Assistant Professor of NeurobiologyLab Homepage: https://andreagomezlab.com/
Genetic programs balance order and variability in the brain. This balancing act relies on molecular cues to sculpt the patterns of brain activity that underlie behavior. The deficit in our knowledge of these mechanisms matches with the lack of clinical solutions for psychiatric disorders. My lab uses a range of techniques to decode the instructive cues that organize neural networks, including electrophysiology, functional imaging, and molecular biology. We focus on mechanisms that specify synaptic properties and how these properties bias the timescales of neuronal computation. We are working to discover how synaptic dysfunction manifests in conditions like autism, intellectual disability, and neurodegenerative disorders.
Neurons utilize transsynaptic signaling at cell-to-cell contacts to pattern, organize, and connect the brain in stereotyped ways. Combinations of transsynaptic signaling underlie the specification of synaptic properties, yet how are these combinations generated and regulated in distinct cell populations? My research program aims to gain mechanistic insight into how regulation at the RNA level translates into organizing signals that direct the assembly and maintenance of neural circuits.
Alternative RNA splicing and neural function: Amongst vertebrates, the number of genes does not scale with brain complexity. Thus, we look to alternative RNA splicing for its potential to vastly expand proteomic diversity. Given that 95% of multi-exon genes are alternatively spliced and the extent of alternative splicing scales with network complexity, we focus on how alternative splicing shapes cell type transcriptomes for neuronal function. Yet, how does this potential increase in molecular complexity operate selectively in neural networks? To answer this, we query the output of splicing regulators that act in nonoverlapping cell populations in the brain using two strategies:
- We identify cell type-specific transcriptional fingerprints tuned by alternative splicing.
- We link these RNA encoded cues to cell type-specific dynamics of ionic flux.
Multiplexed synaptic organization in axons. A single axon from a CA3 pyramidal neuron in the hippocampus can terminate onto 30,000 targets that include different cell types. Little is known about how presynaptic components distribute to a neuron's many axon terminals, despite knowing that synaptic properties can differ depending on the target neuron. Considering the various targets of CA3 pyramidal neurons, how are distinct synaptic properties established? We use cell type-specific genetic strategies to reveal the cellular rules by which single neurons communicate with different targets.
Uncovering the cellular basis for input-specific responses and their role in neuronal integration:
CA1 pyramidal neurons in the hippocampus receive tens of thousands of inputs from different brain regions, each with unique synaptic properties. These inputs are organized and processed in discrete subcellular compartments, generating distinct dynamics of ionic flux necessary for synaptic integration and neuronal computation. However, it is unclear how input-specific cellular responses coordinate changes to synapses from discrete inputs and alter local and global time windows for integration. To better understand these responses, we combine functional imaging and electrophysiology to observe the local and global rules that emerge from transsynaptic signaling.
The RNA biology of psychedelics
In neurological disorders, our ability to move, learn, remember, empathize, or recover from trauma is not limited by will but by the capacity of our neurons to synthesize components for cognitive flexibility. Plasticity in the brain counters this rigidity, yet we lack insight into opening plasticity windows in the brain. Psychedelics have been used in Indigenous healing practices for millennia to engage cognitive connection and open pathways to healing. We propose to synthesize two rapidly evolving fields - RNA biology and psychedelics - to discover novel plasticity RNAs and understand how they coordinate large-scale neural plasticity.
Gomez, AM, Traunmüller, L. and Scheiffele, P. (2021) Neurexins: molecular codes for shaping neuronal synapses. Nature Review Neuroscience, 22:137–151
Luo L, Ambrozkiewicz MC, Benseler F, Chen C, Dumontier E, Falkner S, Furlanis E, Gomez AM, Hoshina N, Huang WH, Hutchison MA, Itoh-Maruoka Y, Lavery LA, Li W, Maruo T, Motohashi J, Pai EL, Pelkey KA, Pereira A, Philips T, Sinclair JL, Stogsdill JA, Traunmüller L, Wang J, Wortel J, You W, Abumaria N, Beier KT, Brose N, Burgess HA, Cepko CL, Cloutier JF, Eroglu C, Goebbels S, Kaeser PS, Kay JN, Lu W, Luo L, Mandai K, McBain CJ, Nave KA, Prado MAM, Prado VF, Rothstein J, Rubenstein JLR, Saher G, Sakimura K, Sanes JR, Scheiffele P, Takai Y, Umemori H, Verhage M, Yuzaki M, Zoghbi HY, Kawabe H, Craig AM. (2020) Optimizing Nervous System-Specific Gene Targeting with Cre Driver Lines: Prevalence of Germline Recombination and Influencing Factors. Neuron. Feb 5. doi:10.1016/j.neuron.2020.01.008
Tora D, Gomez AM, Michaud JF, Yam PT, Charron F, Scheiffele P. (2017) Cellular Functions of the Autism Risk Factor PTCHD1 in mice. Journal of Neuroscience Nov 8. pii: 1393-17
Traunmüller L*, Gomez AM*, Nguyen TM, Scheiffele P. (2016) Control of neuronal synapse specification by a highly dedicated alternative splicing program. Science, 352 (6288): 982-6
Gomez AM, Froemke RC, Burden SJ (2014) Synaptic plasticity and cognitive function are disrupted in the absence of Lrp4. eLife, 2014;3:e04287
Gomez AM and Burden SJ (2011). The Extracellular Region of Lrp4 Is Sufficient to Mediate Neuromuscular Synapse Formation. Developmental Dynamics, 240, 2626-2633
Kim N, Stiegler AL, Cameron TO, Hallock PT, Gomez AM, Huang JH, Hubbard SR, Dustin ML, Burden SJ. (2008) Lrp4 is a receptor for Agrin and forms a complex with MuSK. Cell, 135(2):334-42
Last Updated 2021-08-05