No abstract

Electroconvulsive seizure therapy (ECS) is a clinically proven treatment for depression and is often effective even in patients resistant to chemical antidepressants. However, the molecular mechanisms underlying the therapeutic efficacy of ECS are not fully understood. One theory that has gained attention is that ECS and other antidepressants increase the expression of select neurotrophic factors that could reverse or block the atrophy and cell loss resulting from stress and depression. To further address this topic, we examined the expression of other neurotrophic-growth factors and related signaling pathways in the hippocampus in response to ECS using a custom growth factor microarray chip. We report the regulation of several genes that are involved in growth factor and angiogenic-endothelial signaling, including neuritin, stem cell factor, vascular endothelial growth factor (VEGF), VGF (nonacronymic), cyclooxygenase-2, and tissue inhibitor of matrix metalloproteinase-1. Some of these, as well as other growth factors identified, including VEGF, basic fibroblast growth factor, and brain-derived neurotrophic factor, have roles in mediating neurogenesis and cell proliferation in the adult brain. We also examined gene expression in the choroid plexus and found several growth factors that are enriched in this vascular tissue as well as regulated by ECS. These data suggest that an amplification of growth factor signaling combined with angiogenic mechanisms could have an important role in the molecular action of ECS. This study demonstrates the applicability of custom-focused microarray technology in addressing hypothesis-driven questions regarding the action of antidepressants.

Exercise has many health benefits, including antidepressant actions in depressed human subjects, but the mechanisms underlying these effects have not been elucidated. We used a custom microarray to identify a previously undescribed profile of exercise-regulated genes in the mouse hippocampus, a brain region implicated in mood and antidepressant response. Pathway analysis of the regulated genes shows that exercise upregulates a neurotrophic factor signaling cascade that has been implicated in the actions of antidepressants. One of the most highly regulated target genes of exercise and of the growth factor pathway is the gene encoding the VGF nerve growth factor, a peptide precursor previously shown to influence synaptic plasticity and metabolism. We show that administration of a synthetic VGF-derived peptide produces a robust antidepressant response in mice and, conversely, that mutation of VGF in mice produces the opposite effects. The results suggest a new role for VGF and identify VGF signaling as a potential therapeutic target for antidepressant drug development.

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/b-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, b. Treatment of primary cultures with lithium-or VPA-lowered levels of miR-34a and elevated levels of GRM7, a predicted effector of miR34a. 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.

The molecular pathogenesis of bipolar disorder (BPD) is poorly understood. Using human-induced pluripotent stem cells (hiPSCs) to unravel such mechanisms in polygenic diseases is generally challenging. However, hiPSCs from BPD patients responsive to lithium offered unique opportunities to discern lithium's target and hence gain molecular insight into BPD. By profiling the proteomics of BDP-hiPSCderived neurons, we found that lithium alters the phosphorylation state of collapsin response mediator protein-2 (CRMP2). Active nonphosphorylated CRMP2, which binds cytoskeleton, is present throughout the neuron; inactive phosphorylated CRMP2, which dissociates from cytoskeleton, exits dendritic spines. CRMP2 elimination yields aberrant dendritogenesis with diminished spine density and lost lithium responsiveness (LiR). The "set-point" for the ratio of pCRMP2:CRMP2 is elevated uniquely in hiPSC-derived neurons from LiR BPD patients, but not with other psychiatric (including lithium-nonresponsive BPD) and neurological disorders. Lithium (and other pathway modulators) lowers pCRMP2, increasing spine area and density. Human BPD brains show similarly elevated ratios and diminished spine densities; lithium therapy normalizes the ratios and spines. Consistent with such "spine-opathies," human LiR BPD neurons with abnormal ratios evince abnormally steep slopes for calcium flux; lithium normalizes both. Behaviorally, transgenic mice that reproduce lithium's postulated site-of-action in dephosphorylating CRMP2 emulate LiR in BPD. These data suggest that the "lithium response pathway" in BPD governs CRMP2's phosphorylation, which regulates cytoskeletal organization, particularly in spines, modulating neural networks. Aberrations in the posttranslational regulation of this developmentally critical molecule may underlie LiR BPD pathogenesis. Instructively, examining the proteomic profile in hiPSCs of a functional agent-even one whose mechanism-of-action is unknownmight reveal otherwise inscrutable intracellular pathogenic pathways. have proven valuable for studying the molecular pathology of monogenic diseases, one of the technique's greatest challenges has been to offer similar insights into the molecular pathogenesis of polygenic, multifactorial disorders for which the underlying pathophysiology is unknown. The struggle has been to go beyond phenotypic description to discerning underlying molecular mechanisms. Neuropsychiatric illnesses are a prototype for such complex conditions (1-3). They are difficult to model not only because of the likelihood of polygenic influences, but also because of the subjectivity with which these diseases must often be diagnosed, the empirical fashion with which drugs are prescribed, and the heterogeneity of patient response. Of such maladies, bipolar disorder

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 α-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-3β, 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-3β 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.α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor | internalization | kinesin light chain 2

No abstract

Psychiatric illnesses are disabling disorders with poorly understood underlying pathophysiologies. However, it is becoming increasingly evident that these illnesses result from disruptions across whole cellular networks rather than any particular monoamine system. Recent evidence continues to support the hypothesis that these illnesses arise from impairments in cellular plasticity cascades, which lead to aberrant information processing in the circuits that regulate mood, cognition, and neurovegetative functions (sleep, appetite, energy, etc). As a result, many have begun to consider future therapies that would be capable of affecting global changes in cellular plasticity to restore appropriate synaptic function and neuronal connectivity. MicroRNAs (miRNAs) are non-coding RNAs that can repress the gene translation of hundreds of their targets and are therefore well-positioned to target a multitude of cellular mechanisms. Here, we review some properties of microRNAs and show they are altered by stress, glucocorticoids, mood stabilizers, and in a particular psychiatric disorder, schizophrenia. While this field is still in its infancy, we consider their potential for regulating behavioral phenotypes and targeting key predicted signaling cascades that are implicated in psychiatric illness. Clearly, considerable research is required to better determine any therapeutic potential of targeting microRNAs; however, these agents may provide the next generation of effective therapies for psychiatric illnesses.