A major focus of our lab is to understand how the development of neuronal circuits is orchestrated in the brain to enable the execution of complex tasks like learning and memory and how failures in this process contribute to disease.
Our work has uncovered novel mechanisms that function to restrict synapse and circuit development in the hippocampus. The focus of our research will be to uncover the molecular mechanisms that underlie synaptic restriction using high-resolution live imaging of an intact circuit. In combination with molecular and biochemical approaches, we aim to define what are the molecular mediators controlling this process and how they function to restrict synaptic development.
This work may have direct relevance for several human neurological diseases since several of the factors we have identified may contribute to neurological conditions such as Alzheimer’s disease and Parkinsons’s disease. We have acquired mouse models for both these diseases and aim to uncover what role molecules involved in the establishment of hippocampal circuitry play in brain dysfunction resulting from these devastating neurological conditions.
Jacob R. Mann, Amanda M. Gleixner, Jocelyn C. Mauna, Edward Gomes, Michael R. DeChellis-Marks, Patrick G. Needham, Katie E. Copley, Bryan Hurtle, Bede Portz, Noah J. Pyles, Lin Guo, Christopher B. Calder, Zachary P. Wills, Udai B. Pandey, Julia K. Kofler, Jeffrey L. Brodsky, Amantha Thathiah, James Shorter, Christopher J. Donnelly, RNA Binding Antagonizes Neurotoxic Phase Transitions of TDP-43, Neuron, Volume 102, Issue 2, 2019, Pages 321-338.e8, ISSN 0896-6273, https://doi.org/10.1016/j.neuron.2019.01.048.
Bai, Yang & Li, Miao & Zhou, Yanmei & Ma, Lei & Qiao, Qian & Hu, Wanling & Li, Wei & Wills, Zachary & Gan, Wen-Biao. (2017). Abnormal dendritic calcium activity and synaptic depotentiation occur early in a mouse model of Alzheimer’s disease. Molecular Neurodegeneration. 12. 10.1186/s13024-017-0228-2.
Wills ZP, Mandel-Brehm C, Mardinly AR, McCord AE, Giger RJ, Greenberg ME. The nogo receptor family restricts synapse number in the developing hippocampus. Neuron. 2012 Feb 9;73(3):466-81.
Odajima J, Wills ZP, Ndassa YM, Terunuma M, Kretschmannova K, Deeb TZ, Geng Y, Gawrzak S, Quadros IM, Newman J, Das M, Jecrois ME, Yu Q, Li N, Bienvenu F, Moss SJ, Greenberg ME, Marto JA, Sicinski P. Cyclin E constrains Cdk5 activity to regulate synaptic plasticity and memory formation.Dev Cell. 2011 Oct 18;21(4):655-68.
Margolis SS, Salogiannis J, Lipton DM, Mandel-Brehm C, Wills ZP, Mardinly AR, Hu L, Greer PL, Bikoff JB, Ho HY, Soskis MJ, Sahin M, Greenberg ME. EphB-mediated degradation of the RhoA GEF Ephexin5 relieves a developmental brake on excitatory synapse formation. Cell. 2010 Oct 29;143(3):442-55.