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Research Identifies Gene Involved in Fear-Response Learning

Finding Builds Foundation for Understanding Biology of Anxiety
October 14, 2007


A terrorizing fear of animals, an aversion to novel situations, a drive to constantly close all the doors…As many caregivers know, individuals with autism often exhibit anxiety, such as phobias, withdrawal in social situations, or obsessive/compulsive behaviors. Unfortunately, the scientific community does not yet understand the biological basis of such social “fears,” but research has identified specific brain regions that are responsible for perceiving frightening situations and, if necessary, learning to avoid them. One such region is a cluster of nerve cells under the temporal lobe that functions as the brain's “fear center.” This cluster is called the amygdala, meaning "almond-shaped."

Investigators have long suspected that in individuals with autism the amygdala functions differently. Some studies report differences in the size of the amygdala in autistic subjects, and functional MRI (brain imaging) studies have shown that amygdala activation differs in autistic and non-autistic subjects as they experience something frightening. For instance, Simon Baron-Cohen, Ph.D. at the University of Cambridge used brain imaging to measure activity in amygdala neurons of adults with Asperger's Syndrome (AS), a form of autism, while subjects looked at threatening faces. Individuals with AS had difficulty distinguishing neutral states from emotionally charged ones, particularly if emotions were conveyed by the eyes; more significantly, amygdala activity in subjects with AS was lower than that of controls while viewing threatening faces, supporting the idea that the amygdala is a “threat-detector” that may not function optimally in some forms of autism. Other more recent work by Richie Davidson, Ph.D. and colleagues at the University of Wisconsin has actually found the opposite, that overactivation of the amygdala may occur in some individuals with autism. (This discrepancy may have to do with differences in subgroups of patients being studied or variations in experimental design). Thus, while the nature of the amygdala deficits remains controversial, it is has been found that the amygdala exhibits abnormal activity in individuals with autism.

Although the amygdala is well-established as a fear center, the molecular mechanisms that allow it to serve this function are not understood. To build scientific understanding of how the amygdala functions and why it may be mal-functioning in autism, in 1999 Cure Autism Now awarded a grant to the laboratory of Eric Kandel, M.D., Ph.D, winner of the 2000 Nobel Prize in Physiology and Medicine. The hope is that knowledge about amygdala function can provide better insight into the possible causes of anxiety-related behaviors in autism.

At the end of last year, Dr. Kandel and a team of collaborators led by Gleb Shumyatsky, Ph.D. at Rutgers University identified a specific gene, stathmin, which is required for mice to learn fear-associated behaviors. The discoveries began in 2002, when Dr. Shumyatsky's team searched for genes that were more highly expressed in the amygdala than in the rest of the brain; among others, they discovered stathmin. At the time, few would have predicted a connection between stathmin and fear. Several years earlier a group of researchers at Albert Einstein College of Medicine had suspected the stathmin gene was necessary for cell division and had genetically deleted it from mouse DNA to see its effects. Such mice lacking the stathmin gene are call stathmin knock-outs or mutants. Surprisingly, the stathmin knock-out mice showed few obvious developmental defects and the exact function of the stathmin gene was not revealed.

However, upon their discovery of the stathmin gene in the amygdala, Dr. Shumyatsky's group took another look at the stathmin mutant mice, subjecting them to fear-inducing tests that revealed two previously overlooked behavioral defects. In this new study, published in the prestigious journal Cell, the researchers report that the knock-out mice show less innate fear (such as of open spaces), and have difficulty learning to associate a sound with an accompanying small electric shock. In other words, mice without a stathmin gene do not show “appropriate” responses to fear-inducing stimuli, neither innate nor learned.

Knowing this, one might predict that dysfunction of the amygdala—or of genes critical to its function, like stathmin—would make an animal less fearful. However, animal models with damaged amygdale exhibit a more complex array of behaviors known collectively as Kluver-Bucy syndrome; these include a reduction in innate fear, such as the fear of snakes, but paradoxically, increased social isolation and docility, which are signs of increased fearfulness. Some individuals on the autism spectrum exhibit similar inconsistencies. In fact, diagnostic criteria for autism as defined in the DSM-IV manual states that individuals with autism can “show a lack of fear in response to real dangers, and an excessive fearfulness in response to harmless objects.” Thus, a more complete hypothesis is that amygdala dysfunction makes animals and humans fear the “wrong” things. By showing in mice that the loss of a single gene highly expressed in the amygdala can simulate many defects resulting from a damaged amygdala, Dr. Shumyatsky's team has helped to focus on a gene that could lie at the heart of some of these highly complex behaviors witnessed in autism.

How the loss of a single gene can produce such dramatic effects lies in the function of the protein produced by that gene. Work from Dr. Tim Mitchison's lab at UCSF has shown that stathmin protein regulates other proteins, called “microtubules,” that essentially form the molecular skeleton of neurons. Unlike bony skeletons, which are rigid, microtubules constantly shrink and expand; in fact the ability of nerve cells to remodel their “skeleton” is absolutely required for neurons to make connections with each other. Interestingly, the stathmin protein acts in cells to inhibit the growth of the microtubule skeleton. Dr. Shumyatsky's group found that deleting the stathmin gene (which eliminates production of the stathmin protein) resulted in an overly stable network of microtubules in amygdala neurons. Why an indestructible wall of microtubules blocks a neuron's ability to respond appropriately to a fearful stimulus is unknown.
The authors speculate that, in order to establish appropriate memories of fearful experiences, nerve cells must be able to make and receive new connections, using stathmin to help dynamically remodel the cellular skeleton. Without such an ability to remodel, the cellular connections cannot function as normal, the physiology of the amygdala neurons is affected, and the regulation of fear responses is disrupted.

Clearly, questions remain regarding the relevance of the stathmin gene to fear and anxiety-related behaviors in humans, such as those seen in autism. Further study is required, both in mice (do the apparently fearless stathmin knock-out mice ever exhibit misplaced or inappropriate fears?) and in individuals on the autism spectrum (are mutations in the gene associated with the types of anxiety-related behaviors seen in these individuals?) If stathmin dysfunction in humans is found to be relevant to the aberrant fear responses and anxieties seen in autism, this research offers a highly significant step forward in devising strategies for treatment. An identified protein offers a target for development of anti-anxiety pharmacological therapy, and the animal model offers a way in which to develop and test appropriate and effective treatments. The promise of identifying the source of anxiety in autism is clear--for our children, alleviating their anxiety will make it easier for them to learn about the world and the people surrounding them.

References

Adolphs R, Tranel D, Hamann S, Young AW, Calder AJ, Phelps EA, Anderson A, Lee GP, Damasio AR. (1999) Recognition of facial emotion in nine individuals with bilateral amygdala damage. Neuropsychologia 37:1111-1117.

Baron-Cohen S, Ring HA, Wheelwright S, Bullmore ET, Brammer MJ, Simmons A, Williams SC. (1999) Social intelligence in the normal and autistic brain: an fMRI study. European Journal of Neuroscience 11, 1891-1898.

Belmont LD and Mitchison TJ. (1996) Identification of a protein that interacts with tubulin dimers and increases the catastrophe rate of microtubules. Cell 84, 623-631.

Dalton KM, Nacewicz BM, Johnstone T, Schaefer HS, Gernsbacher MA, Goldsmith, HH, Alexander AL, Davidson RJ. (2005) Gaze fixation and the neural circuitry of face processing in autism. Nature Neuroscience 8, 519-526.

Schubart UK, Yu, Amat JA, Wang Z, Hoffmann MK, Edelmann Y. (1996) Normal development of mice lacking metablastin (P19), a phosphoprotein implicated in cell cycle regulation. Journal of Biological Chemistry 24, 14062-14066.

Shumyatsky GP, Tsvetkov E, Malleret G, Vronskaya S, Hatton M, Hampton L, Battey JF, Dulac C, Kandel ER, Bolshakov VY. (2002) Identification of a signaling network in lateral nucleus of amygdala important for inhibiting memory specifically related to learned fear. Cell. 111(6):905-18.

Shumyatsky GP, Malleret G, Shin RM, Takizawa S, Tully K, Tsvetkov E, Zakharenko SS, Joseph J, Vronskaya S, Yin D, Schubart UK, Kandel ER, Bolshakov VY. (2005) Stathmin, a gene enriched in the amygdala, controls both learned and innate fear. Cell 123(4):697-709.