[Show abstract][Hide abstract] ABSTRACT: Bipolar disorder (BPD) is characterized by altered intracellular calcium (Ca(2+)) homeostasis. Underlying mechanisms involve dysfunctions in endoplasmic reticulum (ER) and mitochondrial Ca(2+) handling, potentially mediated by B-cell lymphoma 2 (Bcl-2), a key protein that regulates Ca(2+) signaling by interacting directly with these organelles, and which has been implicated in the pathophysiology of BPD. Here, we examined the effects of the Bcl-2 gene single nucleotide polymorphism (SNP) rs956572 on intracellular Ca(2+) dynamics in patients with BPD.
Live cell fluorescence imaging and electron probe microanalysis were used to measure intracellular and intra-organelle free and total calcium in lymphoblasts from 18 subjects with BPD carrying the AA, AG, or GG variants of the rs956572 SNP. Analyses were carried out under basal conditions and in the presence of agents that affect Ca(2+) dynamics.
Compared with GG homozygotes, variant AA-which expresses significantly reduced Bcl-2 messenger RNA and protein-exhibited elevated basal cytosolic Ca(2+) and larger increases in inositol 1,4,5-trisphosphate receptor-mediated cytosolic Ca(2+) elevations, the latter in parallel with enhanced depletion of the ER Ca(2+) pool. The aberrant behavior of AA cells was reversed by chronic lithium treatment and mimicked in variant GG by a Bcl-2 inhibitor. In contrast, no differences between SNP variants were found in ER or mitochondrial total Ca(2+) content or in basal store-operated Ca(2+) entry.
These results demonstrate that, in patients with BPD, abnormal Bcl-2 gene expression in the AA variant contributes to dysfunctional Ca(2+) homeostasis through a specific ER inositol 1,4,5-trisphosphate receptor-dependent mechanism.
[Show abstract][Hide abstract] ABSTRACT: Emerging evidence suggests that synaptic plasticity is intimately involved in the pathophysiology and treatment of bipolar
disorder (BPD). Under certain conditions, over-strengthened and/or weakened synapses at different circuits in the brain could
disturb brain functions in parallel, causing manic-like or depressive-like behaviors in animal models. In this chapter, we
summarize the regulation of synaptic plasticity by medications, psychological conditions, hormones, and neurotrophic factors,
and their correlation with mood-associated animal behaviors. We conclude that increased serotonin, norepinephrine, dopamine,
brain-derived neurotrophic factor (BDNF), acute corticosterone, and antidepressant treatments lead to enhanced synaptic strength
in the hippocampus and also correlate with antidepressant-like behaviors. In contrast, inhibiting monoaminergic signaling,
long-term stress, and pathophysiological concentrations of cytokines weakens glutamatergic synaptic strength in the hippocampus
and is associated with depressive-like symptoms.
KeywordsBDNF-Bipolar disorder-Cytokine-Mood stabilizer-Stress-Synaptic plasticity
[Show abstract][Hide abstract] ABSTRACT: Glutamatergic dysfunction is strongly implicated in schizophrenia and mood disorders. GluA1 knockout (KO) mice display schizophrenia- and depression-related abnormalities. Here, we asked whether GluA1 KO show mania-related abnormalities. KO were tested for behavior in approach/avoid conflict tests, responses to repeated forced swim exposure, and locomotor responses under stress and after psychostimulant treatment. The effects of rapid dopamine depletion and treatment with lithium or a GSK-3β inhibitor (SB216763) on KO locomotor hyperactivity were tested. Results showed that KO exhibited novelty- and stress-induced locomotor hyperactivity, reduced forced swim immobility and alterations in approach/avoid conflict tests. Psychostimulant treatment and dopamine depletion exacerbated KO locomotor hyperactivity. Lithium, but not SB216763, treatment normalized KO anxiety-related behavior and partially reversed hyperlocomotor behavior, and also reversed elevated prefrontal cortex levels of phospho-MARCKS and phospho-neuromodulin. Collectively, these findings demonstrate mania-related abnormalities in GluA1 KO and, combined with previous findings, suggest this mutant may provide a novel model of features of schizoaffective disorder.
Neurobiology of Disease 12/2010; 40(3):608-21. DOI:10.1016/j.nbd.2010.08.005 · 5.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Lithium has been the gold standard in the treatment of bipolar disorder (BPD) for 60 y. Like lithium, glycogen synthase kinase 3 (GSK-3) inhibitors display both antimanic-like and antidepressant-like effects in some animal models. However, the molecular mechanisms of both lithium and GSK-3 inhibitors remain unclear. Here we show that the GSK-3 inhibitor AR-A014418 regulated alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA)-induced GluR1 and GluR2 internalization via phosphorylation of kinesin light chain 2 (KLC2), the key molecule of the kinesin cargo delivery system. Specifically, AMPA stimulation triggered serine phosphorylation of KLC2 and, subsequently, the dissociation of the GluR1/KLC2 protein complex. This suggests that GSK-3 phosphorylation of KLC2 led to the dissociation of AMPA-containing vesicles from the kinesin cargo system. The peptide TAT-KLCpCDK, a specific inhibitor for KLC2 phosphorylation by GSK-3beta, reduced the formation of long-term depression. Furthermore, the TAT-KLCpCDK peptide showed antimanic-like effects similar to lithium's on amphetamine-induced hyperactivity, a frequently used animal model of mania. It also induced antidepressant-like effects in the tail suspension and forced swim tests, two commonly used animal models of depression. Taken together, the results demonstrated that KLC2 is a cellular target of GSK-3beta capable of regulating synaptic plasticity, particularly AMPA receptor trafficking, as well as mood-associated behaviors in animal models. The kinesin cargo system may provide valuable novel targets for the development of new therapeutics for mood disorders.
Proceedings of the National Academy of Sciences 06/2010; 107(25):11573-8. DOI:10.1073/pnas.0913138107 · 9.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors (AMPARs) convey fast synaptic transmission in the CNS and mediate various forms of hippocampal plasticity. Disruption of glutamate receptor type 1 (GluR1), a member of the AMPAR family, causes synaptic alterations and learning/memory deficits in mice. To gain mechanistic insight into the synaptic and behavioral changes associated with GluR1 deletion, hippocampal genome-wide expression profiling was conducted using groups of GluR1 knockout (KO) mice and their wild-type littermates. Regulation of 38 genes was found to be altered more than 30% (P < 0.01, n = 8), and seven of these genes were studied with additional quantitative experiments. A large portion of the altered genes encoded molecules involved in calcium signaling, including calcium channel components, calcium-binding proteins and calcium-calmodulin-dependent protein kinase II subunits. At the protein level, we further evaluated some genes in the calcium pathway that were altered in GluR1 KO mice. Protein levels of two key molecules in the calcium pathway - GluR, ionotropic, N-methyl-d-aspartate-1 and calcium/calmodulin-dependent protein kinase II alpha - showed similar changes to those observed in mRNA levels. These findings raise the possibility that calcium signaling and other plasticity molecules may contribute to the hippocampal plasticity and behavioral deficits observed in GluR1 KO mice.
European Journal of Neuroscience 12/2009; 30(12):2318-26. DOI:10.1111/j.1460-9568.2009.07022.x · 3.67 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: It has become increasingly clear that glucocorticoid (GC) signaling not only comprises classic nuclear receptor binding-that is, glucocorticoid receptors (GRs) to their response element in the nucleus-but also involves rapid, non-genomic efforts to regulate signaling cascades and other cell functions in the cytoplasm as well as other cell organelles. In a recent study, we found that GRs form a complex with B-cell lymphoma 2 (Bcl-2), trans- locate to mitochondria in response to corticosterone (CORT), and modulate mitochondrial calcium and oxidation in an inverted U-shaped manner. It is also well established that steroid and thyroid hormone receptors regulate mitochondrial function to protect cells against various challenges and modulate synaptic plasticity. Here, we explore how such work reveals a fundamental mechanism whereby GCs regulate mitochondrial functions, and provides a mechanistic basis for therapeutic methods to rescue mitochondrial dysfunction during chronic stress or related psychiatric and neurodegenerative disorders.
[Show abstract][Hide abstract] ABSTRACT: Increased prevalence of deep white matter hyperintensities (DWMHs) has been consistently observed in patients with geriatric depression and bipolar disorder. DMWHs are associated with chronicity, disability, and poor quality of life. They are thought to be ischemic in their etiology and may be related to the underlying pathophysiology of mood disorders in the elderly. Notably, these lesions strikingly resemble radiological findings related to the cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephelopathy (CADASIL) syndrome. CADASIL arises from mutations in Notch3, resulting in impaired signaling via cellular Fas-associated death domain-like interleukin-1-beta-converting enzyme-inhibitory protein (c-FLIP) through an extracellular signal-regulated kinase (ERK)-dependent pathway. These signaling abnormalities have been postulated to underlie the progressive degeneration of vascular smooth muscle cells (VSMC). This study investigates the possibility that the anticonvulsant valproate (VPA), which robustly activates the ERK mitogen-activated protein kinase (MAPK) cascade, may exert cytoprotective effects on VSMC through the Notch3/c-FLIP pathway.
Human VSMC were treated with therapeutic concentrations of VPA subchronically. c-FLIP was knocked down via small interfering ribonucleic acid transfection. Cell survival, apoptosis, and protein levels were measured.
VPA increased c-FLIP levels dose- and time-dependently and promoted VSMC survival in response to Fas ligand-induced apoptosis in VSMC. The anti-apoptotic effect of VPA was abolished by c-FLIP knockdown. VPA also produced similar in vivo effects in rat brain.
These results raise the intriguing possibility that VPA may be a novel therapeutic agent for the treatment of CADASIL and related disorders. They also suggest that VPA might decrease the liability of patients with late-life mood disorders to develop DWMHs.
[Show abstract][Hide abstract] ABSTRACT: Glucocorticoids play an important biphasic role in modulating neural plasticity; low doses enhance neural plasticity and spatial memory behavior, whereas chronic, higher doses produce inhibition. We found that 3 independent measures of mitochondrial function-mitochondrial oxidation, membrane potential, and mitochondrial calcium holding capacity-were regulated by long-term corticosterone (CORT) treatment in an inverted "U"-shape. This regulation of mitochondrial function by CORT correlated with neuroprotection; that is, treatment with low doses of CORT had a neuroprotective effect, whereas treatment with high doses of CORT enhanced kainic acid (KA)-induced toxicity of cortical neurons. We then undertook experiments to elucidate the mechanisms underlying these biphasic effects and found that glucocorticoid receptors (GRs) formed a complex with the anti-apoptotic protein Bcl-2 in response to CORT treatment and translocated with Bcl-2 into mitochondria after acute treatment with low or high doses of CORT in primary cortical neurons. However, after 3 days of treatment, high, but not low, doses of CORT resulted in decreased GR and Bcl-2 levels in mitochondria. As with the in vitro studies, Bcl-2 levels in the mitochondria of the prefrontal cortex were significantly decreased, along with GR levels, after long-term treatment with high-dose CORT in vivo. These findings have the potential to contribute to a more complete understanding of the mechanisms by which glucocorticoids and chronic stress regulate cellular plasticity and resilience and to inform the future development of improved therapeutics.
Proceedings of the National Academy of Sciences 03/2009; 106(9):3543-8. DOI:10.1073/pnas.0812671106 · 9.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A growing body of data suggests that hyperactivation of the immune system has been implicated in the pathophysiology of major depressive disorder (MDD). Several pro-inflammatory cytokines, such as tumour necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL-1) have been found to be significantly increased in patients with MDD. This review focuses on these two cytokines based on multiple lines of evidence from genetic, animal behaviour, and clinical studies showing that altered levels of serum TNF-alpha and IL-1 are associated with increased risk of depression, cognitive impairments, and reduced responsiveness to treatment. In addition, recent findings have shown that centrally expressed TNF-alpha and IL-1 play a dual role in the regulation of synaptic plasticity. In this paper, we review and critically appraise the mechanisms by which cytokines regulate synaptic and neural plasticity, and their implications for the pathophysiology and treatment of MDD. Finally, we discuss the therapeutic potential of anti-inflammatory-based approaches for treating patients with severe mood disorders. This is a promising field for increasing our understanding of the mechanistic interaction between the immune system, synaptic plasticity, and antidepressants, and for the ultimate development of novel and improved therapeutics for severe mood disorders.
The International Journal of Neuropsychopharmacology 03/2009; 12(4):561-78. DOI:10.1017/S1461145709009924 · 5.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Accumulating evidence suggests that mitochondrial dysfunction plays a critical role in the progression of a variety of neurodegenerative and psychiatric disorders. Thus, enhancing mitochondrial function could potentially help ameliorate the impairments of neural plasticity and cellular resilience associated with a variety of neuropsychiatric disorders. A series of studies was undertaken to investigate the effects of mood stabilizers on mitochondrial function, and against mitochondrially mediated neurotoxicity. We found that long-term treatment with lithium and valproate (VPA) enhanced cell respiration rate. Furthermore, chronic treatment with lithium or VPA enhanced mitochondrial function as determined by mitochondrial membrane potential, and mitochondrial oxidation in SH-SY5Y cells. In-vivo studies showed that long-term treatment with lithium or VPA protected against methamphetamine (Meth)-induced toxicity at the mitochondrial level. Furthermore, these agents prevented the Meth-induced reduction of mitochondrial cytochrome c, the mitochondrial anti-apoptotic Bcl-2/Bax ratio, and mitochondrial cytochrome oxidase (COX) activity. Oligoarray analysis demonstrated that the gene expression of several proteins related to the apoptotic pathway and mitochondrial functions were altered by Meth, and these changes were attenuated by treatment with lithium or VPA. One of the genes, Bcl-2, is a common target for lithium and VPA. Knock-down of Bcl-2 with specific Bcl-2 siRNA reduced the lithium- and VPA-induced increases in mitochondrial oxidation. These findings illustrate that lithium and VPA enhance mitochondrial function and protect against mitochondrially mediated toxicity. These agents may have potential clinical utility in the treatment of other diseases associated with impaired mitochondrial function, such as neurodegenerative diseases and schizophrenia.
The International Journal of Neuropsychopharmacology 02/2009; 12(6):805-22. DOI:10.1017/S1461145708009802 · 5.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Considerable biochemical evidence suggests that the protein kinase C (PKC) signaling cascade may be a convergent point for the actions of anti-manic agents, and that excessive PKC activation can disrupt prefrontal cortical regulation of thinking and behavior. To date, however, brain protein targets of PKC's anti-manic effects have not been fully identified. Here we showed that PKC activity was enhanced in the prefrontal cortex of animals treated with the psychostimulant amphetamine. Phosphorylation of MARCKS, a marker of PKC activity, was increased in the prefrontal cortex of animals treated with the psychostimulant amphetamine, as well as in sleep-deprived animals (another animal model of mania), but decreased in lithium-treated animals. The antidepressant imipramine, which shows pro-manic properties in patients with bipolar disorder (BPD), also enhanced phospho-MARCKS in prefrontal cortex in vivo. We further explored the functional targets of PKC in mania-associated behaviors. Neurogranin is a brain-specific, postsynaptically located PKC substrate. PKC phosphorylation of neurogranin was robustly increased by pro-manic manipulations and decreased by anti-manic agents. PKC phosphorylation of the NMDA receptor site GluN1S896 and the AMPA receptor site GluA1T840 was also enhanced in the prefrontal cortex of animals treated with the antidepressant imipramine, as well as in behaviorally sleep-deprived animals, in striking contrast to the reduced activity seen in lithium-treated animals. These results suggest that PKC may play an important role in regulating NMDA and AMPA receptor functions. The biochemical profile of the PKC pathway thus encompasses both pro- and anti-manic effects on behavior. These results suggest that PKC modulators or their intracellular targets may ultimately represent novel avenues for the development of new therapeutics for mood disorders.
[Show abstract][Hide abstract] ABSTRACT: MicroRNAs (miRNAs) regulate messenger RNA (mRNA) translation in a sequence-specific manner and are emerging as critical regulators of central nervous system plasticity. We found hippocampal miRNA level changes following chronic treatment with mood stabilizers (lithium and valproate (VPA)). Several of these miRNAs were then confirmed by quantitative PCR: let-7b, let-7c, miR-128a, miR-24a, miR-30c, miR-34a, miR-221, and miR-144. The predicted effectors of these miRNAs are involved in neurite outgrowth, neurogenesis, and signaling of PTEN, ERK, and Wnt/beta-catenin pathways. Interestingly, several of these effector-coding genes are also genetic risk candidates for bipolar disorder. We provide evidence that treatment with mood stabilizers increases these potential susceptibility genes in vivo: dipeptidyl-peptidase 10, metabotropic glutamate receptor 7 (GRM7), and thyroid hormone receptor, beta. Treatment of primary cultures with lithium- or VPA-lowered levels of miR-34a and elevated levels of GRM7, a predicted effector of miR-34a. Conversely, miR-34a precursor treatment lowered GRM7 levels and treatment with a miR-34a inhibitor enhanced GRM7 levels. These data confirm that endogenous miR-34a regulates GRM7 levels and supports the notion that miR-34a contributes to the effects of lithium and VPA on GRM7. These findings are the first to demonstrate that miRNAs and their predicted effectors are targets for the action of psychotherapeutic drugs.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 09/2008; 34(6):1395-405. DOI:10.1038/npp.2008.131 · 7.83 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Recent microarray studies with stringent validating criteria identified Bcl-2-associated athanogene (BAG1) as a target for the actions of medications that are mainstays in the treatment of bipolar disorder (BPD). BAG1 is a Hsp70/Hsc70-regulating cochaperone that also interacts with glucocorticoid receptors (GRs) and attenuates their nuclear trafficking and function. Notably, glucocorticoids are one of the few agents capable of triggering both depressive and manic episodes in patients with BPD. As a nexus for the actions of glucocorticoids and bipolar medications, we hypothesized that the level of BAG1 expression would play a pivotal role in regulating affective-like behaviors. This hypothesis was investigated in neuron-selective BAG1 transgenic (TG) mice and BAG1 heterozygous knockout (+/-) mice. On mania-related tests, BAG1 TG mice recovered much faster than wild-type (WT) mice in the amphetamine-induced hyperlocomotion test and displayed a clear resistance to cocaine-induced behavioral sensitization. In contrast, BAG1+/- mice displayed an enhanced response to cocaine-induced behavioral sensitization. The BAG1 TG mice showed less anxious-like behavior on the elevated plus maze test and had higher spontaneous recovery rates from helplessness behavior compared with WT mice. In contrast, fewer BAG1+/- mice recovered from helplessness behavior compared with their WT controls. BAG1 TG mice also exhibited specific alterations of hippocampal proteins known to regulate GR function, including Hsp70 and FKBP51. These data suggest that BAG1 plays a key role in affective resilience and in regulating recovery from both manic-like and depression-like behavioral impairments.
Proceedings of the National Academy of Sciences 07/2008; 105(25):8766-71. DOI:10.1073/pnas.0803736105 · 9.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In addition to its clinical antimanic effects, lithium also has efficacy in the treatment of depression. However, the mechanism by which lithium exerts its antidepressant effects is unclear. Our objective was to further characterize the effects of peripheral and central administration of lithium in mouse models of antidepressant efficacy as well as to investigate the role of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors in these behaviors. We utilized the mouse forced swim test (FST) and tail suspension test (TST), intracerebroventricular (ICV) lithium administration, AMPA receptor inhibitors, and BS3 crosslinking followed by Western blot. Both short- and long-term administration of lithium resulted in robust antidepressant-like effects in the mouse FST and TST. Using ICV administration of lithium, we show that these effects are due to actions of lithium on the brain, rather than to peripheral effects of the drug. Both ICV and rodent chow (0.4% LiCl) administration paradigms resulted in brain lithium concentrations within the human therapeutic range. The antidepressant-like effects of lithium in the FST and TST were blocked by administration of AMPA receptor inhibitors. Additionally, administration of lithium increased the cell surface expression of GluR1 and GluR2 in the mouse hippocampus. Collectively, these data show that lithium exerts centrally mediated antidepressant-like effects in the mouse FST and TST that require AMPA receptor activation. Lithium may exert its antidepressant effects in humans through AMPA receptors, thus further supporting a role of targeting AMPA receptors as a therapeutic approach for the treatment of depression.
[Show abstract][Hide abstract] ABSTRACT: Ketamine exerts a robust, rapid, and relatively sustained antidepressant effect in patients with major depression. Understanding the mechanisms underlying the intriguing effects of N-methyl d-aspartate (NMDA) antagonists could lead to novel treatments with a rapid onset of action.
The learned helplessness, forced swim, and passive avoidance tests were used to investigate ketamine's behavioral effects in mice. Additional biochemical and behavioral experiments were undertaken to determine whether the antidepressant-like properties of ketamine and other NMDA antagonists involve alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor throughput.
Subanesthetic doses of ketamine treatment caused acute and sustained antidepressant-like effects. At these doses, ketamine did not impair fear memory retention. MK-801 (dizocilpine) and Ro25-6981, an NR2B selective antagonist, also exerted antidepressant-like effects; these effects, however, were not sustained as long as those of ketamine. Pre-treatment with NBQX, an AMPA receptor antagonist, attenuated both ketamine-induced antidepressant-like behavior and regulation of hippocampal phosphorylated GluR1 AMPA receptors.
NMDA antagonists might exert rapid antidepressant-like effects by enhancing AMPA relative to NMDA throughput in critical neuronal circuits.
[Show abstract][Hide abstract] 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 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 Journal of Neuroscience : The Official Journal of the Society for Neuroscience 02/2008; 28(1):68-79. DOI:10.1523/JNEUROSCI.3080-07.2008 · 6.75 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A growing body of data suggests that the glutamatergic system may be involved in the pathophysiology and treatment of severe mood disorders. Chronic treatment with the antimanic agents, lithium and valproate, resulted in reduced synaptic expression of the AMPA(-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) receptor subunit GluR1 in the hippocampus, while treatment with an antidepressant (imipramine) enhanced the synaptic expression of GluR1. The anticonvulsants, lamotrigine (6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine) and riluzole (2-amino-6-trifluoromethoxybenzothiazole), have been demonstrated to have efficacy in the depressive phase of bipolar disorder. We therefore sought to determine the role of these anticonvulsants, compared to that of the predominantly antimanic anticonvulsant valproate, on AMPA receptor localization. We found that the agents with a predominantly antidepressant profile, namely lamotrigine and riluzole, significantly enhanced the surface expression of GluR1 and GluR2 in a time- and dose-dependent manner in cultured hippocampal neurons. By contrast, the predominantly antimanic agent, valproate, significantly reduced surface expression of GluR1 and GluR2. Concomitant with the GluR1 and GluR2 changes, the peak value of depolarized membrane potential evoked by AMPA was significantly higher in lamotrigine- and riluzole-treated neurons, supporting the surface receptor changes. Phosphorylation of GluR1 at the PKA (cAMP-dependent protein kinase) site (S845) was enhanced in both lamotrigine- and riluzole-treated hippocampal neurons, but reduced in valproate-treated neurons. In addition, lamotrigine and riluzole, as well as the traditional antidepressant imipramine, also increased GluR1 phosphorylation at GluR1 (S845) in the hippocampus after chronic in vivo treatment. Our findings suggest that regulation of GluR1/2 surface levels and function may be responsible for the different clinical profile of anticonvulsants (antimanic or antidepressant), and may suggest avenues for the development of novel therapeutics for these illnesses.