The goal of this proposal is to elucidate the role of dendritic Ca2+ spikes in learning-dependent synaptic plasticity in the mouse cortex. Dendritic Ca2+ spikes enhance the computational power of individual neurons by amplifying synchronously activated excitatory synaptic inputs. In vitro studies have shown that dendritic Ca2+ spikes play an important role in activity-dependent synaptic potentiation and depression. The in vivo function of dendritic Ca2+ spikes in synaptic plasticity remains elusive. Our preliminary studies show that different motor learning tasks induce dendritic Ca2+ spikes on different apical tuft branches of layer V (L5) pyramidal neurons in the mouse primary motor cortex. We propose to investigate how such task-and branch-specific dendritic Ca2+ spikes affect the induction and maintenance of synaptic plasticity in the motor cortex. With a combination of experimental approaches including in vivo two-photon imaging and pharmacogenetic manipulations of neuronal activity, we will determine how dendritic Ca2+ spikes cause synaptic potentiation and depotentiation on different apical branches of individual L5 pyramidal neurons in response to different motor learning tasks. We will also investigate whether dendritic Ca2+ spikes promote branch-specific formation of new dendritic spines and whether newly-formed spines are co-active with adjacent spines in a task-specific manner. Our preliminary studies indicate that inactivation of somatostatin-expressing interneurons disrupts branch-specific generation of Ca2+ spikes. We will further investigate if such disruption affects the induction and maintenance of synaptic plasticity during motor learning. In addition, we will examine how the activity of somatostatin- expressing interneurons, the generation of branch-specific Ca2+ spikes and dendritic spine plasticity are altered in a mouse model of Fragile X syndrome. The proposed experiments will reveal the fundamental role of branch-specific dendritic Ca2+ spikes in the induction and maintenance of synaptic plasticity during learning and memory formation. These studies will also provide novel insights into developing new strategies for the treatment of intellectual disability and autism.

Public Health Relevance

The main goal of this proposal is to determine the mechanisms underlying changes of neuronal connectivity during learning and memory. By imaging neurons and their processes in the brains of awake behaving mice, we will elucidate how motor skill learning induces calcium elevations in neuronal processes to cause long-lasting changes in brain connectivity. The proposed studies address fundamental mechanisms underlying learning and memory and will help to better understand the pathophysiology of intellectual disability and autism.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neurobiology of Learning and Memory Study Section (LAM)
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Lavaute, Timothy M
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New York University
Schools of Medicine
New York
United States
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Lai, Baoling; Li, Miao; Hu, Wanling et al. (2018) The Phosphodiesterase 9 Inhibitor PF-04449613 Promotes Dendritic Spine Formation and Performance Improvement after Motor Learning. Dev Neurobiol 78:859-872
Lai, Cora Sau Wan; Adler, Avital; Gan, Wen-Biao (2018) Fear extinction reverses dendritic spine formation induced by fear conditioning in the mouse auditory cortex. Proc Natl Acad Sci U S A 115:9306-9311
Zhou, Yanmei; Lai, Baoling; Gan, Wen-Biao (2017) Monocular deprivation induces dendritic spine elimination in the developing mouse visual cortex. Sci Rep 7:4977
Cichon, Joseph; Blanck, Thomas J J; Gan, Wen-Biao et al. (2017) Activation of cortical somatostatin interneurons prevents the development of neuropathic pain. Nat Neurosci 20:1122-1132
Bai, Yang; Li, Miao; Zhou, Yanmei et al. (2017) Abnormal dendritic calcium activity and synaptic depotentiation occur early in a mouse model of Alzheimer's disease. Mol Neurodegener 12:86
Li, Wei; Ma, Lei; Yang, Guang et al. (2017) REM sleep selectively prunes and maintains new synapses in development and learning. Nat Neurosci 20:427-437
Cichon, Joseph; Gan, Wen-Biao (2015) Branch-specific dendritic Ca(2+) spikes cause persistent synaptic plasticity. Nature 520:180-5
Magrané, Jordi; Cortez, Czrina; Gan, Wen-Biao et al. (2014) Abnormal mitochondrial transport and morphology are common pathological denominators in SOD1 and TDP43 ALS mouse models. Hum Mol Genet 23:1413-24
Yang, Guang; Lai, Cora Sau Wan; Cichon, Joseph et al. (2014) Sleep promotes branch-specific formation of dendritic spines after learning. Science 344:1173-8
Marvin, Jonathan S; Borghuis, Bart G; Tian, Lin et al. (2013) An optimized fluorescent probe for visualizing glutamate neurotransmission. Nat Methods 10:162-70

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