During brain development, after initial circuit formation, neuronal arbors are further refined by experience during a period of activity-dependent plasticity. This use-dependent selection of appropriate connections, leads to retention of some branches while others are eliminated, and is critical for generating efficient functional circuits. It is thought that many neurodevelopmental disorders, including ones that effect visual perception, result from disruption of experience-dependent plasticity leading to deficits in synaptic connectivity, stabilization, or maturation. Unfortunately, little is known about the molecular mechanisms regulating selective synapse and dendrite stabilization in response to activity. In the previous grant periods we showed that cpg15, discovered in a screen for activity-regulated genes, is regulated by light-driven neural activity in the visual system, and that the CPG15 protein promotes dendritic and axonal arbor growth, and enhances synaptic maturation. We propose investigating the cpg15 KO mouse towards the goal of understanding in molecular detail the mechanisms that underlie activity-dependent plasticity. Based on preliminary data we hypothesize that CPG15 acts to stabilize nascent synapses on dendritic spines resulting in spine and arbor stabilization and synaptic maturation. When CPG15 is expressed in response to activity, it provides a saliency signal for selective stabilization of active synapses. We propose combining molecular genetics with electrophysiology, visual manipulations, in vivo two-photon microscopy, and optical imaging of intrinsic signal, to test the hypothesis that CPG15 is required and sufficient for experience- dependent stabilization of synaptic and neuronal structures and that its function is critical for experience- dependent developmental plasticity. Our studies focus on the visual cortex, where anatomical and physiological studies provide a rich and well-characterized experimental toolkit for manipulating experience, and where our previous work has shown that spatio-temporal cpg15 expression coincides with developmental sites and times of activity-dependent circuit wiring.

Public Health Relevance

It is thought that many neurodevelopmental disorders, including ones that effect visual perception, result from disruption of experience-dependent plasticity leading to deficits in synaptic connectivity, stabilization, or maturation. Not surprisingly, the activity-dependent transcriptional program is a nexus for genetic mutations that give rise to neurological disorders in humans. cpg15, discovered in a screen for activity-regulated genes, is regulated by light-driven neural activity in the visual system, and promotes dendritic and axonal arbor growth, and synaptic maturation. We propose investigating the cpg15 KO mouse towards the goal of understanding in molecular detail the mechanisms that underlie activity-dependent plasticity. Understanding these mechnisms opens the door to therapeutics for correction of a broad range of disorders that derive from defective brain circuitry.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY011894-14
Application #
8204630
Study Section
Special Emphasis Panel (ZRG1-MDCN-T (02))
Program Officer
Steinmetz, Michael A
Project Start
1997-07-01
Project End
2012-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
14
Fiscal Year
2012
Total Cost
$403,200
Indirect Cost
$163,200
Name
Massachusetts Institute of Technology
Department
Miscellaneous
Type
Schools of Arts and Sciences
DUNS #
001425594
City
Cambridge
State
MA
Country
United States
Zip Code
02139
Picard, Nathalie; Leslie, Jennifer H; Trowbridge, Sara K et al. (2014) Aberrant development and plasticity of excitatory visual cortical networks in the absence of cpg15. J Neurosci 34:3517-22
Chen, Jerry L; Villa, Katherine L; Cha, Jae Won et al. (2012) Clustered dynamics of inhibitory synapses and dendritic spines in the adult neocortex. Neuron 74:361-73
Fujino, Tadahiro; Leslie, Jennifer H; Eavri, Ronen et al. (2011) CPG15 regulates synapse stability in the developing and adult brain. Genes Dev 25:2674-85
Leslie, Jennifer H; Nedivi, Elly (2011) Activity-regulated genes as mediators of neural circuit plasticity. Prog Neurobiol 94:223-37
Loebrich, Sven; Nedivi, Elly (2009) The function of activity-regulated genes in the nervous system. Physiol Rev 89:1079-103
Fujino, Tadahiro; Wu, Zhen; Lin, Walter C et al. (2008) cpg15 and cpg15-2 constitute a family of activity-regulated ligands expressed differentially in the nervous system to promote neurite growth and neuronal survival. J Comp Neurol 507:1831-45