Homeostatic synaptic scaling adjusts a neuron's excitatory synaptic strengths up or down to compensate for perturbations in activity. This form of plasticity is expressed in large part through changes in postsynaptic AMPAR accumulation, but despite intense recent interest the complete molecular pathway(s) linking altered neuronal activity to homeostatic changes in AMPAR accumulation are not known. Recently we found that synaptic scaling up is transcription-dependent, and requires the GluR2 subunit of the AMPAR for its expression, indicating that transcription of a factor or factors results in enhanced AMPAR accumulation through interactions with GluR2. Here we will determine which GluR2 domains are essential for the homeostatic regulation of synaptic strengths, identify transcription- dependent factors that participate in the synaptic scaling pathway, and finally, use our ability to selectively block synaptic scaling to assess the role of synaptic scaling in experience-dependent plasticity in the intact visual cortex. These experiments will further our understanding of when, where, and how synaptic scaling operates within central cortical circuits, and will generate important insights into how circuits adapt during experience-driven plasticity.
Homeostatic synaptic scaling adjusts a neuron's excitatory synaptic strengths up or down to compensate for perturbations in activity, and acts to stabilize the function of neurons and circuits in the face of developmental or experience-dependent perturbations in drive. This form of plasticity is likely critical for maintaining stable brain function and for preventing the development of overexcitable states such as epilepsy. Despite intense recent interest in understanding the molecular pathway(s) underlying synaptic scaling, the signaling pathways and molecular players that subserve synaptic scaling are not known. The studies outlined in this grant seek to further our understanding of when, where, and how synaptic scaling operates within central cortical circuits, and will generate important insights into how circuits adapt during experience-driven plasticity. Ultimately, these studies will illuminate the genesis of aberrant states, such as addiction or epilepsy that involve adaptive plasticity and/or imbalances in synaptic excitation and inhibition.
|Gainey, Melanie A; Tatavarty, Vedakumar; Nahmani, Marc et al. (2015) Activity-dependent synaptic GRIP1 accumulation drives synaptic scaling up in response to action potential blockade. Proc Natl Acad Sci U S A 112:E3590-9|
|Taft, Christine E; Turrigiano, Gina G (2014) PSD-95 promotes the stabilization of young synaptic contacts. Philos Trans R Soc Lond B Biol Sci 369:20130134|
|Loebrich, Sven; Djukic, Biljana; Tong, Zachary J et al. (2013) Regulation of glutamate receptor internalization by the spine cytoskeleton is mediated by its PKA-dependent association with CPG2. Proc Natl Acad Sci U S A 110:E4548-56|
|Tatavarty, Vedakumar; Sun, Qian; Turrigiano, Gina G (2013) How to scale down postsynaptic strength. J Neurosci 33:13179-89|
|Hengen, Keith B; Lambo, Mary E; Van Hooser, Stephen D et al. (2013) Firing rate homeostasis in visual cortex of freely behaving rodents. Neuron 80:335-42|
|Lambo, Mary E; Turrigiano, Gina G (2013) Synaptic and intrinsic homeostatic mechanisms cooperate to increase L2/3 pyramidal neuron excitability during a late phase of critical period plasticity. J Neurosci 33:8810-9|
|Blackman, Melissa P; Djukic, Biljana; Nelson, Sacha B et al. (2012) A critical and cell-autonomous role for MeCP2 in synaptic scaling up. J Neurosci 32:13529-36|
|Sun, Qian; Turrigiano, Gina G (2011) PSD-95 and PSD-93 play critical but distinct roles in synaptic scaling up and down. J Neurosci 31:6800-8|
|Steinmetz, Celine C; Turrigiano, Gina G (2010) Tumor necrosis factor-Î± signaling maintains the ability of cortical synapses to express synaptic scaling. J Neurosci 30:14685-90|
|Gainey, Melanie A; Hurvitz-Wolff, Jennifer R; Lambo, Mary E et al. (2009) Synaptic scaling requires the GluR2 subunit of the AMPA receptor. J Neurosci 29:6479-89|
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