A growing body of data is showing that the AMPA subtype of glutamate receptors play a major role in regulating short- and long-term forms of synaptic plasticity. Furthermore, it is now clear that regulation of plasticity occurs """"""""in large part"""""""" by regulating the trafficking of AMPA receptor subunits, and their insertion and removal from the synapse. Notably, this trafficking is now known to be dependent , in large part, upon AMPA receptor subunit phosphorylation by 3 major signaling pathways known to be targets for mood stablilizers ? the PKC, PKA and MAPK cascades. In view of the growing body of data suggesting that severe mood disorders may be associated with impairments of cellular plasticity, we undertook the present series of studies to determine if two clinically effective, but structurally highly dissimilar antimanic agents, lithium & VPA regulate synaptic expression of AMPA receptor subunit GluR1. Administration of chronic lithium or valproate (at therapeutically relevant concentrations) reduced rat hippocampal synaptosomal levels of GluR1 after by 40% and 20%, respectively. In cultured hippocampal neurons, both lithium and VPA also significantly down-regulated the surface expression of GluR1 ~ 40% maximumally, in a dose and time-dependent manner. Surface staining with an anti-N terminal GluR1 antibody confirmed the result. Double-immunostaining of GluR1 and synaptotagmin showed that the numbers of GluR1 positive synapses of lithium and valproate-treated neurons were attenuated after chronic treatment. However, total protein levels of GluR1, and synaptotagmin remained unchanged after lithium and valproate treatment in vitro and in vivo. Phosphorylation of a specific PKA site (GluRp845) was significantly attenuated by lithium and valproate treatment by 52 and 33% respectively. Sp-cAMP treatment reversed the attenuation of phosphorylation by lithium and valproate and also brought GluR1s back to the surface, suggesting that phosphorylation of GluRp845 is involved in the mechanism of GluR1 surface attenuation. In striking contrast, drugs, which are known to induce mania, such as imipramine increase the synaptic expression of GluR1 in vivo in hippocampus. These studies suggest that regulation of glutamatergically mediated synaptic plasticity may play a role in the treatment of mood disorders, and raises the possibility that agents more directly affecting synaptic GluR1 may represent novel therapies for this devastating illness.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Intramural Research (Z01)
Project #
1Z01MH002831-01
Application #
6824392
Study Section
(LMP)
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2003
Total Cost
Indirect Cost
Name
U.S. National Institute of Mental Health
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Catapano, Lisa A; Manji, Husseini K (2008) Kinases as drug targets in the treatment of bipolar disorder. Drug Discov Today 13:295-302
Catapano, Lisa A; Manji, Husseini K (2007) G protein-coupled receptors in major psychiatric disorders. Biochim Biophys Acta 1768:976-93
Du, Jing; Suzuki, Katsuji; Wei, Yanling et al. (2007) The anticonvulsants lamotrigine, riluzole, and valproate differentially regulate AMPA receptor membrane localization: relationship to clinical effects in mood disorders. Neuropsychopharmacology 32:793-802
DU, Jing; Quiroz, Jorge; Yuan, Peixiong et al. (2004) Bipolar disorder: involvement of signaling cascades and AMPA receptor trafficking at synapses. Neuron Glia Biol 1:231-43