The main goal of our work is focused on understanding neuropsychiatric disorders while dissecting the neuronal circuits controlling behaviors. We study synaptic and postsynaptic density proteins implicated in autism and schizophrenia in specific cell-types and neuronal circuits. We want to understand how synaptic computations give rise to social behavioral programs and to uncover the genetic elements that regulate sociability. To achieve our goals, we use a combination of molecular genetics, optogenetics and electrophysiological approaches. We also apply our expertise in the development on novel, genetically engineered mouse models to create tools usable by the neuroscience community.
Current projects in the lab include:
Environmental and Epigenetic Alterations Affecting Social behaviors
Social interactions are complex behaviors displayed by most animal species. Overt dysfunction in sociability is a hallmark of neuropsychiatric disorders such as autism and schizophrenia, but abnormal social interaction in otherwise healthy individuals is itself a trigger for mental health disorders. For instance, several forms of social stress are well described to contribute to the onset of posttraumatic stress disorder and major depression. Early deprivation of maternal care is another form of social stress and is acknowledged to have a long-term effect on animal behavior and is one of the most potent, naturally occurring stressors. Early life deprivation and adversity (EDA) are forms of stress that trigger alterations in gene expression through epigenetic mechanisms and that increase the risk for psychiatric disorders in adulthood. Chronic stress mediates structural modification in neuronal circuit function, leading to perturbed behavioral strategies. Nevertheless, the modifications occurring as a consequence of EDA, and the interplay between epigenetic mechanisms and circuit dysfunctions are not yet completely understood.
mGluR Signaling in Autism Spectrum Disorders
Autism spectrum disorders (ASDs) are early onset neurodevelopmental conditions characterized by persistent problems in social interaction and communication, as well as by the presence of stereotypies, restricted interests and repetitive behaviors. Genetic and genomic studies have identified a wide range of candidate genes scattered across the genome that display significant alterations ranging from single nucleotide rare variants to large chromosomal abnormalities. A key molecular focal point are the metabotropic glutamate receptors (mGluRs). Nevertheless, despite their clear involvement in autism pathology, the underlying molecular and cellular pathways regulating these receptors under disease conditions are poorly understood. Therefore, we are currently studying autism candidate genes that intersect with the regulation of mGluRs and that may spur a new understanding of the pathophysiological mechanism underlying forms of ASDs where there is mGluR dysfunction.
(Opto)Genetic Engineering and Tool Development
We have wide range expertise in mouse molecular genetics, having developed several animal models and transgenic tools. Some of our present interests are in the field of Optogenetics. Channelrhodopsin-2 (ChR2) is a key component in optogenetic applications absorbing blue light to cause a switch in the all-trans-retinal chromophore, and a subsequent conformational change in the protein. During long term transgenic expression, the channel does not require exogenous co-factors and retains its ability to induce neuronal firing with millisecond precision. The rapid opening and closure of the channel, the presence of retinal in most vertebrate cells, and the fact that ChR2 can be genetically encoded are attractive features that make ChR2 a useful tool for therapeutic applications. However, most optogenetic tools are excited only by blue light, and the few exceptions display problematic sustained depolarization between light pulses and generally display inadequate currents. To overcome these limitations, we are investigating and developing novel ChR2 mutants.