The premiere research event for everything brain-related takes place once a year in the late Fall. This year Washington, D.C. played host to more than 30,000 neuroscientists from around the world, including many Autism Speaks grantees, for the five day Society for Neuroscience meeting November 15-19.
Exciting developments in the neurosciences and other related scientific fields were presented; below are the highlights that pertain to autism:
Exploring a Link Between Autism and the Immune System
For the last few years the link between the nervous and immune systems in autism has been an expanding field of exploration. At this year's Society for Neuroscience (SFN) meeting, the connection was explored in much greater detail. Previously researchers have shown that activation of the maternal immune system during pregnancy, by infection or inflammation, results in altered offspring behaviors reminiscent of autism. Autism Speaks-funded research results from the laboratory of Nicholas Ponzio, Ph.D., UMDNJ, extended the findings on the impact of maternal immune activation in a new direction. Whereas previous research has focused on the effects that maternal immune activation have upon the offspring's brain development, Dr. Ponzio presented preliminary data showing that in utero exposure to immune stimuli also impacts development of the offspring's own immune system. Specifically he found that their peripheral blood cells were skewed more toward Th1 or Th17 responses, both of which are known to be involved in the pathogenesis of autoimmune diseases, and thus might contribute to immune abnormalities.
Using a different model system and focusing on the brain, John Panos, Ph.D., from Western Michigan University, examined the overall effect of pro-inflammatory cytokines (mediators of immune responses) on the development of the glutamate neurotransmitter system. His team found that direct administration of particular cytokines immediately after birth leads to unusual locomotor behaviors in adults challenged with phencyclidine (an anesthetic). Most interestingly, the responses differed between males and females, reminiscent of autism's overall gender bias. Autism Speaks-grantee Kimberly McAllister, Ph.D. (UCDavis) is undertaking a finer-grained analysis to look at the direct effect of cytokines on synapses. Using an in vitro cell culture model of brain development, her lab found that the same pro-inflammatory cytokines previously determined to be elevated in brains of individuals with autism can, indeed, directly affect development of glutamate-containing synapses. In her exciting preliminary experiments presented at the meeting, IGF-1, TNF?, TGF?, and MCP-1, all were found to increase the density of glutamate synapses. Once again, this hints at the profound but previously unknown impact that immune molecules may have on brain development. This avenue of research perhaps represents the most rapidly expanding new area of autism research.
Tracking Down the Biology of Environmental Factors
Sergiu Pasca and colleagues from Iuliu Hatieganu University of Medicine and Pharmacy (Romania) and University of Szeged (Hungary) reported on the activity of an enzyme believed to help counteract the toxic effects of organophosphates in a population of Romanian children with autism. The enzyme, called paraoxonase, is believed to protect against oxidative damage of lipids and was less active in children with autism. The gene that codes for the variant called Paraoxonase 1 (PON1) has previously been reported to show aberrant variations in some individuals with autism. Although these authors did not find correlations between gene mutations and enzymatic activity, the demonstration of lower function of PON1 may suggest a weakened ability to tolerate organophosphates in individuals with autism.
Also of specific interest to autism, a group of investigators from the NY Institute for Basic Research presented initial results on a mouse model of animals exposed during infancy to the triad of chemicals found to be very elevated in the drinking water of Brick Township, NJ, an area of the country with an unusually high autism prevalence. Although animals exposed to the same concentrations found in Brick Township showed no obvious effects, animals given extremely high doses (10-100 times the Brick Township concentrations) did begin to show behavioral phenotypes. The results appeared significant only for the male mice, indicating that males are more susceptible to these toxic exposures, and the investigators are now pursuing which biochemical pathways have been disrupted by the Brick Township chemicals.
In a series of novel presentations, the laboratory of Richard Lin, Ph.D., University of Mississippi, described new findings regarding how in utero exposure to a common medication, citalopram, one of the selective serotonin reuptake inhibitors (SSRI), can profoundly affect brain development in previously unexplored ways. Because imaging studies have documented abnormal white matter in children with autism, the group is currently focusing on the effects of citalopram on oligodendrocytes, the cells that compose the brain white matter. Other environmental factors discussed during the meeting include the cell biological effects of ethanol and heavy metals upon glutathione synthesis by Richard Deth, Ph.D., Northeastern University, and the mechanisms of cell death caused by long-term, low-dose methylmercury exposure by the laboratory of former Autism Speaks Board member, Manny DiCicco-Bloom, M.D., Ph.D., UNMDJ.
Finally, in research published earlier this year, Gregory Barnes, M.D. (Vanderbilt University) reported that mice deficient in the protein neuropilin 2 (NPN2) have decreased counts of inhibitory interneurons in the hippocampus and are susceptible to seizure. At this year's meeting Dr. Barnes recapitulated the results in mice deficient in the molecule SEMA 3F, which is the ligand, or molecular partner, for NPN2. Because the SEMA 3F gene is susceptible to inactivation by methylmercury, these studies may also support a role for environmental factors regulating the development of inhibitory circuitry. Inhibitory circuitry is extremely important in nervous system function and, due to the frequency of seizures, believed to be relevant to the development of autism.
Unique Model Systems for Autism
Several sessions of the five day meeting focused on animal models of autism. One of the most novel models presented was the disruption of neuroligin gene activity in the worm C. elegans. The neuroligin genes, involved in synapse function, are associated with a subset of individuals with autism and are therefore being heavily investigated for what they may reveal about the biology of autism. Humans and mice have several neuroligin genes, making it difficult to dissect out their specific functions or how loss of the gene products leads to behavioral defects. The worm, on the other hand, has a single neuroligin gene and, in comparison, an extremely simple nervous system that is easily manipulated experimentally. For these reasons it has become a model system of choice for many geneticists and behaviorists. Using a grant from Autism Speaks awarded to create a worm that lacks neuroligin activity, Jim Rand, Ph.D. (University of Oklahoma) now reports that the animals, which look and act roughly normal, have very specific sensory abnormalities including differences in integrating sensory information and sensitivity to thermal stimuli. Moreover, in a surprising and potentially very exciting convergence, Dr. Rand found that these worms that have been engineered to be deficient in a synapse protein are also hypersensitive to oxidative stress and appear to be in a more oxidated state. These unexpected results may ultimately unite the metabolic and functional connectivity theories of biological dysfunction in autism, two theories that have been until now pursued in isolation.
In the past years, thanks in large part to Autism Speaks' Autism Genetic Resource Exchange (AGRE) and Autism Genome Project, several genetic risk factors have been linked to individuals with autism. Sometimes these changes cause deletions of genes but sometimes they only result in changes of a single letter in a specific gene (called a "point mutation"). For example, as described above, in rare cases people with autism have a very specific point mutation in the Neuroligin-3 gene. Autism Speaks grantee Craig Powell, M.D., Ph.D. (UT Southwestern) created mice in which the original Neuroligin-3 gene was replaced by the mutated form of the gene. The resulting mice looked normal but had specific changes in their neuronal connectivity – the amount of inhibitory transmission at their synapses in the somatosensory cortex was increased by 50%. These mice also exhibited some subtly impaired social behaviors and enhanced spatial learning abilities, consistent with a model for autism. In a surprising twist though, mice with a complete deletion of the gene showed none of the phenotypes that the mice with the point mutation did. This suggests that the protein made by the gene with the autism point mutation acts detrimentally by gaining some unknown new function rather than just by losing all of its normal function. This information leads to very different implications for how to construct a potential treatment and demonstrates the extreme importance of the type of nuanced information that can be derived from model systems.
Highlighting Exciting New Therapeutic Possibilities for Autism
The above findings were presented in a mini-symposium chaired by Dr. Powell on mouse models and treatment strategies. Clearly a highlight of the meeting, several hundred researchers in attendance heard thrilling stories of new treatment strategies for neurodevelopmental disorders associated with autism. For example, it has been found that a reduction of a specific glutamate receptor (mGluR5) in mice can reverse most of the phenotypes of mice lacking the gene that causes Fragile X; an mGluR5 antagonist is already in development as a potential therapeutic for the disorder. Moreover, a mouse model for Angelman syndrome showed improvement by manipulations that modified a single specific biochemical pathway. Adding to this exciting development, in a separate session researchers from Dublin, Ireland showed that they could successfully use HDAC inhibition to reverse some social defects in the valproic acid model of autism.
Hope for treatment in another human neurodevelopment disorder, Tuberous Sclerosis (TS) was presented by the laboratory of Alcino Silva, Ph.D (UCLA). TS is caused by mutations in either the Tsc1 and Tsc2 genes. Mice carrying one mutant copy of the Tsc2 gene show cognitive impairments in learning and memory. In a series of important experiments, the researchers identified that the mutation causes a particular biochemical signaling pathway, known as mTOR signaling, to be excessively activated. Armed with this knowledge, the investigators found that simple administration of a drug known to shut down this signaling pathway reversed the learning deficits in these mice. In different mutant mice whose nerve cells carry two defective copies of the other TS gene, Tsc1, the same drug improved survival, decreased brain enlargement and improved neurological findings.
Hormones and Autism
The "extreme male brain" theory of autism hypothesizes that the social and communication deficits in autism are caused by an elevated exposure of the fetus to testosterone, the male sex hormone. Researchers from the laboratory of Flavio Keller, M.D., ( Università Campus Biomedico di Roma) sought to use an animal model of autism to test whether changing the ratio of sex hormones in infancy can indeed impact behavior. To directly test the theory, they used a genetic model of autism in which one copy of the reelin gene, important for the development of the cerebellum, is deleted. Reelin mice display a number of subtle deficits that are anatomically related to those found in autism, and which differ in presentation between male and female mice. The researchers administered the sex hormone estradiol to neonatal reelin mice and found this corrected a variety of different behaviors, including perseverative behaviors in male reelin mice. These observations support the notion that an imbalance in estrogen/testosterone levels may be etiological for behaviors observed in autism and, more importantly, that the activities and signaling pathways of these hormones can be targeted therapeutically.
Using another type of animal model, the prairie vole, to investigate if social behaviors are amenable to treatment, Autism Speaks-grantee Larry Young, Ph.D. (Emory University) is also examining another hormone system that has been implicated in autism. His group hypothesized that d-cycloserine (DCS), a drug known to enhance human cognition, may act synergistically with oxytocin, the "trust" hormone, to promote partner bonding in this species. When they injected DCS into the brain region where oxytocin acts, they found that it did promote social bonding and partner preference in the female voles. Future studies will determine how the drug acts, perhaps in partnership with oxytocin, and may represent a possible therapy for the social cognitive deficits observed in autism. Such investigations are important because they show that, complex as they are, behaviors reminiscent of autism may be susceptible to simple pharmacological intervention.
Perception, Brain Circuitry and Motor Planning
Perception involves the cognitive processing of sensory information. It has long been known that many individuals with autism experience either heightened or dampened sensory sensitivity, though little science was available to explain these experiences. This year, altered perception in individuals with autism was the subject of many of different studies.
Autism Speaks-grantee Mark Tommerdahl, Ph.D., and his laboratory at UNC Chapel Hill reported observing a surprising response to repeated vibratory stimulation applied to the skin. People with autism showed less adaptation to previous stimulation than typical control subjects. Adaptation is a sensory phenomenon that serves to adjust the dynamic range of sensation to be appropriate for the current environment. For example, people typically adapt to the sensation of their own clothing, making them relatively unaware of the continued presence of clothing, however any new stimulation, such as a brush on the arm from someone walking by, would be immediately sensed. The new findings may suggest that people with autism continue responding to "background" activity that typical sensory systems discount, putting them into a constant heightened sensory alert. Current models of sensory adaptation suggest that this phenomenon is related to alterations in the inhibitory circuitry, which fits well with many of the changes in synaptic activity seen in animal models. The tests that Dr. Tommerdahl developed are very fast and non-invasive, so they could easily be used to detect improvements in these inhibitory circuits following treatments.
Mark Wallace, M.D., and his group at Vanderbilt University found that individuals with autism were taking longer time periods to integrate multisensory stimuli than do individuals without autisn, possibly contributing to difficulties in processing multimodal social communication. Encouragingly, they showed that perceptual training can shorten the window of integration and that the training effects can generalize to other aspects of multisensory integration. If these experiments hold true, they could offer an important entry point into improving some of the perceptual problems in individuals with autism.
Finally, there was also very interesting progress in understanding the apparent problems of children with autism in activating the mirror neuron network. The mirror neuron network is thought to be important for imitating and learning n
w motor skills. Now, Giacomo Rizzolatti, M.D., and his group from Parma, Italy provided evidence suggesting that although the mirror neuron system is functional in children with autism for individual movements such as reaching and grasping, the deficit is in understanding the intention and planning of motor actions - rather than taking into account the final goal of a multistep action, children with autism appear to be processing each step of a complicated motor sequence one step at a time. This work was highlighted as part of one of the major lectures presented to thousands of the researchers at the conference, generating much discussion over how this illuminates many of the great challenges faced by individuals with autism every day.
Final Emerging Theme from the 2008 SFN Meeting
Altogether these research advances demonstrate the ostensible "treatability" of the component features of autism despite varying etiologies proposed (genetic, immunologic, endocrinologic, perceptional). Such results, which have emerged only in the last two years, are rapidly redirecting researchers to an entire new field of research that is energizing the movement for autism treatment. The results also suggest that the complexity of autism will not require one "cure-all" strategy but an arsenal of therapies that is adaptable to the underlying biology of the presenting symptoms in each individual.