The rules governing synaptic metaplasticity (the plasticity of plasticity) are of special importance in the developing nervous system, where experience has an important role in the patterning of neural responses and the influence of prior synaptic activity on future synaptic change can have profound consequences. We have developed and employed a fosGFP transgenic mouse to identify the locus of experience-dependent change in somatosensory neocortex. In control animals, NMDAR-dependent LTP can be generated at layer 4-2/3 synapses in vitro, and normal experience results in the progressive strengthening of these synapses over the second and third postnatal week. Whisker stimulation enhances synaptic strength and leads to a transformation in the molecular mechanisms that underlie plasticity, from NMDAR-dependent to mGluR-dependent potentiation. This proposal seeks to identify how cumulative, experience-dependent plasticity is initiated and maintained by the activation by specific subtypes of glutamate receptors, using both in vivo and in vitro analysis.

Public Health Relevance

Learning frequently takes place over repeated stimulus presentations and is cumulative over time, especially in the neocortex. The cellular and molecular basis for this type of cumulative synaptic change requires identification and analysis of the specific synapses that are undergoing continuous modifications. Using a fosGFP transgenic mice to locate the precise area of the neocortex where plasticity is occurring, we can identify the synaptic substrates of experience-dependent plasticity and determine the molecular mechanisms that are invoked during this form of learning. We have found that the direction of NMDAR-dependent plasticity is reversed after the onset of experience-dependent plasticity in sensory neocortex, and that subsequent synaptic strengthening requires activation of mGluRs. The molecular mechanisms by which experience alters the function and localization of glutamate receptor subtypes is of essential interest to studies of learning and memory.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA017188-10
Application #
8471676
Study Section
Neurobiology of Learning and Memory Study Section (LAM)
Program Officer
Wu, Da-Yu
Project Start
2003-09-23
Project End
2014-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
10
Fiscal Year
2013
Total Cost
$311,043
Indirect Cost
$103,431
Name
Carnegie-Mellon University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
052184116
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Glazewski, Stanislaw; Barth, Alison L (2015) Stimulus intensity determines experience-dependent modifications in neocortical neuron firing rates. Eur J Neurosci 41:410-9
Urban-Ciecko, Joanna; Fanselow, Erika E; Barth, Alison L (2015) Neocortical somatostatin neurons reversibly silence excitatory transmission via GABAb receptors. Curr Biol 25:722-31
Chandrasekaran, Santosh; Navlakha, Saket; Audette, Nicholas J et al. (2015) Unbiased, High-Throughput Electron Microscopy Analysis of Experience-Dependent Synaptic Changes in the Neocortex. J Neurosci 35:16450-62
Jouhanneau, Jean-Sébastien; Ferrarese, Leiron; Estebanez, Luc et al. (2014) Cortical fosGFP expression reveals broad receptive field excitatory neurons targeted by POm. Neuron 84:1065-78
Barth, Alison L; Kuhlman, Sandra J (2013) The many layers of specification and plasticity in the neocortex. Neuron 79:829-31
Wen, Jing A; DeBlois, Mark C; Barth, Alison L (2013) Initiation, labile, and stabilization phases of experience-dependent plasticity at neocortical synapses. J Neurosci 33:8483-93
Benedetti, Brett L; Takashima, Yoshio; Wen, Jing A et al. (2013) Differential wiring of layer 2/3 neurons drives sparse and reliable firing during neocortical development. Cereb Cortex 23:2690-9
Barth, Alison L; Poulet, James F A (2012) Experimental evidence for sparse firing in the neocortex. Trends Neurosci 35:345-55
Wen, Jing A; Barth, Alison L (2011) Input-specific critical periods for experience-dependent plasticity in layer 2/3 pyramidal neurons. J Neurosci 31:4456-65
Yassin, Lina; Benedetti, Brett L; Jouhanneau, Jean-Sebastien et al. (2010) An embedded subnetwork of highly active neurons in the neocortex. Neuron 68:1043-50

Showing the most recent 10 out of 17 publications