the plasticity of these networks, making it difficult in many cases to separate initial deficits from homeostatic compensation. Here we explore the contrasting evidence for primary defects in inhibition or excitation in ASDs and attempt to integrate the findings in terms of the brain’s ability to maintain functional homeostasis. Over 10 years ago, John Rubenstein and Michael Merzenich published an influential review (Rubenstein and Merzenich, 2003Rubenstein J.L. Merzenich M.M. Model of autism: increased ratio of excitation/inhibition in key neural systems.Genes Brain Behav. 2003; 2: 255-267Crossref PubMed Scopus (656) Google Scholar) suggesting that autism and related disorders might reflect an increase in the ratio between excitation and inhibition leading to hyper-excitability of cortical circuits. The theory was attractive because it provided a potential explanation for the frequent observation of reduced GABAergic signaling in the brains of autistics (Cellot and Cherubini, 2014Cellot G. Cherubini E. GABAergic signaling as therapeutic target for autism spectrum disorders.Front Pediatr. 2014; 2: 70Crossref Google Scholar), as well as their propensity to develop epilepsy. In addition, since inhibition was known or believed to contribute to sharpening the selectivity of excitatory responses in many brain areas, the loss of inhibition could lead to enhanced “noise” and imprecision in learning and cognition. Since this initial formulation, however, other studies have suggested a nearly opposite hypothesis; namely, that at least some Autism Spectrum Disorders (ASDs) are characterized by a reduction in the ratio between excitation and inhibition. In this Review, we first summarize some of the major lines of evidence supporting primary increases and decreases in the ratio of excitatory to inhibitory synaptic transmission in Autism and related disorders. We then argue that a homeostatic view of how activity propagates through cortical circuits predicts such contradictory findings and offers a framework for integrating them. It is important to acknowledge at the outset that the concept of a single “E/I balance” determining whether brain circuits are normal or “autistic” is obviously overly simplistic. This is true both because different microcircuits in different brain regions may be characterized by different mixtures of excitation and inhibition and because even within a single microcircuit different sources of excitation and inhibition affect different aspects of neuronal function and target distinct cellular compartments. For example, in sensory regions of neocortex, pyramidal neurons receive excitatory synaptic input from different sources on different portions of their dendritic trees (Petreanu et al., 2009Petreanu L. Mao T. Sternson S.M. Svoboda K. The subcellular organization of neocortical excitatory connections.Nature. 2009; 457: 1142-1145Crossref PubMed Scopus (277) Google Scholar). Here, as in the rest of the forebrain, specific populations of interneurons are specialized to regulate distinct subcellular compartments (Kepecs and Fishell, 2014Kepecs A. Fishell G. Interneuron cell types are fit to function.Nature. 2014; 505: 318-326Crossref PubMed Scopus (60) Google Scholar). Therefore, the ratio between excitation and inhibition may vary from one cellular component to another. There is a paucity of studies that have addressed the effects of autism-related mutations on these different components of excitatory and inhibitory transmission. Nor is it straightforward to define a single physiological measurement that accurately captures the balance between excitation and inhibition. One recent study measured both the excitatory and inhibitory evoked synaptic input to visual cortical pyramidal neurons and found that although total input varied between cells the ratio of excitatory and inhibitory input was constant (Xue et al., 2014Xue M. Atallah B.V. Scanziani M. Equalizing excitation-inhibition ratios across visual cortical neurons.Nature. 2014; 511: 596-600Crossref PubMed Scopus (24) Google Scholar). Furthermore, perturbing the activity of pyramidal neurons perturbed this balance specifically by changing the strength of perisomatic inhibition mediated by parvalbumin-postive inteurneurons. Despite the complexities of defining and measuring the excitatory/inhibitory ratio, we think there are good reasons that the concept continues to be an influential one in thinking about the misregulation of brain circuits in developmental disorders. Since many of the signaling molecules and activity-dependent processes that affect excitatory synapses (and some classes of inhibitory synapses) are conserved across multiple brain regions, it is not unreasonable to suppose the existence of genetic conditions that could initially affect a distributed set of glutamatergic or GABAergic synapses. In addition, although we are trying to identify pathophysiological threads linking diverse ASDs as well as other developmental disorders, it is clear that these disorders are highly heterogeneous and may have unique mechanisms and consequences. We focus primarily on monogenic syndromes, even though these represent only about 10% of ASDs, because the ability to model these syndromes in animals allows testing of specific hypotheses about circuit dysfunction. Autistic patients develop epilepsy at a rate up to 25 times that of the general population (Bolton et al., 2011Bolton P.F. Carcani-Rathwell I. Hutton J. Goode S. Howlin P. Rutter M. Epilepsy in autism: features and correlates.Br. J. Psychiatry. 2011; 198: 289-294Crossref PubMed Scopus (41) Google Scholar). Epilepsy is the medical disorder most commonly associated with Autism, occurring in up to one-third of affected individuals (Muhle et al., 2004Muhle R. Trentacoste S.V. Rapin I. The genetics of autism.Pediatrics. 2004; 113: e472-e486Crossref PubMed Google Scholar). The prevalence of epileptiform EEG without overt seizures is even higher. Although the association may vary as diagnostic criteria for ASDs are altered, even the exclusion of particular populations such as patients with Rett Syndrome, who have especially high rates of epilepsy (e.g., 70%), is unlikely to dramatically reduce the overall association (Gilby and O’Brien, 2013Gilby K.L. O’Brien T.J. Epilepsy, autism, and neurodevelopment: kindling a shared vulnerability?.Epilepsy Behav. 2013; 26: 370-374Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar). Given the enormous genetic and phenotypic heterogeneity of ASDs, it is perhaps not surprising that individual syndromes vary in the typical age range of onset of epilepsy relative to other aspects of the disorder (Table 1). Some genetic causes of ASDs are virtually invariably associated with early-onset epilepsy, and we hypothesize that these are more likely to reflect primary deficits in inhibition because of the lack of an asymptomatic period during which homeostatic compensation could develop. Rescue experiments showing the reversal of symptoms is the gold standard for establishing a causal impact. However, for developmental disorders that affect differentiation and cell migration, reversal could be difficult to achieve in an adult animal. In these cases, the etiology can be analyzed via modeling the disorder in a selective cellular subpopulation. This way, in a number of cases, the etiology can be traced rather directly to failures in the normal neurogenesis, migration, differentiation, and/or function of cortical interneurons. One of the defining examples of such a syndrome involves mutation in the transcription factor Aristaless (ARX) in which major subsets of forebrain interneurons fail to migrate into the cortex from the medial ganglionic eminence leading to profound and early-onset seizures and major disruptions of cognitive development (for review, see Shoubridge et al., 2010Shoubridge C. Fullston T. Gécz J. ARX spectrum disorders: making inroads into the molecular pathology.Hum. Mutat. 2010; 31: 889-900Crossref PubMed Scopus (65) Google Scholar). Knocking ARX out selectively in forebrain interneurons recapitulates many symptoms seen in human mutations (Marsh et al., 2009Marsh E. Fulp C. Gomez E. Nasrallah I. Minarcik J. Sudi J. Christian S.L. Mancini G. Labosky P. 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Med. 2012; 18: 156-163Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar Open table in a new tab Another syndrome in which severe childhood epilepsy is linked to autistic symptoms is Dravet’s Syndrome, usually caused by heterozygous loss of function of the sodium channel subunit Scn1a. Recent work indicates that knocking out one copy of the channel selectively in forebrain GABAergic neurons recapitulates all the major symptoms including seizures, hyperactivity, social dysfunction, anxiety, ataxia, and sleep disorders (Cheah et al., 2012Cheah C.S. Yu F.H. Westenbroek R.E. Kalume F.K. Oakley J.C. Potter G.B. Rubenstein J.L. Catterall W.A. Specific deletion of NaV1.1 sodium channels in inhibitory interneurons causes seizures and premature death in a mouse model of Dravet syndrome.Proc. Natl. Acad. Sci. USA. 2012; 109: 14646-14651Crossref PubMed Google Scholar, Han et al., 2012Han S. Tai C. Westenbroek R.E. Yu F.H. Cheah C.S. Potter G.B. Rubenstein J.L. Scheuer T. de la Iglesia H.O. Catterall W.A. Autistic-like behaviour in Scn1a+/- mice and rescue by enhanced GABA-mediated neurotransmission.Nature. 2012; 489: 385-390Crossref PubMed Scopus (105) Google Scholar, Ito et al., 2013Ito S. Ogiwara I. Yamada K. Miyamoto H. Hensch T.K. Osawa M. Yamakawa K. Mouse with Nav1.1 haploinsufficiency, a model for Dravet syndrome, exhibits lowered sociability and learning impairment.Neurobiol. Dis. 2013; 49: 29-40Crossref PubMed Scopus (16) Google Scholar, Tai et al., 2014Tai C. Abe Y. Westenbroek R.E. Scheuer T. Catterall W.A. Impaired excitability of somatostatin- and parvalbumin-expressing cortical interneurons in a mouse model of Dravet syndrome.Proc. Natl. Acad. Sci. USA. 2014; 111: E3139-E3148Crossref PubMed Scopus (6) Google Scholar). This appears to be a case in which a channelopathy produces an interneuronopathy since NaV1.1 (the protein product of Scn1a) is localized to the axon initial segments of parvalbumin positive (Pv+) fast-spiking and Somatostatin-positive (SST) interneurons in the neocortex and hippocampus, as well as to purkinje neurons of the cerebellum, which also exhibit fast-spiking behavior. Loss of function of one allele of Scn1a prevents sustained fast spiking (FS) in Pv+ neurons (Ogiwara et al., 2007Ogiwara I. Miyamoto H. Morita N. Atapour N. Mazaki E. Inoue I. Takeuchi T. Itohara S. Yanagawa Y. Obata K. et al.Nav1.1 localizes to axons of parvalbumin-positive inhibitory interneurons: a circuit basis for epileptic seizures in mice carrying an Scn1a gene mutation.J. Neurosci. 2007; 27: 5903-5914Crossref PubMed Scopus (264) Google Scholar) and decreases seizure threshold even when this manipulation is largely restricted to these neurons (Dutton et al., 2013Dutton S.B. Makinson C.D. Papale L.A. Shankar A. Balakrishnan B. Nakazawa K. Escayg A. Preferential inactivation of Scn1a in parvalbumin interneurons increases seizure susceptibility.Neurobiol. Dis. 2013; 49: 211-220Crossref PubMed Scopus (23) Google Scholar). Scn1a is only one of several sodium channel subunits that are upregulated in Pv+ FS interneurons during the period of development when they begin to exhibit fast-spiking behavior (Okaty et al., 2009Okaty B.W. Miller M.N. Sugino K. Hempel C.M. Nelson S.B. Transcriptional and electrophysiological maturation of neocortical fast-spiking GABAergic interneurons.J. Neurosci. 2009; 29: 7040-7052Crossref PubMed Scopus (100) Google Scholar) and several of these including scn1b, scn8a, and scn9a have also been associated with Dravet Syndrome itself (Scn1b), or with modifying Dravet Syndrome susceptibility (scn9a) or with other epilepsy syndromes (Meisler et al., 2010Meisler M.H. O’Brien J.E. Sharkey L.M. Sodium channel gene family: epilepsy mutations, gene interactions and modifier effects.J. Physiol. 2010; 588: 1841-1848Crossref PubMed Scopus (95) Google Scholar). It is important to point out that even the conditional mutants used to analyze Dravet’s Syndrome and Arx demonstrate only the sufficiency of the loss of function in specific inhibitory neurons to produce particular symptoms. It is not unlikely that for some symptoms of autistic patients with these mutations, alterations in other cells and circuits also contribute and indeed genetic background can influence cellular phenotypes of the haploinsufficiency in mice (Rubinstein et al., 2015Rubinstein M. Westenbroek R.E. Yu F.H. Jones C.J. Scheuer T. Catterall W.A. Genetic background modulates impaired excitability of inhibitory neurons in a mouse model of Dravet syndrome.Neurobiol. Dis. 2015; 73: 106-117Crossref PubMed Scopus (1) Google Scholar) and contributions of the haploinsufficiency in subsets of excitatory neurons modify the seizure phenotype without producing effects on their own (Ogiwara et al., 2013Ogiwara I. Iwasato T. Miyamoto H. Iwata R. Yamagata T. Mazaki E. Yanagawa Y. Tamamaki N. Hensch T.K. Itohara S. Yamakawa K. Nav1.1 haploinsufficiency in excitatory neurons ameliorates seizure-associated sudden death in a mouse model of Dravet syndrome.Hum. Mol. Genet. 2013; 22: 4784-4804Crossref PubMed Scopus (24) Google Scholar). Demonstrating that the mutation in specific forebrain inhibitory neurons is not only sufficient but also necessary would require selectively rescuing the behavioral phenotype by rescuing the effects of the mutation in those cells. Although genetic rescue experiments have not yet been performed, behavioral symptoms in a mouse model of Dravet’s syndrome are suppressed by pharmacological increase in GABAergic neurotransmission, pinning a deficit of inhibitory transmission as the cause of these symptoms (Han et al., 2012Han S. Tai C. Westenbroek R.E. Yu F.H. Cheah C.S. Potter G.B. Rubenstein J.L. Scheuer T. de la Iglesia H.O. Catterall W.A. Autistic-like behaviour in Scn1a+/- mice and rescue by enhanced GABA-mediated neurotransmission.Nature. 2012; 489: 385-390Crossref PubMed Scopus (105) Google Scholar). Another genetic disorder associated with seizures and autistic behaviors is Tuberous Sclerosis (TS), named for the presence of cortical malformations called tubers. The disorder is caused by mutations in Tsc1 (hamartin) and Tsc2 (tuberin), which together exist in a complex that inhibits mTOR (mammalian target of rapamycin) signaling, thereby regulating translational machinery and growth in many tissues. Epilepsy is present in the vast majority of patients and ∼20%–60% of TS patients meet diagnostic criteria for autism (Numis et al., 2011Numis A.L. Major P. Montenegro M.A. Muzykewicz D.A. Pulsifer M.B. Thiele E.A. Identification of risk factors for autism spectrum disorders in tuberous sclerosis complex.Neurology. 2011; 76: 981-987Crossref PubMed Scopus (62) Google Scholar). The pathophysiology of this disorder is still far from clear. For example, although tubers have long been suspected to be the source of epileptic activity and are still removed surgically in TS patients with intractable epilepsy, a number of mouse models of the disorder present with spontaneous seizures but lack tubers (Goorden et al., 2007Goorden S.M.I. van Woerden G.M. van der Weerd L. Cheadle J.P. Elgersma Y. Cognitive deficits in Tsc1+/- mice in the absence of cerebral lesions and seizures.Ann. Neurol. 2007; 62: 648-655Crossref PubMed Scopus (103) Google Scholar, Lozovaya et al., 2014Lozovaya N. Gataullina S. 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Tuberous sclerosis and epilepsy: role of astrocytes.Glia. 2012; 60: 1244-1250Crossref PubMed Scopus (4) Google Scholar), as does deletion in forebrain excitatory neurons, suggesting multiple potential pathways for generating seizures from loss of function of the TS complex. One recent study performed detailed physiological analyses following sparse cre-mediated deletion of a conditional Tsc1 allele in hippocampal neurons. Bateup and colleagues (Bateup et al., 2013Bateup H.S. Johnson C.A. Denefrio C.L. Saulnier J.L. Kornacker K. Sabatini B.L. Excitatory/inhibitory synaptic imbalance leads to hippocampal hyperexcitability in mouse models of tuberous sclerosis.Neuron. 2013; 78: 510-522Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar) concluded that the primary, cell-autonomous deficit was a reduction in inhibitory input to pyramidal neurons. In addition to cell-autonomous postsynaptic effects (presumed to be on GABA receptors), reduced presynaptic release was also seen with more widespread deletion of Tsc1. Effects on neuronal excitability and on excitatory synapses were also present but were in the wrong direction to produce circuit hyperexcitability and were instead presumed to reflect homeostatic responses of the circuit to abnormal activity. Although this study demonstrated critical effects of deleting Tsc1 in pyramidal neurons and largely ruled out a contribution to the observed results from loss of mTOR signaling in interneurons, another study recently demonstrated increased mortality and decreased seizure threshold in mice in which Tsc1 was selectively deleted from interneuron progenitors using a Dlx5/6 cre driver strain (Fu et al., 2012Fu C. Cawthon B. Clinkscales W. Bruce A. Winzenburger P. Ess K.C. GABAergic interneuron development and function is modulated by the Tsc1 gene.Cereb. Cortex. 2012; 22: 2111-2119Crossref PubMed Scopus (26) Google Scholar). Studies reporting positive effects of deleting Tsc1 in inhibitory neurons and glia highlight the difficulty of teasing apart primary from secondary effects and raise the possibility that disruption of core biological pathways, like the mTOR pathway, can lead to multiple primary effects in different cell types. The approach of cell-type-specific deletion can help clarify this situation. For example, the Bateup et al. study above reversed earlier conclusions from the same group that the network hyperexcitability was due to a primary deficit in LTD and a corresponding enhancement of excitatory synaptic transmission (Bateup et al., 2011Bateup H.S. Takasaki K.T. Saulnier J.L. Denefrio C.L. Sabatini B.L. Loss of Tsc1 in vivo impairs hippocampal mGluR-LTD and increases excitatory synaptic function.J. Neurosci. 2011; 31: 8862-8869Crossref PubMed Scopus (72) Google Scholar). A similar “embarrassment of riches” in terms of primary and secondary effects is present for other ASDs that result from disruptions of pathways serving important roles in many cell types. Like TS, Fragile X syndrome (FXS) and Angelman Syndrome (AS) target aspects of protein metabolism critical for synaptic function, and also like TS, both FXS and AS have been associated with abnormalities of both excitatory and inhibitory synaptic transmission. FMRP (Fragile X Mental Retardation Protein) is an RNA binding protein linked to trafficking and translation of synaptic proteins (Darnell et al., 2011Darnell J.C. Van Driesche S.J. Zhang C. Hung K.Y.S. Mele A. Fraser C.E. Stone E.F. Chen C. Fak J.J. Chi S.W. et al.FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism.Cell. 2011; 146: 247-261Abstract Full Text Full Text PDF PubMed Scopus (394) Google Scholar), which when knocked out in mouse recapitulates many features of the disorder (Brennan et al., 2006Brennan F.X. Albeck D.S. Paylor R. Fmr1 knockout mice are impaired in a leverpress escape/avoidance task.Genes Brain Behav. 2006; 5: 467-471Crossref PubMed Scopus (34) Google Scholar, Musumeci et al., 2000Musumeci S.A. Bosco P. Calabrese G. Bakker C. De Sarro G.B. Elia M. Ferri R. Oostra B.A. Audiogenic seizures susceptibility in transgenic mice with fragile X syndrome.Epilepsia. 2000; 41: 19-23Crossref PubMed Google Scholar, The Dutch-Belgian Fragile X Consortium, 1994The Dutch
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