REGULATION OF HOMEOSTATIC PLASTICITY BY PROTEIN PHOSPHATASE 1
Document Type
Presentation
Start Date
22-10-2010 3:00 PM
End Date
22-10-2010 4:30 PM
Description
Individual neurons in the hippocampus and neocortex receive thousands of electrical inputs at synapses along extensive dendritic processes. The term homeostatic plasticity refers to global regulation of these inputs in order to maintain an optimal or normalized level of excitability. We are investigating the signaling mechanisms underlying how individual neurons intrinsically down scale excitability in response to over-stimulation. Discoveries regarding these underlying mechanisms of homeostatic plasticity allow us to understand how the nervous system maintains normalized activity amongst a wide range of inputs and processing. And understanding how the central nervous system maintains stability in turn facilitates the understanding and treatment of clinical manifestations of neural network instability, such as Epilepsy.
Our results indicate that Protein Phosphatase 1 (PP1) is activated in response to a overstimulation of neurons. After network disinhibition via Bicuculline, we have observed phosphorylation of an endogenous PP1 inhibitor, lnhibitor-2 (12) by the Ataxia Telegenasia Mutated Kinase (ATM). Phosphorylation of 12 disrupts a conserved PP1-I2 binding motif and results in dissociation of the PP1-I2 holoenzyme and PP1 activation. PP1 subsequently dephosphorylates several important mediators of excitability, including potassium channels (delayed rectifier Kv2.1 ), AMPA receptor subunits (ionotropic, GluR2), and critical synaptic scaffolding protein, PSD95. The result of PP1 mediated dephosphorylation at specific and established residues on these substrates in the neuron results in an increase in outward potassium conductance and a collapse of the post synaptic architecture that serves to reduce ionotropic surface AMPA receptors. Thus, the net effect of over-stimulation induced ATM phosphorylation of 12 and subsequent PP1 activity is to scale down neuronal excitability and stabilize action potential firing.
This work supported by NIHRO1(NS060879), NSF (IOS-0824393) and LSUHSC Research Enhancement Fund (REF).
Recommended Citation
Siddoway, Benjamin; Hou, Hailong; Gao, Jing-Xia; and Xia, Hohui, "REGULATION OF HOMEOSTATIC PLASTICITY BY PROTEIN PHOSPHATASE 1" (2010). Dr. Joseph M. Moerschbaecher, III Graduate Research Day. 22.
https://digitalscholar.lsuhsc.edu/grad_rs/2010/poster2/22
REGULATION OF HOMEOSTATIC PLASTICITY BY PROTEIN PHOSPHATASE 1
Individual neurons in the hippocampus and neocortex receive thousands of electrical inputs at synapses along extensive dendritic processes. The term homeostatic plasticity refers to global regulation of these inputs in order to maintain an optimal or normalized level of excitability. We are investigating the signaling mechanisms underlying how individual neurons intrinsically down scale excitability in response to over-stimulation. Discoveries regarding these underlying mechanisms of homeostatic plasticity allow us to understand how the nervous system maintains normalized activity amongst a wide range of inputs and processing. And understanding how the central nervous system maintains stability in turn facilitates the understanding and treatment of clinical manifestations of neural network instability, such as Epilepsy.
Our results indicate that Protein Phosphatase 1 (PP1) is activated in response to a overstimulation of neurons. After network disinhibition via Bicuculline, we have observed phosphorylation of an endogenous PP1 inhibitor, lnhibitor-2 (12) by the Ataxia Telegenasia Mutated Kinase (ATM). Phosphorylation of 12 disrupts a conserved PP1-I2 binding motif and results in dissociation of the PP1-I2 holoenzyme and PP1 activation. PP1 subsequently dephosphorylates several important mediators of excitability, including potassium channels (delayed rectifier Kv2.1 ), AMPA receptor subunits (ionotropic, GluR2), and critical synaptic scaffolding protein, PSD95. The result of PP1 mediated dephosphorylation at specific and established residues on these substrates in the neuron results in an increase in outward potassium conductance and a collapse of the post synaptic architecture that serves to reduce ionotropic surface AMPA receptors. Thus, the net effect of over-stimulation induced ATM phosphorylation of 12 and subsequent PP1 activity is to scale down neuronal excitability and stabilize action potential firing.
This work supported by NIHRO1(NS060879), NSF (IOS-0824393) and LSUHSC Research Enhancement Fund (REF).
Comments
See abstract book page 66