ALTERATIONS IN THE GLUTAMATERGIC SYSTEM AND THEIR ASSOCIATIONS WITH CLINICAL AND NEUROPATHOLOGICAL FEATURES OF NEURODEGENERATIVE DISEASES

Ph.DDOCTOR OF PHILOSOPH

Differential Alterations of Neocortical GluN Receptor Subunits in Patients with Mixed Subcortical Ischemic Vascular Dementia and Alzheimer's Disease

JOURNAL OF ALZHEIMERS DISEASE442431-437NETHERLAND

Decreased immunoreactivities of neocortical AMPA receptor subunits correlate with motor disability in Lewy body dementias

10.1007/s00702-013-1067-0JOURNAL OF NEURAL TRANSMISSION121171-78AUSTRI

Upregulation of AMPA receptor GluR2 (GluA2) subunits in subcortical ischemic vascular dementia is repressed in the presence of Alzheimer's disease

10.1016/j.neuint.2011.03.010NEUROCHEMISTRY INTERNATIONAL587820-825UNITED KINGDO

Cdk5-Mediated Phosphorylation of delta-Catenin Regulates Its Localization and GluR2-Mediated Synaptic Activity

10.1523/JNEUROSCI.6062-09.2010JOURNAL OF NEUROSCIENCE30258457-8467United State

Cdk5-Mediated Phosphorylation of delta-Catenin Regulates Its Localization and GluR2-Mediated Synaptic Activity

Cyclin-dependent kinase 5 (Cdk5)-mediated phosphorylation plays an important role in proper synaptic function and transmission. Loss of Cdk5 activity results in abnormal development of the nervous system accompanied by massive disruptions in cortical migration and lamination, therefore impacting synaptic activity. The Cdk5 activator p35 associates with delta-catenin, the synaptic adherens junction protein that serves as part of the anchorage complex of AMPA receptor at the postsynaptic membrane. However, the implications of Cdk5-mediated phosphorylation of delta-catenin have not been fully elucidated. Here we show that Cdk5-mediated phosphorylation of delta-catenin regulates its subcellular localization accompanied by changes in dendritic morphogenesis and synaptic activity. We identified two Cdk5 phosphorylation sites in mouse delta-catenin, serines 300 and 357, and report that loss of Cdk5 phosphorylation of delta-catenin increased its localization to the membrane. Furthermore, mutations of the serines 300 and 357 to alanines to mimic nonphosphorylated delta-catenin resulted in increased dendritic protrusions accompanied by increased AMPA receptor subunit GluR2 localization at the membrane. Consistent with these observations, loss of Cdk5 phosphorylation of delta-catenin increased the AMPA/NMDA ratio. This study reveals how Cdk5 phosphorylation of the synaptic mediator protein delta-catenin can alter its localization at the synapse to impact neuronal synaptic activity