The Role of Hippocampal GluR1 and GluR2 Receptors in Manic-Like Behavior

Abstract

The cellular basis underlying the complex clinical symptomatology of bipolar disorder and the mechanisms underlying the actions of its effective treatments have not yet been fully elucidated. This study investigated the role of hippocampal synaptic AMPA receptors. We found that chronic administration of the antimanic agents lithium and valproate (VPA) reduced synaptic AMPA receptor GluR1/2 in hippocampal neurons in vitro and in vivo. Electrophysiological studies confirmed that the AMPA/NMDA ratio was reduced in CA1 regions of hippocampal slices from lithium-treated animals. Reduction in GluR1 phosphorylation at its cAMP-dependent protein kinase A site by the synthetic peptide TAT-S845, which mimics the effects of lithium or VPA, was sufficient to attenuate surface and synaptic GluR1/2 levels in hippocampal neurons in vitro and in vivo. Intrahippocampal infusion studies with the AMPA-specific inhibitor GYKI [4-(8-methyl-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepin-5-yl)-benzenamine hydrochloride], a GluR1-specific TAT-S845 peptide, showed that GluR1/2 was essential for the development of manic/hedonic-like behaviors such as amphetamine-induced hyperactivity. These studies provide novel insights into the role of hippocampal GluR1/2 receptors in mediating facets of the manic syndrome and offer avenues for the development of novel therapeutics for these disorders.

Dynamic regulation of mitochondrial function by glucocorticoids

“…Protein concentrations were determined by using the BCA protein assay kit (Pierce, Rockford, IL). Western blot analysis was similar to a previously published procedure with minor modifications (29,30). Detailed methods are provided in the SI.…”

A kinesin signaling complex mediates the ability of GSK-3β to affect mood-associated behaviors

“…In addition, recent studies found that the hippocampus is involved in dopaminergic signaling circuits, and that the ventral subiculum of the hippocampus modulates dopaminergic neuronal activity (33,34). Rats receiving hippocampal infusion of the AMPA-specific antagonists GYKI 52466, Tat-S845 (which inhibits GluR1 phosphorylation at S845), or TAT-TGL (which inhibits AMPA synaptic localization) exhibited significant reductions in AMPH-induced locomotion (7). In the present study, the inhibition of AMPAR internalization in hippocampal neurons by GSK-3 may have contributed to the increased surface GluR1 levels in hippocampal neurons.…”

“…Accumulating studies from our laboratory and those of other investigators have shown that glutamatergic synaptic plasticity, particularly α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor (AMPAR) trafficking, may be a convergent point in the treatment of mood disorders (7)(8)(9)(10). For instance, rats receiving hippocampal infusions of AMPA-specific inhibitors exhibited significant reductions in manic-like behaviors assessed through the AMPH-induced locomotion (7).…”

“…For instance, rats receiving hippocampal infusions of AMPA-specific inhibitors exhibited significant reductions in manic-like behaviors assessed through the AMPH-induced locomotion (7). In contrast, administration of antidepressant agents-such as the tricyclic antidepressant (TCA) imipramine or the mood stabilizers lamotrigine and riluzoleenhanced surface AMPAR expression and phosphorylation of GluR1S845 in hippocampal neurons in vitro and in vivo (8).…”

The Effect of L-Proline on Two Recombinant AMPA Glutamate Receptors

“…GluR1/2 heteromers are the major receptor type within the hippocampus and increases in activity and numbers of both subunits are associated with manic-like behavior (Wenthold et al 1996;Du et al 2008). When expressed in mammalian cell lines the homomeric GluR1/2 exhibits a non-rectifying current-voltage (I-V) relationship and differ from the GluR1 homomers in their lower permeability to Ca 2+ .…”