The mammalian brain is composed of billions of neurons. Each of these neurons forms up to several thousand synaptic connections, asymmetric intercellular junctions that transmit signals essential for our abilities to perceive the external world, generate behavioral responses, learn and remember. Synapses are sophisticated structures built with hundreds of different proteins. Mutations in genes encoding these proteins have been implicated in a broad spectrum of neurodegenerative and psychiatric disorders including Alzheimer’s disease, Parkinson’s disease, Autism Spectrum Disorders, Bipolar Disorder and Schizophrenia.
Our laboratory uses the power of mouse genetics to study how neurons establish their connectivity patterns during development, and how they maintain and re-organize synapses in the adult brain. We employ a variety of experimental approaches ranging from imaging of specific genetically targeted neuronal types in intact circuits to behavioral analyses of mice engineered to have mutations in genes of interest or to manipulate synaptic communication with small molecules. Our primary model system is the Dentate Gurus, a brain region that relays information essential for multiple cognitive tasks from the cerebral cortex to the hippocampus.
A part of our research program is focused on dissecting the mechanisms controlling transcription of synapse-related genes. The majority of these genes become activated when the developing brain starts receiving inputs from peripheral sensory neurons responding to light, odors, sounds, and mechanical stimuli. Experience also profoundly influences gene expression in the adult brain, and this process plays a critical role in learning and memory. We are interested in identifying transcriptional activators and repressors that sense neuronal activity and orchestrate global or cell-type-specific changes in their transcriptional profiles, and in elucidating the roles of these factors in synapse formation and information processing. In conjunction with these studies, we also search for factors that regulate synaptic connectivity between human neurons differentiated in vitro from non-neuronal cells.
A second major interest in our laboratory is in membrane trafficking. Neurons communicate with each other by secreting a variety of molecules including classical neurotransmitters, guidance cues, neuropeptides and trophic factors. These molecules are stored in specialized vesicular organelles that deliver and release cargo at distinct spatially-restricted sites such as presynaptic boutons, tips of axons, and dendritic spines. We combine genetic methods with high-resolution time-lapse imaging of fluorescent reporters in live neurons to study the mechanisms underlying vesicle sorting, transport and exocytosis.
The progress of contemporary neurobiology depends on continuous development of new tools for targeting discrete structurally and functionally diverse neuronal populations in the brain, controlling their activity, and monitoring the outcomes of these manipulations at molecular, cellular and systems levels. We design and improve such tools for our own research, and freely distribute them to the neuroscience community around the globe.
Our studies are currently funded by the National Institute of Mental Health, Novartis Advanced Discovery Institute, Baxter Foundation, Helen Dorris Neuroscience Fellowship program and the Life Science Research Foundation.
Sando R, Pieraut S, Gounko N, Liao L, Yates J, Maximov A (2012) HDAC4 governs a transcriptional program essential for synaptic plasticity and memory. Cell 151(4):821-834.
Cao P, Maximov A, Südhof TC (2011) Activity-dependent IGF-1 exocytosis is controlled by the Ca2+-sensor Synaptotagmin-10. Cell 145(2): 300-311.
Maximov A, Tang J, Yang X, Pang Z, Südhof TC (2009) Complexin controls the force transfer from SNARE complexes to membranes in fusion. Science 323(5913):516-521.
Tang J #, Maximov A #, Shin OH, Dai H, Rizo J, Südhof TC (2006) A complexin/synaptotagmin-1 switch controls fast synaptic vesicle exocytosis. Cell 126(6):1175-87. #These authors contributed equally to this work.
Maximov A, Südhof TC (2005) Autonomous function of synaptotagmin-1 in triggering synchronous release independent of asynchronous release. Neuron 48(4):547-554.