It was only a short train ride from New Jersey to Washington, DC to reach the annual Society for Neuroscience meeting. As this was my first time attending, I wasn’t exactly sure what to expect. I had been told that this was a very large meeting, but I soon realized that “very large” didn’t quite capture the scope of its enormity. Upon first entering the Walter E. Washington Convention center, my initial thought was that this must be what it would look like if 32,000 scientists got together to occupy an international airport.
As I oriented myself and planned out my schedule, I was immediately struck by the incredibly broad scope of topics and the myriad talks, lectures, and presentations, which made for some difficult choices between concurrent events. I’m generally pleased with my choices and I’m happy to share the highlights of those events with you.
Neurotrophins: From Axon Growth to Synaptic Plasticity
Mu-ming Poo, University of California, Berkeley
The first Presidential Lecture kicked off with Mu-ming Poo on the topic of neurotrophins and their effects on axonal differentiation and plasticity. Early in his talk, he had an interesting suggestion for a method to motivate graduate students: tell them that you don’t believe their data. In the case of one of his graduate students who had data that suggested BDNF could act as both an attractant and a repellant to growing axons, depending on cellular conditions, he recalled offering to crawl around a table like a dog if the data proved to be accurate (I can only assume that he eventually made good on his offer).
Ultimately, the research presented showed that BDNF acts as an axon growth regulator, one, by acting as an attractant or a repellant to the axonal growth cone, and two, by acting as a polarizing factor to trigger axon differentiation (this has only yet been shown in vitro, so it may or may not be the case in vivo). The value of in vitro data was supported by what Dr. Poo calls “Poo’s Dictum”, which suggests that something neat found in vitro is bound to be used somewhere in vivo. Regardless of whether or not this is true, it is definitely a comforting mantra while tending to cell cultures in the lab.
Furthermore, his data suggested that BDNF can act as a synaptic modulator by potentiating basal transmission and by sensitizing synapses to activity in order to induce a persistent active state that may be important to the mechanisms of things such as drug addiction. Secretion of BDNF from dendrites was shown to be spike timing dependent and interestingly, bidirectional transport of BDNF through endosomes can allow rapid communication between input and output synapses leading to coordinated synaptic refinement during development and learning.
Epigenetic Enhancement of BDNF Signaling Rescues Synaptic Plasticity in Aging
Yan Zeng, UCLA School of Medicine
Dr. Zeng’s presentation concerned the topic of the molecular mechanisms responsible for aging-related cognitive declines. Specifically, her research described the epigenetic role via chromatin remodeling in regulating synaptic and cognitive function. While it has been shown that histone acetylation generally leads to enhanced gene transcription, her data suggested that by inhibiting histone deacetylase (HDAC), the corresponding increase in acetylation reverses age dependent long-term potentiation decline in the hippocampus.
There is evidence that histone acetylation deficits lead to decreased BDNF and TrkB expression, and that inhibition of HDACs activates BDNF regulated signaling pathways. This is of particular interest since age-dependent deficits in long-term plasticity of synapses are closely associated with reduced histone acetylation, upregulation of HDAC2, and decreased histone acetyltransferase expression in the rat hippocampus. This reduced BDNF expression was shown to inhibit the TrkB-activated signaling pathways resulting in reduced dendritic spine density.
The presence of HDAC inhibitors reversed the observed synaptic deficits by upregulating BDNF and TrkB expression. Alternatively, it was also confirmed that synaptic deficits could be rescued by addition of a selective TrkB agonist that mimics the effect of HDAC inhibitors. This was a rather exciting result since one could easily imagine the development of a treatment that specifically targets TrkB to improve cognitive function in those affected by age-related cognitive decline.
Rett Syndrome: Linking Epigenetics and Neuronal Plasticity
Huda Zoghbi, Baylor College of Medicine
Dr. Zoghbi’s presentation began with an interesting story describing how she first became interested in Rett syndrome, where during her pediatric neurology residency, she serendipitously came across a patient that presented with rather unique symptoms, just as she had read an article describing Rett syndrome and its symptoms. As the disease was very rarely diagnosed at the time, she quickly became an expert in the disease by searching patients’ charts for similar symptoms until she had multiple Rett syndrome patients who would likely have otherwise been misdiagnosed.
Rett syndrome is believed to be caused by a mutation in the MECP2 gene that encodes Methyl-CpG binding protein 2 (MeCP2). The correct level of expression is also critical to normal cognitive function as doubling of the MECP2 gene also leads to severe defects. This protein is believed to be involved in controlling the expression levels of many other genes through its effect on chromatin remodeling. MeCP2 is critical for the normal functioning of neurons and has been shown to directly modulate the number of glutamatergic synapses in the brain. Interestingly, Cre-Lox targeted knockout of GABAergic neurons replicated the symptoms of Rett syndrome.
In order to determine an appropriate treatment for Rett syndrome, the specific mechanism of the disease needed to be understood. Given the disease’s delayed onset it was important to determine whether the MECP2 mutation was inhibiting postnatal development of neurons or the ability to maintain neurons. To make this determination, Dr. Zoghbi used mice to show that by knocking out the gene late in development, the same phenotype was achieved as that seen in mice that never had the functional MECP2 gene. Therefore, Rett syndrome is a deficiency in the ability to maintain neurons and would require chronic treatment to alleviate its symptoms.
Genes, the Environment, and Decisions
Cornelia Bargmann, Rockefeller University
Dr. Bargmann began her talk by describing the limitations of relying solely on genomics for the determination of disease risk. An example often brought up in the realm of epigenetics is the fact that identical twins that theoretically share 100% of their genomes do not always develop the same diseases. Of particular interest for this lecture was the flexible nature of neuronal circuits and how the connectome, or the map of all neural connections, also plays a vital role alongside the genome in determining eventual phenotype.
The model system used by Dr. Bargmann is the nematode, C. elegans. The relative simplicity of C. elegans allows for a complete anatomical wiring diagram that shows all of its electrical and chemical synapses. However, even a complete connectome is not sufficient to describe or predict behaviors. One of the primary reasons for this insufficiency is the fact that the diagram does not take into account neuromodulators and neuropeptides that can allow neurons to switch between specific functions.
It is therefore more useful to think of the connectome as a set of flexible connections that contain overlapping circuits instead of a rigid and determinant map. This would suggest that the connectome is of similar use as the genome given the fact that just knowing a genetic code cannot tell you much about gene expression profiles or other factors affected by epigenetics.
Down Regulation of Specific miRNAs in Cell Death Vulnerability of SCA6
Tsutomu Tanabe, Tokyo Medical & Dental University
Spinocerebellar ataxia type 6 (SCA6) is an autosomal dominant neurodegenerative disease affecting the cerebellar Purkinje cells. The disease is caused by polyglutamine expansion in the C-terminus of the P/Q-type Ca2+ channels (Cav2.1). Although it is generally believed that pathogenesis is due to channel disruption from polyglutamine expansion, Dr. Tanabe’s research has shown that the mechanism of disease is likely independent of this expansion and is instead due to toxicity caused by the C-terminal fragment itself. Evidence for this was the fact that cell viability was similar between the wild type and affected cells under normal conditions, but affected cells were more vulnerable to oxidative stress induced by Cd2+.
Since recent reports indicated that miRNA is involved in similar polyglutamine expansion diseases such as Huntington’s disease, Dr. Tanabe set out to determine if miRNA plays a role in SCA6 pathogenesis. By generally knocking down miRNA through knockdown of Dicer, cell survival was significantly decreased, particularly in the affected cell type. Given this information, microarray analysis was used to determine which miRNAs were expressed at a lower level in the affected cells, which led to the identification of 6 miRNAs. These 6 miRNAs that were expressed at significantly lower levels are currently being analyzed for causal relationships to pathogenesis.
The Epigenetic Basis of Common Human Disease
Andrew Feinberg, Johns Hopkins University
“What is the basis of phenotypic variation?” Dr. Feinberg posed this rather complex question early in his talk and I think it is on the mind of many, if not all, geneticists. To emphasize the fact that genetic variation is not completely behind phenotypic variation, he then pointed out how the same organ between two different species (a chimpanzee’s stomach compared to a human’s stomach) is much more similar than different organs within an individual (a human’s eye compared to a human’s stomach). Although the former is due to genetic variation, the much more striking example of difference is due to epigenetic variation.
Dr. Feinberg suggests that just as many diseases can be analyzed by genotypic analysis, it may be of equal interest to conduct epigenetic analysis of disease risk as determined by methylation patterns, which may be influenced by age, environment and genetic sequence. One specific example of an epigenetic component of disease is how epigenetic variation in cancer cells can allow for aberrant expression of oncogenes or suppression of tumor suppressors. While methylation patterns are typically specific to cell type, one interesting discovery was that some cancer cells developed methylation patterns of the incorrect cell type (such as pancreatic cancer cells showing liver-specific methylation patterns). Dr. Feinberg presented data to emphasize this apparent confusion of cancer cells regarding their identity, which may play a role in cancer pathogenesis.
What was perhaps most interesting about the talk was the idea that there is a stochastic nature to the epigenome that is Lamarckian in nature. That is, the propensity for variation at specific sites within the genome for epigenetic marks is itself heritable rather than a specific epigenetic code. This is certainly a new idea for me, and it definitely goes a long way to explain complex traits that are unable to be explained by genomics alone.
MeCP2 Phosphorylation in Synaptogenesis, Long- term Potentiation, Learning and Memory
Hongda Li, University of Wisconsin, Madison
Dr. Li’s research concerns Methyl-CpG binding protein 2 (MeCP2), which is critical for proper cognitive function, as mutations in the MECP2 gene lead to Rett syndrome. Of particular interest to Dr. Li’s lab is the phosphorylation of MeCP2 that takes place in response to neural activity. This phosphorylation leads to the release of MeCP2 from the BDNF promoter. In order to determine the phenotypic effect of this phosphorylation, a mutant mouse strain was created that is incapable of phosphorylating MeCP2.
Interestingly, by preventing phosphorylation of MeCP2, the mutant mice showed a specific effect in the hippocampal region resulting in improved memory formation, enhanced long-term potentiation, and increased excitatory synaptogenesis. Dr. Li’s data also showed that this mutation led to an increased ability of MeCP2 to bind to specific promoter sites to alter expression of those genes. Therefore, MeCP2 may play a vital role in neuromodulatory activities within the brain.
Epigenetic and Gene Expression Profiles in Psychiatric Brains
Kevin Bowling, Hudson Alpha Institute for Biotechnology
Given that monozygotic twins share the same genome, yet do not share the same vulnerability to disease, it is apparent that epigenetic factors play a role in determining phenotypes. Dr. Bowling’s research examines DNA methylation patterns on a genome-wide scale to determine if specific epigenetic patterns are associated with specific diseases. An overarching goal of determining this relationship between methylation patterns and diseases is to determine biomarkers for the diagnosis of disease, as well as to identify disease specific genes that are affected by these methylation patterns.
The method used to analyze these methylation patterns is known as Reduced Representation Bisulfite Sequencing. Initial results showed that methylation patterns are specific to brain regions, which suggests that methylation patterns are involved in determining the identity of each brain region. Regarding methylation identity in diseases, there was evidence that aberrant methylation patterns do exist in the three mental disease samples (schizophrenia, bipolar disorder, and major depression), with some changes isolated to specific brain regions. Further studies by Dr. Bowling will delve into RNA-seq to sequence the mRNA that is present in the samples and confirm that differential methylation patterns are altering the gene expression patterns in pathogenic brains.
** A big thanks from EpiGenie goes out to Michael D’Ecclessis, who is a Graduate Fellow in the Hart Lab at Rutgers University, for providing this conference coverage.