Ca2+ influx through NMDARs (N-methyl-D-aspartate receptors) triggers long-lasting changes; in synaptic efficacy such as LTP (long-term potentiation). The NMDAR-mediated rise in postsynaptic Ca2+ activates a network of kinases and phosphatases that promotes long-lasting changes in synaptic strength. Recent findings by our laboratories indicate that Ca2+ permeability of neuronal NMDARs and NMDAR-mediated Ca2+ influx during induction of LTP are under the control of the cAMP/PKA signaling cascade. Moreover, PKA modulates NMDAR-mediated Ca2+ rises in activated dendritic spines. Our data link PKA-dependent synaptic plasticity to Ca2+ signalling in spines and thus provide a novel mechanism whereby PKA regulates induction of LTP.
SPECIFIC AIMS are as follows: 1) To examine mechanisms underlying PKA modulation of Ca2+ permeability of synaptic (NR1/NR2A) vs. extrasynaptic (NR1/NR2B) NMDARs in hippocampal neurons. Although our data show that PKA selectively modulates Ca2+ permeability of synaptic NMDARs, the impact of PKA activation on extra-synaptic NMDARs is less clear. We hypothesize that PKA differentially modulates synaptic and extra-synaptic NMDARs. We further propose that extracellular signals that modulate cAMP or protein phosphatases at postsynaptic sites will bi-directionally regulate Ca2+ permeation through synaptic NMDARs and induction of LTP. 2) To examine developmental regulation of PKA actions on NMDAR-mediated Ca+ influx in dendritic spines. Although PKA modulates Ca2+ permeability of NMDARs in mature brain, the impact of PKA activation on synaptic (NR1/NR2B) NMDARs in neonatal brain is less clear. At birth, NMDARs contain NR1 and NR2B subunits. During postnatal development, there is a progressive inclusion of the NR2A subunit. Preliminary studies with recombinant NMDARs suggest that PKA differentially regulates NR2A- vs. NR2B-containing receptors. Thus, we hypothesize that PKA modulation of NMDAR-mediated currents is less selective at early ages and becomes highly selective for NMDAR-mediated Ca2+ influx at mature synapses. 3) To identify the molecular target of PKA that controls Ca2+ permeation through NMDARs. Although the NMDAR is a known functional target of PKA, the molecular target that control Ca2+ permeation through NMDARs is unknown. We hypothesize that PKA phosphorylates one or more residues on NR1 or NR2A/B subunit and thereby alters the geometry of the channel pore; when PKA is inactive, NMDARs are rapidly dephosphorylated. The cAMP/PKA signalling cascade and calcium are crucial for synaptic plasticity. Given the widespread localization of NMDARs and PKA in the CNS, regulation of NMDA function by PKA is a powerful mechanism to modulate synaptic efficacy. Ca2+ influx via NMDARs is also implicated in the excitotoxic neuronal death associated with stroke, epilepsy, head trauma, Huntington's disease, Alzheimer's disease, AIDS/dementia, and schizophrenia. Findings from the proposed studies are relevant to our understanding of these devastating and often fatal disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS020752-19
Application #
7028981
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Silberberg, Shai D
Project Start
1984-07-01
Project End
2010-03-01
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
19
Fiscal Year
2006
Total Cost
$374,290
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Neurosciences
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
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