The role of hippocampal GluR1 and GluR2 receptors in manic-like behavior.

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 52466 [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.

The anti-apoptotic, glucocorticoid receptor cochaperone protein BAG-1 is a long-term target for the actions of mood stabilizers.

Increasing data suggest that impairments of cellular plasticity/resilience underlie the pathophysiology of bipolar disorder. A series of microarray studies with validating criteria have recently revealed a common, novel target for the long-term actions of the structurally highly dissimilar mood stabilizers lithium and valproate: BAG-1 [BCL-2 (B-cell CLL/lymphoma 2)-associated athanogene]. Because BAG-1 attenuates glucocorticoid receptor (GR) nuclear translocation, activates ERK (extracellular signal-regulated kinase) MAP (mitogen-activated protein) kinases, and potentiates anti-apoptotic functions of BCL-2, extensive additional studies were undertaken. Chronic administration of both agents at therapeutic doses increased the expression of BAG-1 in rat hippocampus. Furthermore, these findings were validated at the protein level, and the effects were seen in a time frame consistent with therapeutic effects and were specific for mood stabilizers. Functional studies showed that either lithium or valproate, at therapeutically relevant levels, inhibited dexamethasone-induced GR nuclear translocation and inhibited GR transcriptional activity. Furthermore, small interfering RNA studies showed that these inhibitory effects on GR activity were mediated, at least in part, through BAG-1. The observation that BAG-1 inhibits glucocorticoid activation suggests that mood stabilizers may counteract the deleterious effects of hypercortisolemia seen in bipolar disorder by upregulating BAG-1. Additionally, these studies suggest that regulation of GR-mediated plasticity may play a role in the treatment of bipolar disorder and raise the possibility that agents affecting BAG-1 more directly may represent novel therapies for this devastating illness.

Modulation of synaptic plasticity by antimanic agents: the role of AMPA glutamate receptor subunit 1 synaptic expression.

Increasing data suggest that impairments of cellular plasticity underlie the pathophysiology of bipolar disorder. In this context, it is noteworthy that AMPA glutamate receptor trafficking regulates synaptic plasticity, effects mediated by signaling cascades, which are targets for antimanic agents. The present studies were undertaken to determine whether two clinically effective, but structurally highly dissimilar, antimanic agents lithium and valproate regulate synaptic expression of AMPA receptor subunit glutamate receptor 1 (GluR1). Chronic (but not acute) treatment of rats with therapeutically relevant concentrations of lithium or valproate reduced hippocampal synaptosomal GluR1 levels. The reduction in synaptic GluR1 by lithium and valproate was attributable to a reduction of surface GluR1 distribution onto the neuronal membrane as demonstrated by three independent assays in cultured hippocampal neurons. Furthermore, these agents induced a decrease in GluR1 phosphorylation at a specific PKA site (GluR1p845), which is known to be critical for AMPA receptor insertion. Sp-cAMP treatment reversed the attenuation of phosphorylation by lithium and valproate and also brought GluR1 back to the surface, suggesting that phosphorylation of GluR1p845 is involved in the mechanism of GluR1 surface attenuation. In addition, GluR1p845 phosphorylation also was attenuated in hippocampus from lithium- or valproate-treated animals in vivo. In contrast, imipramine, an antidepressant that can trigger manic episodes, increased synaptic expression of GluR1 in hippocampus in vivo. These studies suggest that regulation of glutamatergically mediated synaptic plasticity may play a role in the treatment of bipolar disorder and raise the possibility that agents more directly affecting synaptic GluR1 may represent novel therapies for this devastating illness.

The use of mood stabilizers as plasticity enhancers in the treatment of neuropsychiatric disorders.

Mood disorders have traditionally been conceptualized as neurochemical disorders, but there is now evidence from a variety of sources demonstrating regional reductions in central nervous system (CNS) volume, as well as reductions in the numbers and/or sizes of glia and neurons in discrete brain areas. Although the precise cellular mechanisms underlying these morphometric changes remain to be fully elucidated, the data suggest that severe mood disorders are associated with impairments of structural plasticity and cellular resilience. It is thus noteworthy that lithium and valproate have recently been demonstrated to robustly increase the expression of the cytoprotective protein bcl-2 (an abbreviation for the B-cell lymphoma/leukemia-2 gene) in the CNS in vivo and in cells of human neuronal origin. Lithium and valproate also robustly activate a signaling cascade utilized by endogenous growth factors-the extracellular signal-regulated kinase (ERK) mitogen-activated protein (MAP) kinase pathway. Complementary human studies have shown that chronic lithium administration significantly increases gray matter content in a regionally selective manner, suggesting a reversal of illness-related atrophy and an increase in the volume of the neuropil. These unique and unexpected properties of lithium and valproate suggest that they may have broader utility as adjunctive agents in the treatment of a variety of neuropsychiatric disorders associated with cell atrophy or loss. The adjunctive use of these agents-at low doses-may provide the trophic support necessary to restore, enhance, and maintain normal synaptic connectivity, thereby allowing the chemical signal to reinstate the optimal functioning of critical circuits necessary for normal functioning.

Structurally dissimilar antimanic agents modulate synaptic plasticity by regulating AMPA glutamate receptor subunit GluR1 synaptic expression.

A growing body of data from clinical and preclinical studies suggests that the glutamatergic system may represent a novel therapeutic target for severe recurrent mood disorders. Since synapse-specific glutamate receptor expression/localization is known to play critical roles in synaptic plasticity, we investigated the effects of mood stabilizers on AMPA receptor expression. Rats were treated chronically with lithium or valproate, hippocampal synaptosomes were isolated, and GluR1 levels were determined. Additionally, hippocampal neurons were prepared from E18 rat embryos and treated with lithium or valproate. Surface expression of GluR1 was determined using a biotinylation assay, and double-immunostaining with anti-GluR1 and anti-synaptotagmin antibodies was used to determine synaptic GluR1 levels. The AMPA receptor subunit GluR1 expression in hippocampal synaptosomes was significantly reduced by both chronic lithium and valproate. Overall, these studies show that AMPA receptor subunit GluR1 is a common target for two structurally highly dissimilar, but highly efficacious, mood stabilizers, lithium and valproate. These studies suggest that regulation of glutamatergically mediated synaptic plasticity may play a role in the treatment of mood disorders, and raise the possibility that agents more directly affecting synaptic GluR1 may represent novel therapies for this devastating illness.

Regulation of cellular plasticity cascades in the pathophysiology and treatment of mood disorders: role of the glutamatergic system.

There is increasing evidence from a variety of sources that mood disorders are associated with regional reductions in brain volume, as well as reductions in the number, size, and density of glia and neurons in discrete brain areas. Although the precise pathophysiology underlying these morphometric changes remains to be fully elucidated, the data suggest that severe mood disorders are associated with impairments of structural plasticity and cellular resilience. In this context, it is noteworthy that a growing body of data suggests that the glutamatergic system--which is known to play a major role in neuronal plasticity and cellular resilience--may be involved in the pathophysiology and treatment of mood disorders. Preclinical studies have shown that the glutamatergic system represents targets (often indirect) for the actions of antidepressants and mood stabilizers. There are a number of glutamatergic "plasticity enhancing" strategies that may be of considerable utility in the treatment of mood disorders. Among the most immediate ones are NMDA antagonists, inhibitors of glutamate-release agents, and AMPA potentiators; this research progress holds much promise for the development of novel therapeutics for the treatment of severe, refractory mood disorders.

Regulation of cellular plasticity and resilience by mood stabilizers: the role of AMPA receptor trafficking.

There is increasing evidence from a variety of sources that severe mood disorders are associated with regional reductions in brain volume, as well as reductions in the number, size, and density of glia and neurons in discrete brain areas. Although the precise pathophysiology underlying these morphometric changes remains to be fully elucidated, the data suggest that severe mood disorders are associated with impairments of structural plasticity and cellular resilience. In this context, it is noteworthy that a growing body of data suggests that the glutamaiergic system (which is known to play a major role in neuronal plasticity and cellular resilience) may be involved in the pathophysiology and treatment of mood disorders. Glutamate α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) GluR1 receptor trafficking plays a critical role in regulating various forms of neural plasticity. It is thus noteworthy that recent studies have shown that structurally dissimilar mood stabilizers lithium and valproate regulate GluR1 receptor subunit trafficking and localization at synapses. 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 represent novel therapies for these devastating illnesses.

Antidepressant treatment reduces serotonin-1A autoreceptor binding in major depressive disorder.

BACKGROUND: Chronic selective serotonin reuptake inhibitor (SSRI) administration to rodents desensitizes or downregulates raphe 5-hydroxytryptamine 1A (5-HT1A) autoreceptors. We previously found elevated 5-HT1A binding in antidepressant-naive and not recently medicated major depressive disorder (MDD) and now report the effect of SSRI treatment on 5-HT1A autoreceptors in depressed patients. METHODS: 5-HT1A binding (BPF) was quantified in medication-free subjects using positron emission tomography (PET) with [11C]-WAY-100635 before and after treatment of MDD with an SSRI for 5 to 9 weeks (mean 47 ± 8 days). Nineteen subjects without recent history of antidepressant pharmacotherapy completed both [11C]WAY-100635 PET scans with a metabolite-corrected arterial input function and depression severity was rated before and after the treatment course. RESULTS: 5-HT1A autoreceptor BPF in the raphe was reduced 18% on SSRI treatment (df = 1,18; F = 5.12; p = .036). However, the degree of reduction in 5-HT1A autoreceptor BPF was unrelated to improvement in depression (df = 1,16; F = 1.27; p = .276). CONCLUSIONS: Downregulation of 5-HT1A autoreceptor binding by SSRI treatment of major depression is consistent with animal studies. This may be a necessary but insufficient requirement for clinical response to SSRIs. A PET agonist ligand that binds selectively to the high-affinity conformation of this receptor can determine whether SSRIs also cause desensitization of the autoreceptor as reported by some rodent studies and whether that effect may be related to clinical response.

Mitochondrially mediated plasticity in the pathophysiology and treatment of bipolar disorder.

Bipolar disorder (BPD) has traditionally been conceptualized as a neurochemical disorder, but there is mounting evidence for impairments of cellular plasticity and resilience. Here, we review and synthesize the evidence that critical aspects of mitochondrial function may play an integral role in the pathophysiology and treatment of BPD. Retrospective database searches were performed, including MEDLINE, abstract booklets, and conference proceedings. Articles were also obtained from references therein and personal communications, including original scientific work, reviews, and meta-analyses of the literature. Material regarding the potential role of mitochondrial function included genetic studies, microarray studies, studies of intracellular calcium regulation, neuroimaging studies, postmortem brain studies, and preclinical and clinical studies of cellular plasticity and resilience. We review these data and discuss their implications not only in the context of changing existing conceptualizations regarding the pathophysiology of BPD, but also for the strategic development of improved therapeutics. We have focused on specific aspects of mitochondrial dysfunction that may have major relevance for the pathophysiology and treatment of BPD. Notably, we discuss calcium dysregulation, oxidative phosphorylation abnormalities, and abnormalities in cellular resilience and synaptic plasticity. Accumulating evidence from microarray studies, biochemical studies, neuroimaging, and postmortem brain studies all support the role of mitochondrial dysfunction in the pathophysiology of BPD. We propose that although BPD is not a classic mitochondrial disease, subtle deficits in mitochondrial function likely play an important role in various facets of BPD, and that enhancing mitochondrial function may represent a critical component for the optimal long-term treatment of the disorder.

EphB receptors influence growth of ephrin-B1-positive statoacoustic nerve fibers.

The Eph family of receptors and ligands has been implicated in a variety of developmental processes, including the provision of inhibitory guidance cues to developing nerve fibers. A unique property of the B class of receptors is that they are able to phosphorylate ephrin-B ligands, allowing for bi-directional, or reverse signalling. While most of the studies to date have focused on central nerve fibers, little is known about the role of Eph molecules in guiding nerve fibers of the peripheral nervous system. In the present study, ephrin-B1 was found to be highly expressed on developing peripheral nerve fibers including auditory and vestibular (statoacoustic) and dorsal root ganglion nerve fibers. In vitro assays revealed that EphB-Fc receptors inhibited further growth of statoacoustic nerve fibers. In contrast, EphA7-Fc and ephrin-B2-Fc did not prevent further growth of SAG. Together, these results suggest a role for EphB receptors in providing guidance signals to ephrin-B1-positive SAG nerve fibers.

Effects of a glycogen synthase kinase-3 inhibitor, lithium, in adenomatous polyposis coli mutant mice.

Glycogen synthase kinase-3 (GSK-3) is an intermediary enzyme in various cellular pathways, and has been implicated in the pathophysiology and treatment of numerous diseases, including Alzheimer's disease, diabetes, and bipolar disorder. There is therefore in developing potent, selective GSK-3 inhibitors for the treatment of these devastating illnesses. A concern, however, is that the Wnt-signaling pathway-of which GSK-3 is an important intermediary molecule-has been implicated in many human cancers. It is thus of considerable importance to determine if GSK-3 inhibitors have tumorigenic potential in systems predisposed to developing tumors by virtue of mutations of the Wnt-signaling pathway. We therefore investigated the effects of a GSK-3 inhibitor, lithium, in a murine model predisposed to the formation of tumors due to activation of the Wnt pathway-the adenomatous polyposis coli (APC) multiple intestinal neoplasia (min) mouse. We found that 60 days of lithium treatment did not produce a significant increase in the number of tumors in these genetically predisposed mice. Lithium treatment resulted in a modest overall increase in the tumor size. The APC (min) mouse has previously been shown to be a robust indicator of tumorigenesis, with large increases in tumor number observed in response to a variety of agents; thus, our results suggest that lithium-and perhaps other inhibitors of GSK-3-pose a low risk for the development of cancers of the Wnt pathway. These results are consistent with the available epidemiological evidence that long-term lithium therapy does not increase cancer morbidity or mortality, but rather is associated with reduced overall mortality in bipolar disorder.