Mathew Weston
- B.A. Echols Interdisciplinary Studies concentration in Writing, English, German, University of Virginia
- Ph.D. Neuroscience, Baylor College of Medicine
My science career started at the University of Virginia in the lab of Patrice Guyenet, where our studies advanced the understanding of how the CNS senses CO 2 and, accordingly, adjusts respiration. I then moved to Baylor College of Medicine, where I obtained a Ph.D. in Neuroscience working in the lab of Christian Rosenmund. There, we uncovered molecular features of glutamate receptor ion channels and transporters that evolved to optimize glutamatergic neurotransmission in the CNS. I then did a postdoc with John Swann investigating the synaptic and network effects of hyperactivation of the mTOR pathway that cause epilepsy. Upon starting my independent lab at the University of Vermont, we focused on understanding the mechanisms through which genetic variants that cause severe childhood seizure disorders disrupt excitation/inhibition balance in cortical networks.
The overall goal of my research program is to understand how the brain balances excitation and inhibition in cortical circuits so that it can generate proper pattens of network activity. To do this, we study gene variants that cause human childhood epilepsies and seek to understand how they alter neuronal physiology to cause network hyperexcitability and seizures. Our premise is that this work will advance our understanding of normal physiological processes, delineate disease mechanisms, and point toward novel therapeutic strategies. The broad nature of this goal requires that we make meaningful connections between different biological scales, thus, our work is highly collaborative and uses multi-level experimental approaches, from single cells to intact animals. There are multiple opportunities for scientists at all levels of experience to participate in our research process.
The gene variants we study cause severe, intractable epilepsies of childhood, collectively referred to as Developmental Epileptic Encephalopathies (DEEs). DEEs have devastating effects on patients and caregivers, making them a significant health problem. Studying this group of diseases provides a strong framework for our goal of linking molecular and cellular changes to whole organism phenotypes. This is due to the fact that, on one end, DEEs have a strong genetic basis: Almost half of patients that come to the clinic are given a genetic diagnosis, and there are up to 50 verified genes that cause DEEs. Together with our collaborators, we have been at the forefront of taking DEE-causing gene variants discovered in the clinic and creating mouse models with orthologous variants. This provides us with a tractable model system that has a defined starting point for molecular pathology and a plethora of molecular genetic tools to employ. On the other end, the primary symptom of DEEs, epileptic seizures, are detectable and rigorously quantifiable in mice. We use electroencephalography (EEG) and in vivo Ca ++ imaging to detect, localize, and characterize seizures and other, more subtle alterations in brain activity.
The gene variant and the seizures are the start and end points, respectively. To interrogate the mechanisms that link the two, we use patch clamp electrophysiology to measure changes in membrane excitability and synaptic transmission, and multicellular Ca ++ imaging to measure microcircuit activity. Importantly, we investigate both excitatory and inhibitory synaptic transmission and neuron types.
McCabe, MP, Shore, AN, Frankel, WN, & Weston, MC (2021). Altered fast synaptic transmission in a mouse model of DNM1-associated developmental epileptic encephalopathy. eNeuro, 8(2), ENEURO.0269-20.2020.
Shore, AN, Colombo, S, Tobin, WF, Petri, S, Cullen, ER, Dominguez, S, Bostick, CD, Beaumont, MA, Williams, D, Khodagholy, D, Yang, M, Lutz, CM, Peng, Y, Gelinas, JN, Goldstein, DB, Boland, MJ, Frankel, WN, & Weston, MC (2020). Reduced GABAergic neuron excitability, altered synaptic connectivity, and seizures in a KCNT1 gain-of-function mouse model of childhood epilepsy. Cell Reports, 33(4), 108303.
McCabe, MP, Cullen, ER, Barrows, CM, Shore, AN, Tooke, KI, Laprade, KA, Stafford, JM, & Weston, MC (2020). Genetic inactivation of mTORC1 or mTORC2 in neurons reveals distinct functions in glutamatergic synaptic transmission. eLife, 9, e51440.
Sah, M, Shore, AN, Petri, S, Kanber, A, Yang, M, Weston, MC, & Frankel, WN (2020). Altered excitatory transmission onto hippocampal interneurons in the IQSEC2 mouse model of X-linked neurodevelopmental disease. Neurobiology of Disease, 137, 104758.
Barrows, CM, McCabe, MP, Chen, H, Swann, JW, & Weston, MC (2017). PTEN loss increases the connectivity of fast synaptic motifs and functional connectivity in a developing hippocampal network. Journal of Neuroscience, 37(36), 8595–8611.
John Lin, CC, Yu, K, Hatcher, A, Huang, TW, Lee, HK, Carlson, J, Weston, MC, Chen, F, Zhang, Y, Zhu, W, Mohila, CA, Ahmed, N, Patel, AJ, Arenkiel, BR, Noebels, JL, Creighton, CJ, & Deneen, B (2017). Identification of diverse astrocyte populations and their malignant analogs. Nature Neuroscience, 20(3), 396–405.
Weston, MC, Chen, H, & Swann, JW (2014). Loss of mTOR repressors Tsc1 or Pten has divergent effects on excitatory and inhibitory synaptic transmission in single hippocampal neuron cultures. Frontiers in Molecular Neuroscience, 7, 1.
Weston, MC, Chen, H, & Swann, JW (2012). Multiple roles for mammalian target of rapamycin signaling in both glutamatergic and GABAergic synaptic transmission. Journal of Neuroscience, 32(33), 11441–11452.
Weston, MC, Nehring, RB, Wojcik, SM, & Rosenmund, C (2011). Interplay between VGLUT isoforms and endophilin A1 regulates neurotransmitter release and short-term plasticity. Neuron, 69(6), 1147–1159.
Chaudhry, C, Weston, MC, Schuck, P, Rosenmund, C, & Mayer, ML (2009). Stability of ligand-binding domain dimer assembly controls kainate receptor desensitization. EMBO Journal, 28(10), 1518–1530.
Weston, MC, Schuck, P, Ghosal, A, Rosenmund, C, & Mayer, ML (2006). Conformational restriction blocks glutamate receptor desensitization. Nature Structural & Molecular Biology, 13(12), 1120–1127.
Moechars, D, Weston, MC, Leo, S, Callaerts-Vegh, Z, Goris, I, Daneels, G, Buist, A, Cik, M, van der Spek, P, Kass, S, Meert, T, D'Hooge, R, Rosenmund, C, & Hampson, RM (2006). Vesicular glutamate transporter VGLUT2 expression levels control quantal size and neuropathic pain. Journal of Neuroscience, 26(46), 12055–12066.
Weston, MC, Gertler, C, Mayer, ML, & Rosenmund, C (2006). Interdomain interactions in AMPA and kainate receptors regulate affinity for glutamate. Journal of Neuroscience, 26(29), 7650–7658.
Mulkey, DK, Stornetta, RL, Weston, MC, Simmons, JR, Parker, A, Bayliss, DA, & Guyenet, PG (2004). Respiratory control by ventral surface chemoreceptor neurons in rats. Nature Neuroscience, 7(12), 1360–1369.
Weston, MC, Stornetta, RL, & Guyenet, PG (2004). Glutamatergic neuronal projections from the marginal layer of the rostral ventral medulla to the respiratory centers in rats. Journal of Comparative Neurology, 473(1), 73–85.
Rosin, DL, Weston, MC, Sevigny, CP, Stornetta, RL, & Guyenet, PG (2003). Hypothalamic orexin (hypocretin) neurons express vesicular glutamate transporters VGLUT1 or VGLUT2. Journal of Comparative Neurology, 465(4), 593–603.
Weston, M, Stornetta, RL, Guyenet, PG (2004). Glutamatergic neuronal projections from the marginal layer of the rostral ventral medulla to the respiratory centers in rats. Journal of Comparative Neurology. 473, 73-85. PMID: 15067719.
For full list: https://www.ncbi.nlm.nih.gov/myncbi/1h5LIU3bxhiAp/bibliography/public/
Reviews and Book Chapters
Weston, MC and Tzingounis, AV (2022). Potassium Channels in Epilepsy: A Functional Perspective. Jasper’s Basic Mechanisms of the Epilepsies (5th Edition) In press.
Cullen, ER and Weston, MC (2021). Glutamate’s Secret Interictal Life. Epilepsy Currents, 21(6), 460–462.
Weston MC (2021). A tRNA variant translates into seizure resistance. Epilepsy Currents, 21(2), 126–128.
Weston MC (2020). Vulnerabilities in a dominant receptor subunit. Epilepsy Currents, 20(2), 97–98.
Tobin, WF and Weston, MC (2018). Focusing on the big picture: Induced focal seizures propagate along synaptic pathways. Epilepsy Currents, 18(1), 47–48.
Weston MC (2017). GRIN and bear the diverse functional effects of rare NMDA receptor variants. Epilepsy Currents, 17(6), 381–383.
McCabe, MP & Weston, MC (2016). Riding the calcium wave to a better understanding of ictal events. Epilepsy Currents, 16(5), 333–334.