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The 2003 paper proposing signaling imbalance in autism

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Parizad M. Bilimoria, Takao K. Hensch
26 February 2013

Abnormal activity: Brain signals that inhibit neuronal activity may be dampened in autism, which may explain the frequency of seizures in the disorder.

A popular unifying theory for what causes autism, first described in 2003, is that the disorder reflects an imbalance between excitation and inhibition in the brain, in particular in circuits governing sensory processes, memory, and social and emotional behaviors.

Various genetic and environmental factors may converge, in different combinations in different individuals, to produce a higher excitation/inhibition (E/I) ratio.

John Rubenstein and Michael Merzenich first described this theory in a paper published in Genes, Brain and Behavior in 20031. Since then, the paper’s theoretical framework for understanding autism has had a broad impact on the study of neurodevelopmental disorders, and a plethora of evidence has emerged to further substantiate the notion of E/I imbalance.

Rubenstein and Merzenich’s hypothesis grew in part from reports suggesting that many individuals with autism experience seizures and display ongoing ‘sharp spike’ activity during sleep2, 3, 4.

Like the seizures, this abnormality is indicative of increased excitability and noisy or unstable networks in the cerebral cortex, a brain region implicated in higher-order cognitive function.  

From a systems level down to individual neuronal junctions and molecules, they provided the field with myriad examples of how an elevated E/I ratio might arise — and how this imbalance might lead to the brain dysfunctions or behavioral differences noted in autism.

Since their publication, data from numerous studies have strengthened the link between seizures and autism, suggesting that epilepsy and autism co-exist in up to 20 percent of children with either disorder5.

Also, molecular studies have bolstered the initial observation that certain markers of inhibitory signaling in the brain — mediated by the chemical messenger gamma-aminobutyric acid (GABA) — are diminished in individuals with autism.

Notably, levels of the enzymes that synthesize GABA and the cell-membrane receptors for GABA are lower in postmortem brain tissue from autism brains than in controls6, 7. Studies have also reported alterations in GABA signaling in numerous animal models of autism8.

Balance genes:

Other molecular studies have substantiated the idea that genes implicated in autism regulate E/I balance.

For example, variations in the chromosomal regions bearing genes for GABA receptor subunits are linked to autism. The same is true for variants in genes controlling excitatory or inhibitory neuron development, migration, connectivity and signaling.

Some of these genes code for cell adhesion molecules that link synapses — neuronal junctions. Others code for proteins that regulate gene expression at the DNA and the protein level (both transcription and translation), enzymes and structural proteins.

Many of these other proteins are also present at synapses or may control their development and function. Often these molecules are part of signaling networks that are regulated by neuronal activity. The result is that mutations in these genes disrupt the process by which environmental experience modifies synapses9, 10, 11, 12.

In addition to describing molecular changes that might produce an elevated E/I ratio, Rubenstein and Merzenich discussed how environmental factors may lead to changes in brain wiring associated with hyperexcitability at the circuit level.

Hyperexcitability in basic sensory processing regions may explain the strong negative reactions that some individuals with autism have to mild sound, touch or visual stimuli.

Rubenstein and Merzenich highlighted ongoing experiments (since confirmed by others) in the rodent auditory system suggesting that abnormal sound experiences during critical periods of brain development can impair the formation of cortical sound maps. Typical sound maps are an orderly distribution of neurons that are evenly dedicated to different sound frequencies. Instead, the auditory cortex may over-represent certain sound frequencies at the expense of others13, 14, 15.

Because cortical circuits mature in a hierarchical fashion, defects in the wiring of primary sensory circuits may ultimately produce difficulties in higher-order brain functions, such as language and socialization.

In one of the earliest demonstrations of the importance of inhibition, cited in the 2003 paper, lowering inhibition in the young mouse brain prevents the visual circuits from properly adapting to experience. In that study, the researchers lowered inhibition by disrupting a key enzyme in GABA synthesis (one of the enzymes thought to be reduced in the brains of individuals with autism)16.

Plasticity, the ability to remodel neuronal connections based on experience, is needed to develop the neural architecture distinguishing left- versus right-eye inputs into the primary visual cortex and, ultimately, visual acuity. Strikingly, enhancing GABA transmission in these mice with drugs — presumably correcting the elevated E/I ratio — restores experience-dependent visual plasticity.

Local inhibitory neurons that secrete GABA play a crucial role in segregating minicolumns, the basic functional units of cortical architecture17, 18. Because of this, changes in the number, activity or structure of these interneurons may contribute to structural abnormalities in minicolumns. Rubenstein and Merzenich pointed out that minicolumns appear to be smaller and more numerous in individuals with autism19.

From cells to behavior:

In syndromic forms of autism, the mutation or loss of a single causative gene leads to the disorder. Mouse models of syndromic autism have been used to dissect the contributions of various brain regions and cell types to disease phenotypes.

Mouse studies of two such disorders, Rett syndrome and tuberous sclerosis complex, published in the past three years revealed that loss of the causative genes in GABA neurons alone can reproduce many of the neurobehavioral symptoms seen with a full deletion20, 21.

Studies have also explored the importance of different subtypes of GABA neurons in autism.

In 2009, a meta-analysis identified deficits in one particular subtype of GABA interneuron, parvalbumin-positive basket cells, in nine different mouse models of autism22. These cells drive gamma rhythms — which represent the synchronized activity of cortical neurons.

Electroencephalography studies have also shown that gamma oscillations are altered in individuals with autism23, 24, 25. Studies further suggest that these are the pivotal GABA cells responsible for orchestrating the timing of critical periods in which the brain undergoes development26, and that critical period plasticity is altered in mouse models of syndromic autism27.

Along these lines, critical period timing may be altered in humans with autism. Infants prenatally exposed to antidepressants — a population that may have a heightened risk of developing autism28 — exhibit an altered trajectory of speech perception. This suggests that higher-order critical periods underlying language development occur earlier in autism29. This is consistent with the altered cortical network function seen in rodents perinatally exposed to antidepressents30.

From a basic neurobiology standpoint, researchers have made significant advances since Rubenstein and Merzenich’s seminal paper toward understanding how inhibitory signals contribute to the function of individual neurons, circuits and networks in the cortex31. This in turn will enlighten us as to how a dysfunction or loss of inhibitory neurons might affect cortical activity in autism.

Conversely, with optogenetic experiments, which use light to turn on neural activity, scientists have shown that elevating the E/I ratio in the prefrontal cortex of mice leads to social deficits32.

As Rubenstein and Merzenich observed, the hypothesis of E/I imbalance gives hope that drugs correcting this balance may treat autism.

Researchers searching for strategies to target the E/I ratio in order to treat autism-like symptoms in mouse models must keep in mind that whereas there is ample evidence for elevated E/I in autism, there are also some cases where this ratio is decreased6, 7. What’s more, how these changes in the ratio develop over time is likely to be important.

The ultimate goal, already starting for some syndromic forms of autism, is to translate the circuit-balancing strategies in mice33, 34 into drug treatments for people35. Ideally, in combination with efforts to diagnose autism earlier, children could be treated while environmental experience has the most impact on sculpting their neural wiring.

Takao K. Hensch is professor of neurology at Boston Children's Hospital and professor of molecular and cellular biology at Harvard University. Parizad M. Bilimoria is communications and outreach director at the Conte Center at Harvard University.

News and Opinion articles on SFARI.org are editorially independent of the Simons Foundation.

References:

1: Rubenstein J.L. and M.M. Merzenich Genes Brain Behav. 2, 255-267 (2003) PubMed

2: Gillberg C. and E. Billstedt Acta. Psychiatr. Scand. 102, 321-330 (2000) PubMed

3: Lewine J.D. et al. Pediatrics 104, 405-418 (1999) PubMed

4: Wheless J.W. et al. Semin. Pediatr. Neurol. 9, 218-228 (2002) PubMed

5: Tuchman R. and M. Cuccaro Curr. Neurol. Neurosci. Rep. 11, 428-434 (2011) PubMed

6: Baroncelli L. et al. Neural Plast. 2011, 286073 (2011) PubMed

7: Gatto C.L. and K. Broadie Front. Synaptic Neurosci. 2, 4 (2010) PubMed

8: Pizzarelli R. and E. Cherubini Neural Plast. 2011, 297153 (2011) PubMed

9: Betancur C. et al. Trends Neurosci. 32, 402-412 (2009) PubMed

10: Qiu S. et al. Dev. Neurosci. 34, 88-100 (2012) PubMed

11: Südhof T.C. Nature 455, 903-911 (2008) PubMed

12: Ebert D.H. and M.E. Greenberg Nature 493, 327-337 (2013) PubMed

13: Zhang L.I. et al. Nat. Neurosci. 4, 1123-1130 (2001) PubMed

14: Chang E.F. and M.M. Merzenich Science 300, 498-502 (2003) PubMed

15: Barkat T.R. et al. Nat Neurosci. 14, 1189-1194 (2011) PubMed

16: Hensch T.K. et al. Science 282, 1504-1508 (1998) PubMed

17: Casanova M.F. et al. Neuroscientist 9, 496-507 (2003) PubMed

18: Hensch T.K. and M.P. Stryker Science 303, 1678-1681 (2004) PubMed

19: Casanova M.F. et al. Neurology 58, 428-432 (2002) PubMed

20: Chao H.T. et al. Nature 468, 263-269 (2010) PubMed

21: Tsai P.T. et al. Nature 488, 647-651 (2012) PubMed

22: Gogolla N. et al. J. Neurodev. Disord. 1, 172-181 (2009) PubMed

23: Brown C. et al. 41, 364-376 (2005) PubMed

24: Grice S.J. et al. Neuroreport 12, 2697-2700 (2001) PubMed

25: Sohal V.S. Biol. Psychiatry 71, 1039-1045 (2012) PubMed

26: Hensch T.K. Nat. Rev. Neurosci. 6, 877-888 (2005) PubMed

27: LeBlanc J.J. and M. Fagiolini Neural Plast. 2011, 921680 (2011) PubMed

28: Croen L.A. et al. Arch. Gen. Psychiatry 68, 1104-1112 (2011) PubMed

29: Weikum W.M. et al. Proc. Natl. Acad. Sci. USA 109 Suppl 2, 17221-17227 (2012) PubMed

30: Simpson K.L. et al. Proc. Natl. Acad. Sci. USA 108, 18465-18470 (2011) PubMed

31: Isaacson J.S. and M. Scanziani Neuron 72, 231-243 (2011) PubMed

32: Yizhar O. et al. Nature 477, 171-178 (2011) PubMed

33: Durand S. et al. Neuron 20, 1078-1090 (2012) PubMed

34: Dölen G. et al. Neuron 56, 955-962 (2007) PubMed

35: Henderson C. et al. Sci. Transl. Med. 4, 152ra128 (2012) PubMed

Comments

Name: Jon Brock
26 February 2013 - 8:45PM

Merzenich and Rubenstein's is obviously an important paper - and it's great to see how the ideas have taken off. However, some credit should go to John Hussman for his paper published two year earlier that focused specifically on GABA as the mechanism of excitation/inhibition imbalance:

"Specifically, the severe disruptions observed in autism may be linked to suppression of GABAergic inhibition, resulting in excessive stimulation of glutamate- specialized neurons and loss of sensory gating. This view recognizes the possibility of multiple etiologies in autism. That is, there may exist a spectrum of genetic and environmental factors which impair inhibitory tone in a manner that expresses itself as autistic pathology."

Hussman, J. (2001). Suppressed GABAergic inhibition as a common factor in suspected etiologies of autism. Journal of Autism and Developmental Disorders, 31, 247-248.

http://hussmanfoundation.com/research/jaddgaba.pdf

Name: Manuel Casanova
26 February 2013 - 9:28PM

I presented a similar idea in different congresses and published a paper that unfortunately took one year to process. The idea of an imbalance was based on our own work on minicolumns (quoted by Merzenich and Rubentein). The citation is: Casanova MF, Buxhoeveden D, Gomez J.Disruption in the inhibitory architecture of the cell minicolumn: implications for autism. Neuroscientist. 2003;9(6):496-507. Review.

Name: Concerned Scientist
27 February 2013 - 2:36AM

Any attempts to associate autism risk with one particular neurotransmitter system in the face of profound genetic heterogeneity uncovered by the Simons Simplex Collection is naive and misguided and has no place in this website. If we learn anything from the spectacular SSC studies is that attributing disease pathophysiology solely to GABAergiic dysfunction is, to say the least, ludicrous. Also I find the concept of altered E/I balance extremely diffuse with little or any heuristic value. To say that E/I is affected is to say that the brain is not working properly (we know that already)

Name: A careful reader
27 February 2013 - 2:47AM

As the article points out, it is the balance of circuit function (rather than one signaling pathway) that is pivotal to the hypothesis. The heuristic value is in the endophenotypes controlling gamma oscillations and critical windows of development, all of which have emerged since the original hypothesis and which can now be mapped systematically across various autisms to better link gene to cognition. Nice to see the earlier Casanova study cited properly as well (reference 17).

Name: Concerned Scientist
27 February 2013 - 5:33AM

..endophenotypes controlling gamma oscillations? I do not even know what this means. and don't get me started with ..gamma oscillations, another construct with zero heuristic value which seems to be the "key" to every previously undecipherable brain disorder (when they may be nothing more interesting than filtered noise). It is sad to see the website of a foundation promoting trailblazing research in genetics promoting such naive and bankrupt ideas.

Name: My 2 cents
27 February 2013 - 3:13PM

Sad to see a "scientist" so dismissive of any attempt to seek circuit-level explanations when "trailbazing research in genetics" has still left us far from understanding these complex cognitive disorders. Kudos to SFARI for exploring legitimate hypotheses.

Name: Anonymous
27 February 2013 - 7:19PM

I think your 2 cents indicate a distorted view of circuit-level explanations
since when GABA-ergic hypofunction or altered E/I ratio is a circuit-based explanation???
I am all for circuit-based explanations but when they are clear and specific and guided by genetics not wishful thinking.

Name: My 2 cents
27 February 2013 - 10:22PM

Exactly. This is just one hypothesis that deserves testing not ridicule for lack of better ideas. It should be broken down into more specific questions. Ultimately brain (dys)function reflects circuit behavior, does it not?

Name: Another Scientist here
1 March 2013 - 12:57AM

First off, as a molecular biologist myself, explanations guided solely by genetics are in and of themselves ludicrous, smacking of the all-too-simplistic notion which built the Central Dogma of Biology. Have we forgotten basic tenets of cell biology? The cell is comprised of far more than just nucleotides. On the topic of the article, while I'm no electrophysiologist I am privy to some current research which points strongly towards gamma oscillatory studies in autism and other neurodevelopmental disorders, ones which provide considerable usefulness in both understanding etiology as well as providing means for treatment of some aspects of the conditions. I look forward to their further publication. I/E inbalance, in the form of overexcitation, is a general model which allows one to test very specific hypotheses, even if there are a variety of underlying causes. Aside from Rubenstein, I have also enjoyed Casanova's work above and highly recommend it as it proffers a neuroanatomical foundation to the general I/E model and even predates some of the better popularized I/E studies. From my own work, I also look forward to furthering molecular research in autism in the near future but am not so silly as to assume that genetics research will "solve" the curious case of autism. It's a heterogeneous condition which requires heterogeneous approaches to understand. Genetics, epigenetics, ecology, the neurosciences including electrophysiology, etc.... all of these work in concert.

Name: Concerned Scientist
2 March 2013 - 5:54AM

I am certainly looking forward to convergent evidence from ecology and electrophysiology
in deciphering any kind of imbalance in autism.

Name: Sarah
2 March 2013 - 5:11PM

well said. As a parent of a child with ASD, I couldn't agree more.

Name: OP AMP Guy
1 March 2013 - 1:24PM

I love the useful exchange of ideas as well as having 2 of the pioneers on board. Dr. Brock was modest and should have quoted his own paper on temporal binding as a useful addition. Also, Casanova pursued his findings and used rTMS to treat the E/I imbalance with gamma oscillations as an outcome measurement. I find the ideas of interest as a way of explaining some of the symptoms of autism, e.g. seizures, sensory abnormalities.

Brock J, Brown CC, Boucher J, Rippon G. The temporal binding deficit hypothesis of autism. Development and Psychopathology 14:209-224, 2002.

Sokhadze EM, El-Baz A, Baruth H, Mathai G, Sears L, Casanova MF. Effects of low frequency repetitive margnetic stimulation (rTMS) on gramma frequency oscillations and even-related potentials during processing of illusory figures in atism. JADD 39(4):619-34, 2008.

Name: Sarah
2 March 2013 - 2:46PM

this makes total sense to me and explains sensory issues and difficulty with self regulation that I see in my son. If only a treatment could be produced that calms the brain and stablizes the signaling. I do not mean an SSRI because I think they are not proper treatment for ASD. Two natural treatments that have helped my son self regulate are Lutimax (luteolin) and Phosphatiydyl serine with DHA.

Name: Sarah
2 March 2013 - 2:46PM

this makes total sense to me and explains sensory issues and difficulty with self regulation that I see in my son. If only a treatment could be produced that calms the brain and stablizes the signaling. I do not mean an SSRI because I think they are not proper treatment for ASD. Two natural treatments that have helped my son self regulate are Lutimax (luteolin) and Phosphatiydyl serine with DHA.

Name: Greg Boustead
5 March 2013 - 10:52PM

Tomorrow's webinar may shed some light on this discussion. Vikaas Sohal will discuss his work showing how excitation-inhibition imbalance in distinct subtypes of neurons may contribute to aspects of autism. And more to the point, his results suggest how the E/I hypothesis might be updated to be useful for designing new experiments and, eventually, therapeutics.

There will also be an opportunity to pose questions to the presenter. You can get more information and register for the talk here:

http://sfari.org/sfari-community/webinar-series/2013/webinar-vikaas-sohal-on-abnormal-neural-circuits-in-autism

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