The growth and retraction of dendritic spines with synapse formation and elimination is thought to underlie experience-dependent changes in brain circuitry during development and in the adult brain, and also may play a role in neurodevelopmental disorders. While much focus has been given to spine growth and associated synapse formation as a key step in the development of brain circuits, the mechanisms and functional implications of spine retraction have been neglected. During late postnatal development, after initial connectivity has been established, dendritic spine densities decrease and half of all synapses are lost in some regions of the cortex. This period coincides with a period of intense learning, suggesting that spine retraction and synapse elimination may have an integral role in learning and memory. The primary goal of the proposed studies is to determine the mechanisms that govern the retraction of dendritic spines and the disassembly of spine synapses during brain development, plasticity, and disease. We have three specific aims. First, we will test our hypothesis that spine retraction is induced by activity patterns that lead to synaptic weakening. Second, we will determine whether spine retraction is preceded, and possibly even initiated, by synapse disassembly. Finally, we will examine whether turnover rates of postsynaptic proteins can influence spine stability. To achieve these goals, we will use focal photolysis of caged glutamate to stimulate individual spines, combined with electrophysiology to measure consequences on spine synapse function, and dual-color time-lapse imaging to monitor the dynamics of postsynaptic proteins during spine retraction. The combined use of two-photon imaging techniques and electrophysiology of single synapses provides a novel way to identify the mechanisms that govern the retraction and disassembly of spine synapses. Results from our experiments will fill major gaps in our current understanding of neural circuit refinement during experience-dependent plasticity. Ultimately, basic knowledge of the mechanisms of spine synapse elimination has strong potential to facilitate the development of therapeutics for neurological diseases.

Public Health Relevance

There is growing evidence that disorders in neural circuit development contribute to the etiology of many neurological diseases, including autism, schizophrenia, bipolar disorder, epilepsy, and X-linked mental retardation syndromes. The proposed experiments promise to increase our basic knowledge about the cellular and molecular mechanisms of neural circuit development in the mammalian cerebral cortex. Ultimately, such knowledge has strong potential to facilitate the development of therapeutics for human neurological diseases, such as Fragile X syndrome and autism.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS062736-05
Application #
8456903
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Mamounas, Laura
Project Start
2009-08-01
Project End
2014-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
5
Fiscal Year
2013
Total Cost
$309,933
Indirect Cost
$103,061
Name
University of California Davis
Department
Neurology
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Stein, Ivar S; Zito, Karen (2018) Dendritic Spine Elimination: Molecular Mechanisms and Implications. Neuroscientist :1073858418769644
Hamilton, A M; Lambert, J T; Parajuli, L K et al. (2017) A dual role for the RhoGEF Ephexin5 in regulation of dendritic spine outgrowth. Mol Cell Neurosci 80:66-74
Lambert, Jason T; Hill, Travis C; Park, Deborah K et al. (2017) Protracted and asynchronous accumulation of PSD95-family MAGUKs during maturation of nascent dendritic spines. Dev Neurobiol 77:1161-1174
Dore, Kim; Stein, Ivar S; Brock, Jennifer A et al. (2017) Unconventional NMDA Receptor Signaling. J Neurosci 37:10800-10807
Chenaux, George; Matt, Lucas; Hill, Travis C et al. (2016) Loss of SynDIG1 Reduces Excitatory Synapse Maturation But Not Formation In Vivo. eNeuro 3:
Gray, John A; Zito, Karen; Hell, Johannes W (2016) Non-ionotropic signaling by the NMDA receptor: controversy and opportunity. F1000Res 5:
Stein, Ivar S; Gray, John A; Zito, Karen (2015) Non-Ionotropic NMDA Receptor Signaling Drives Activity-Induced Dendritic Spine Shrinkage. J Neurosci 35:12303-8
Bishop, Hannah I; Guan, Dongxu; Bocksteins, Elke et al. (2015) Distinct Cell- and Layer-Specific Expression Patterns and Independent Regulation of Kv2 Channel Subtypes in Cortical Pyramidal Neurons. J Neurosci 35:14922-42
Oh, Won Chan; Parajuli, Laxmi Kumar; Zito, Karen (2015) Heterosynaptic structural plasticity on local dendritic segments of hippocampal CA1 neurons. Cell Rep 10:162-9
Bishop, Hannah I; Zito, Karen (2013) The downs and ups of sensory deprivation: evidence for firing rate homeostasis in vivo. Neuron 80:247-9

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