University of Toronto Mississauga; CCT Building, Rm 4061; 3359 Mississauga Road
Mississauga, ON L5L 1C6
My research focuses on how memory is encoded in rodents at the molecular level, and how these molecular changes support the establishment and persistence of a memory. Even though we have known of the molecular basis of memory for over a decade, how the molecular events sum together to give rise to memory is still not understood. Currently I am focused on “transient” players in memory formation, focusing on mRNA itself. This view was spurred by the observation that the synapse is capable of local translation (IE within the synapse) of mRNA into proteins, giving synapses a vital role in local regulation of translation and thus how synapses respond to experience.
Epitranscriptomic modifications (m6A is the most common) regulate nearly every aspect of mRNA, from transport, to translation, and ultimately its degradation. These modifications are added to mRNA (in this case a methylation on adenosine) during transcription. The outcome depends on the location of the m6A within the mRNA and which reader protein is engaged to ‘read’ it. The end result is a highly regulatable system that can promote or inhibit protein production in specific locations within the cell, thus allowing synaptic and nuclear locations to have different translational programs in response to synaptic activity, IE the same mRNA can be handled in opposing ways depending on WHERE in the neuron the mRNA is located. My lab was the first to discover that in the hippocampus m6A is actively promoted (by loss of the m6A eraser FTO) during memory formation. This lead to an overall increase in m6A after memory formation, and viral mediated removal of FTO promoted memory formation in rodents. These findings introduced epitranscriptomics as an active and vital process in memory formation, and FTO specifically as a memory inhibitor.
My interests focus on the synapse, its molecular makeup, and how that changes with memory formation. My current focus on m6A is a logical application of this interest as epitranscriptomics have quickly positioned themselves as key regulators in the protein makeup of the synapse, and importantly they control how that makeup changes with memory. Projects in the laboratory are centered around this idea, but are not limited to it. We are also actively researching how stress, sex, neurological diseases affect synaptic dynamics and ultimately memory formation.
*Park, A, *Jacob, AD, *Walters, BJ, Park S, Rashid, AJ, Jung, JH, Lau, J, Woolley, AG, Frankland, PW, Josselyn, SA A time-dependent role for the transcription factor CREB in neuronal allocation to an engram underlying a fear memory revealed using a novel in vivo optogenetic tool to modulate CREB function. Neuropsychopharmacology. 45, 916–924 (2020). https://doi.org/10.1038/s41386-019-0588-0. *Authors Contributed Equally
Walters BJ, Josselyn SA. Retinoic acid receptor plays both sides of homeostatic plasticity. Proc Natl Acad Sci USA. 2019 May. 11 6(14):6528-6530. Doi 10.1073/pnas.1902400116
Narkaj K, Stefanelli G, Wahdan M, Azam AB, Ramzan F, Steininger CFD Jr, Walters BJ, Zovkic IB. (2018) Blocking H2A.Z Incorporation via Tip60 Inhibition Promotes Systems Consolidation of Fear Memory in Mice. eNeuro. 2018 Nov 8;5(5). pii: ENEURO.0378-18.2018. doi: 10.1523/ENEURO.0378-18.2018. eCollection 2018 Sep-Oct.
Stefanelli G*, Azam AB*, Walters BJ, Brimble MA, Gettens CP, Bouchard-Cannon P, Cheng H-YM, Davidoff AM, Narkaj K, Day JJ, Kennedy JJ, and Zovkic IB (2018) Learning and age-related changes in genome-wide H2A.Z binding in the mouse hippocampus. Cell Reports , Volume 22 , Issue 5 , 1124 - 1131
*These authors contributed equally.
Walters BJ, Mercaldo V, Gillon C, Yipp M, Frankland P, Josselyn SA. (2017) The Role of The RNA Demethylase FTO (Fat Mass and Obesity-Associated) and mRNA Methylation in Hippocampal Memory Formation. Neuropsychopharmacology, 42: 1502-1510.
Walters, BJ., Diao, S., Zheng, F., Walters, B., Layman, W., Zuo, Z. (2015). Pseudo-immortalization of postnatal cochlear progenitor cells yields a scalable cell line capable of transcriptionally regulating mature hair cell genes. Scientific Reports 5: 17792.
Ali A, Reis J, Xia Y, Rashid A, Mercaldo V, Walters BJ, Brechun E, Borisenko V, Josselyn S, Karanicolas J, Woolley A. (2015) Optogenetic Inhibitor of the Transcription Factor CREB. Chemistry & Biology, 22: 1531-1539.
Walters BJ, Zovkic IB. (2015) Building up and knocking down: An emerging role for epigenetics and proteasomeal degradation in systems consolidation (Cover Article). Neurosci. 300: 39-52.
Zovkic IB & Walters BJ. (2015) H2A.Z helps genes remember their history so we can remember ours. Bioessays, 37: 596-601
-Subject of a perspective: Cheung P. You must remember this: How H2A.Z potentially links transcriptional memory to cognitive memory formation
Walters BJ, Lin W, Diao S, Brimble M, Iconaru L, Dearman J, Goktug A, Taosheng C, Zuo J (2014) High-throughput Screening Reveals Alsterpaullone, 2-Cyanoethyl as a Potent p27Kip1 Transcriptional Inhibitor. PLoS One, 9: e91173.
Walters BJ, Hallengren JJ, Theile CS, Ploegh HL, Wilson SM, Dobrunz LE. (2014) A catalytic independent function of the deubiquitinating enzyme USP14 regulates hippocampal short-term synaptic plasticity and vesicle number. J Physiol. 592: 571-586.
-Subject of a perspective: Miller RJ. (2014) How does ubiquitin regulate the synapse? Let me count the ways. J Physiol. 592: 555-556.
Marshall AG, Watson JA, Hallengren JJ, Walters BJ, Dobrunz LE, Francillon L, Wilson JA, Phillips SE, Wilson SM (2013) Genetic background alters the severity and onset of neuromuscular disease caused by the loss of ubiquitin-specific protease 14 (usp14). PLoS One, 8: e84042.
Jin Y, Chen, P, Watson J, Walters BJ., Phillips S, Green K, Schmidt R, Wilson J, Roberson E, Dobrunz LE, Wilson SM (2012) Usp14 deficiency increases tau phosphorylation without altering tau degradation or causing tau-dependent deficits. PLoS One. 7: e47884.
Liu Z*, Walters BJ*, Owen T, Brimble M, Steigelman K, Zhang L, Mellado-Lagarde M, Valentine MB, Yu Y, Cox B, Zuo J (2012) Regulation of p27Kip1 by Sox2 Maintains Quiescence of Inner Pillar Cells in the Murine Auditory Sensory Epithelium. J Neurosci. 32: 10530-10540.
Liu Z, Dearman JA, Cox BC, Walters BJ, Zhang L, Ayrault O, Zindy F, Gan L, Roussel MF, Zuo J (2012) Age-dependent in vivo conversion of mouse cochlear pillar and deiters' cells to immature hair cells by atoh1 ectopic expression. J Neurosci. 32: 6600-6610.
Chen PC, Qin CL, Li XM, Walters BJ, Wilson JA, Mei L, Wilson SM (2009). The proteasome-associated deubiquitinating enzyme Usp14 is essential for the maintenance of synaptic ubiquitin levels and the development of neuromuscular junctions. J Neurosci. 29: 10909-10119.
Walters BJ, Campbell SL, Chen PC, Taylor AP, Schroeder DG, Dobrunz LE, Artavanis-Tsakonas K, Ploegh HL, Wilson JA, Cox GA, Wilson SM (2008) Differential effects of Usp14 and Uch-L1 on the ubiquitin proteasome system and synaptic activity. Mol Cell Neurosci. 39: 539-548.
Stefanelli G, Walters BJ, Narkaj K, Ramzan F, Tao C, Zovkic IB. (2018) Epigenetic regulation of memory. Molecular-Genetic and Statistical Techniques for Behavioral and Neural Research, 345-382. Edited by Gerlai R. 2018
Walters BJ, Zovkic IB. (2020) Transcriptional regulation in memory. The Mechanisms of Memory. Edited by Sweatt JD, Gavin C, Klann E. Invited chapter. (Publication Date: Oct 2020).
Zovkic IB, Walters BJ, Sweatt JD (2020) Epigenetic mechanisms in memory. The Mechanisms of Memory. Edited by Sweatt JD, Gavin C, Klann E. Invited chapter. (Publication Date: Oct 2020).
Role of epitranscriptomics in local translation at synapses and memory formation; Modeling diseases of the nervous system; Molecular mechanisms of memory formation and storage.