Noradrenaline activation of hippocampal dopamine D1 receptors promotes antidepressant effects.

Dopamine D1 receptors (D1Rs) in the hippocampal dentate gyrus (DG) are essential for antidepressant effects. However, the midbrain dopaminergic neurons, the major source of dopamine in the brain, only sparsely project to DG, suggesting possible activation of DG D1Rs by endogenous substances other than dopamine. We have examined this possibility using electrophysiological and biochemical techniques and found robust activation of D1Rs in mouse DG neurons by noradrenaline. Noradrenaline at the micromolar range potentiated synaptic transmission at the DG output and increased the phosphorylation of protein kinase A substrates in DG via activation of D1Rs and ß adrenergic receptors. Neuronal excitation preferentially enhanced noradrenaline-induced synaptic potentiation mediated by D1Rs with minor effects on ß-receptor-dependent potentiation. Increased voluntary exercise by wheel running also enhanced noradrenaline-induced, D1R-mediated synaptic potentiation, suggesting a distinct functional role of the noradrenaline-D1R signaling. We then examined the role of this signaling in antidepressant effects using mice exposed to chronic restraint stress. In the stressed mice, an antidepressant acting on the noradrenergic system induced a mature-to-immature change in the DG neuron phenotype, a previously proposed cellular substrate for antidepressant action. This effect was evident only in mice subjected to wheel running and blocked by a D1R antagonist. These results suggest a critical role of noradrenaline-induced activation of D1Rs in antidepressant effects in DG. Experience-dependent regulation of noradrenaline-D1R signaling may determine responsiveness to antidepressant drugs in depressive disorders.

Hippocampal Inflammation and Gene Expression Changes in Peripheral Lipopolysaccharide Challenged Mice Showing Sickness and Anxiety-Like Behaviors.

Neuroinflammation is often associated with the development of depressive and anxiety disorders. The hippocampus is one of the brain regions affected by inflammation that is associated with these symptoms. However, the mechanism of hippocampal inflammation-induced emotional behavior remains unknown. The aim of this study was to clarify temporal changes in the neuroinflammatory responses in the hippocampus and the response of dentate gyrus (DG) neurons using peripheral lipopolysaccharide (LPS)-challenged mice. LPS administration induced anxiety-like activity in the elevated plus maze test and social interaction test after 24 h, at which time the mice had recovered from sickness behavior. We examined the hippocampal inflammation-related gene expression changes over time. The expression of interleukin-1ß (Il1b) and tumor necrosis factor α (Tnfa) was rapidly enhanced and sustained until 24 h after LPS administration, whereas the expression of Il6 was transiently induced at approx. 6 h. IL-6-dependent downstream signaling of transducer and activator of transcription 3 (STAT3) was also activated approx. 3-6 h after LPS treatment. The expression of innate immune genes including interferon-induced transmembrane proteins such as interferon-induced transmembrane protein 1 (Ifitm1) and Ifitm3 and complement factors such as C1qa and C1qb started to increase approx. 6 h and showed sustained or further increase at 24 h. We also examined changes in the expression of several maturation markers in the DG and found that LPS enhanced the expression of calbindin 1 (Calb1), tryptophan-2,3-dioxigenase 2 (Tdo2), Il1rl, and neurotrophin-3 (Ntf3) at 24 h after LPS treatment. Collectively, these results demonstrate temporal changes of inflammation and gene expression in the hippocampus in LPS-induced sickness and anxiety-like behaviors.

Characterization of Astrocytes in the Minocycline-Administered Mouse Photothrombotic Ischemic Stroke Model.

Astrocytes, together with microglia, play important roles in the non-infectious inflammation and scar formation at the brain infarct during ischemic stroke. After ischemia occurs, these become highly reactive, accumulate at the infarction, and release various inflammatory signaling molecules. The regulation of astrocyte reactivity and function surrounding the infarction largely depends on intercellular communication with microglia. However, the mechanisms involved remain unclear. Furthermore, recent molecular biological studies have revealed that astrocytes are highly divergent under both resting and reactive states, whereas it has not been well reported how the communication between microglia and astrocytes affects astrocyte divergency during ischemic stroke. Minocycline, an antibiotic that reduces microglial activity, has been used to examine the functional roles of microglia in mice. In this study, we used a mouse photothrombotic ischemic stroke model to examine the characteristics of astrocytes after the administration of minocycline during ischemic stroke. Minocycline increased astrocyte reactivity and affected the localization of astrocytes in the penumbra region. Molecular characterization revealed that the induced expression of mRNA encoding the fatty acid binding protein 7 (FABP7) by photothrombosis was enhanced by the minocycline administration. Meanwhile, minocycline did not significantly affect the phenotype or class of astrocytes. The expression of Fabp7 mRNA was well correlated with that of tumor-necrosis factor α (TNFα)-encoding Tnf mRNA, indicating that a correlated expression of FABP7 from astrocytes and TNFα is suppressed by microglial activity.

TC10, a Rho family GTPase, is required for efficient axon regeneration in a neuron-autonomous manner.

Intracellular signaling pathways that promote axon regeneration are closely linked to the mechanism of neurite outgrowth. TC10, a signaling molecule that acts on neurite outgrowth through membrane transport, is a member of the Rho family G proteins. Axon injury increases the TC10 levels in motor neurons, suggesting that TC10 may be involved in axon regeneration. In this study, we tried to understand the roles of TC10 in the nervous system using TC10 knock-out mice. In cultured hippocampal neurons, TC10 ablation significantly reduced axon elongation without affecting ordinary polarization. We determined a role of TC10 in microtubule stabilization at the growth cone neck; therefore, we assume that TC10 limits axon retraction and promotes in vitro axon outgrowth. In addition, there were no notable differences in the size and structure of brains during prenatal and postnatal development between wild-type and TC10 knock-out mice. In motor neurons, axon regeneration after injury was strongly suppressed in mice lacking TC10 (both in conventional and injured nerve specific deletion). In retinal ganglion cells, TC10 ablation suppressed the axon regeneration stimulated by intraocular inflammation and cAMP after optic nerve crush. These results show that TC10 plays an important role in axon regeneration in both the peripheral and central nervous systems, and the role of TC10 in peripheral axon regeneration is neuron-intrinsic.

The effect of electroconvulsive seizure on survival, neuronal differentiation, and expression of the maturation marker in the adult mouse hippocampus.

Electroconvulsive seizure (ECS), a model of electroconvulsive therapy in rodents, strongly increases neurogenesis in the adult hippocampus. Neurogenesis is a multi-step process that spans proliferation, survival, neuronal differentiation, and functional maturation. Our previous study demonstrated that ECS stimulates the proliferation of neural stem-like cells. However, the contribution of ECS to survival, neuronal differentiation, and maturation in newborn cells remains unknown. To evaluate the effect of ECS on these processes, we labeled newborn cells with bromodeoxyuridine (BrdU) before ECS treatment to determine the cell age and examined the survival rate and expression of cellular markers in the BrdU-labeled cells. Our results revealed that exposure to ECS (11 repetitions) during the differentiation phase significantly increased survival and promoted neuronal differentiation of newborn cells in the dentate gyrus. Four of ECS repetitions during the early differentiation phase were sufficient to promote dendritic outgrowth in immature neurons and enhance the expression of the immature neuronal marker, calretinin, in newborn cells. In contrast, exposure to ECS (11 repetitions) during the late maturation phase significantly suppressed the expression of the mature neuronal marker, calbindin, in newborn neurons. These results demonstrate that ECS during the differentiation phase promoted survival and neuronal differentiation and, in contrast, suppressed mature marker expression during the late maturation phase, suggesting that ECS has multiple effects on the different stages of adult neurogenesis.

Rapid and lasting enhancement of dopaminergic modulation at the hippocampal mossy fiber synapse by electroconvulsive treatment.

Electroconvulsive therapy (ECT) is an established effective treatment for medication-resistant depression with the rapid onset of action. However, its cellular mechanism of action has not been revealed. We have previously shown that chronic antidepressant drug treatments enhance dopamine D1-like receptor-dependent synaptic potentiation at the hippocampal mossy fiber (MF)-CA3 excitatory synapse. In this study we show that ECT-like treatments in mice also have marked effects on the dopaminergic synaptic modulation. Repeated electroconvulsive stimulation (ECS), an animal model of ECT, strongly enhanced the dopamine-induced synaptic potentiation at the MF synapse in hippocampal slices. Significant enhancement was detectable after the second ECS, and further repetition of ECS up to 11 times monotonously increased the magnitude of enhancement. After repeated ECS, the dopamine-induced synaptic potentiation remained enhanced for more than 4 wk. These synaptic effects of ECS were accompanied by increased expression of the dopamine D1 receptor gene. Our results demonstrate that robust neuronal activation by ECS induces rapid and long-lasting enhancement of dopamine-induced synaptic potentiation at the MF synapse, likely via increased expression of the D1 receptor, at least in part. This rapid enhancement of dopamine-induced potentiation at the excitatory synapse may be relevant to the fast-acting antidepressant effect of ECT. NEW & NOTEWORTHY: We show that electroconvulsive therapy (ECT)-like stimulation greatly enhances synaptic potentiation induced by dopamine at the excitatory synapse formed by the hippocampal mossy fiber in mice. The effect of ECT-like stimulation on the dopaminergic modulation was rapidly induced, maintained for more than 4 wk after repeated treatments, and most likely mediated by increased expression of the dopamine D1 receptor. These effects may be relevant to fast-acting strong antidepressant action of ECT.

Prostaglandin E2-EP3 signaling induces inflammatory swelling by mast cell activation.

PGE2 has long been known as a potentiator of acute inflammation, but its mechanisms of action still remain to be defined. In this study, we employed inflammatory swelling induced in mice by arachidonate and PGE2 as models and dissected the role and mechanisms of action of each EP receptor at the molecular level. Arachidonate- or PGE2-induced vascular permeability was significantly reduced in EP3-deficient mice. Intriguingly, the PGE2-induced response was suppressed by histamine H1 antagonist treatment, histidine decarboxylase deficiency, and mast cell deficiency. The impaired PGE2-induced response in mast cell-deficient mice was rescued upon reconstitution with wild-type mast cells but not with EP3-deficient mast cells. Although the number of mast cells, protease activity, and histamine contents in ear tissues in EP3-deficient mice were comparable to those in wild-type mice, the histamine contents in ear tissues were attenuated upon PGE2 treatment in wild-type but not in EP3-deficient mice. Consistently, PGE2-EP3 signaling elicited histamine release in mouse peritoneal and bone marrow-derived mast cells, and it exerted degranulation and IL-6 production in a manner sensitive to pertussis toxin and a PI3K inhibitor and dependent on extracellular Ca(2+) ions. These results demonstrate that PGE2 triggers mast cell activation via an EP3-Gi/o-Ca(2+) influx/PI3K pathway, and this mechanism underlies PGE2-induced vascular permeability and consequent edema formation.

Eosinophils control the resolution of inflammation and draining lymph node hypertrophy through the proresolving mediators and CXCL13 pathway in mice.

Resolution of inflammation is critical to restoration of tissue function after an inflammatory response. We previously demonstrated that 12/15-lipoxygenase (12/15-LOX)-expressing eosinophils contribute to this process in murine zymosan-induced peritonitis. In this study, eosinophils promoted resolution by regulating expression of macrophage CXCL13. Microarray analysis revealed that eosinophils significantly increased (∼3-fold) the expression of macrophage CXCL13 by a 12/15-LOX-dependent mechanism. CXCL13 depletion caused a resolution defect, with the reduced appearance of phagocytes carrying engulfed zymosan in the draining lymph nodes. Inflamed lymph node hypertrophy, a critical feature of the resolution process, was reduced by ∼60% in eosinophil-deficient mice, and adoptive transfer of eosinophils or administration of CXCL13 corrected this defect. Administration of the 12/15-LOX-derived mediator lipoxin A4 (LXA4) increased the expression of CXCL13 and restored the defect of lymph node hypertrophy in eosinophil-deficient mice. These results demonstrate that eosinophils control the resolution of inflammation and draining lymph node hypertrophy through proresolving lipid mediators and the CXCL13 pathway in mice.

Quantification of Mastoid Air Cells and Opacification of the Middle Ear in Primary Ciliary Dyskinesia.

OBJECTIVE: To evaluate pneumatization and opacification of the temporal bone on computed tomography (CT) images in patients with primary ciliary dyskinesia (PCD). STUDY DESIGN: Retrospective case-control study. SETTING: Tertiary referral center. PATIENTS: Fifteen patients with PCD (30 ears) and 45 age-matched individuals without PCD (90 ears) as controls. INTERVENTION: Diagnostic only. MAIN OUTCOME MEASURES: Quantification of mastoid air cells in the PCD and control groups and comparison between them. Degree of middle ear opacification on CT images of the temporal bone in the PCD group. RESULTS: The volume of the mastoid air cells was 30% smaller in the PCD group than in the control group ( p < 0.05). The suppression ratio, which is defined to indicate how much the average volume of mastoid air cells in the PCD group is suppressed relative to the control group, was 64% lower in the PCD group ( p < 0.05). Opacification was noted in 47% of the mastoid air cells and 63% of the tympanic cavity on CT images of the temporal bone in the PCD group, which were significantly higher frequencies than in the control group (1.1% and 1.1%, respectively). CONCLUSIONS: Compared with individuals without PCD, those with PCD showed a significantly smaller volume of mastoid air cells and a significantly higher frequency of opacification of mastoid air cells and tympanic cavity on temporal bone CT. Otitis media raises suspicion for PCD, and the otological manifestations of PCD reported here could help to narrow the differential diagnosis and facilitate early treatment.

Congenital choanal atresia where the atretic wall thickened while waiting for an elective surgery.

INTRODUCTION AND IMPORTANCE: Although bilateral congenital choanal atresia (CCA) requires early intervention to open closure walls for safe breathing, it is desirable to be withheld until an infant acquires surgical and anesthetic tolerance. Here we introduce an infant of CCA whose closure wall had thickened during a waiting period for an elective surgery. CASE PRESENTATION: The choana of the patient could not be identified by intranasal fiberscopy and the bilateral CCA was found by CT scan on day 17 after birth. Since he could breathe orally without distress, surgery was withheld until he acquires the tolerance. At nine weeks old, however, CT image detected thickening of the closure wall. At 10 weeks old, he underwent scheduled surgery in which the bilateral closure walls were removed together with attached posterior part of the nasal septum under endoscopic endonasal approach. The patient became able to breath nasally and the choana remained open without restenosis at 3 years after surgery. CLINICAL DISCUSSION: This is the first CCA case reporting closure walls thickened during a waiting period for an elective surgery. Although waiting for surgery was systemically safer by growth, the surgery became more invasive to prevention from restenosis. CONCLUSIONS: This case suggests that we must decide appropriate timing of surgery in an infant, considering dilemma between systemic safety ensuring and lesion aggravation by waiting for surgery.

Prostaglandin E2-mediated attenuation of mesocortical dopaminergic pathway is critical for susceptibility to repeated social defeat stress in mice.

Various kinds of stress are thought to precipitate psychiatric disorders, such as major depression. Whereas studies in rodents have suggested a critical role of medial prefrontal cortex (mPFC) in stress susceptibility, the mechanism of how stress susceptibility is determined through mPFC remains unknown. Here we show a critical role of prostaglandin E(2) (PGE(2)), a bioactive lipid derived from arachidonic acid, in repeated social defeat stress in mice. Repeated social defeat increased the PGE(2) level in the subcortical region of the brain, and mice lacking either COX-1, a prostaglandin synthase, or EP1, a PGE receptor, were impaired in induction of social avoidance by repeated social defeat. Given the reported action of EP1 that augments GABAergic inputs to midbrain dopamine neurons, we analyzed dopaminergic response upon social defeat. Analyses of c-Fos expression of VTA dopamine neurons and dopamine turnover in mPFC showed that mesocortical dopaminergic pathway is activated upon social defeat and attenuated with repetition of social defeat in wild-type mice. EP1 deficiency abolished such repeated stress-induced attenuation of mesocortical dopaminergic pathway. Blockade of dopamine D1-like receptor during social defeat restored social avoidance in EP1-deficient mice, suggesting that disinhibited dopaminergic response during social defeat blocks induction of social avoidance. Furthermore, mPFC dopaminergic lesion by local injection of 6-hydroxydopamine, which mimicked the action of EP1 during repeated stress, facilitated induction of social avoidance upon social defeat. Taken together, our data suggest that PGE(2)-EP1 signaling is critical for susceptibility to repeated social defeat stress in mice through attenuation of mesocortical dopaminergic pathway.

Dual roles of PGE2-EP4 signaling in mouse experimental autoimmune encephalomyelitis.

Experimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis (MS). Although prostaglandin (PG) concentrations are increased in cerebrospinal fluid of MS patients, the role of PGs in MS is unknown. We examined this issue by subjecting mice deficient in each PG receptor type or subtype to EAE induction and using agonists or antagonists selective for each of the four PGE receptor (EP) subtypes. Among PG receptor-deficient mice, only EP4(-/-) mice manifested significant suppression of EAE, which was mimicked in wild-type mice and to a greater extent, in EP2(-/-) mice by administration of the EP4 antagonist ONO-AE3-208 during the immunization phase. EP4 antagonism during immunization also suppressed the generation of antigen-specific T helper (Th) 1 and Th17 cells in wild-type mice and to a greater extent, in EP2(-/-) mice. ONO-AE3-208 administration at EAE onset had little effect on disease severity, and its administration throughout the experimental period did not cause significant reduction of the peak of disease, suggesting that, in addition to its facilitative action during the immunization phase, EP4 exerts a preventive action in the elicitation phase. Administration of the EP4 agonist ONO-AE1-329 at EAE onset delayed and suppressed disease progression as well as inhibited the associated increase in permeability of the blood-brain barrier. Thus, PGE(2) exerts dual functions in EAE, facilitating Th1 and Th17 cell generation redundantly through EP4 and EP2 during immunization and attenuating invasion of these cells into the brain by protecting the blood-brain barrier through EP4.

KNT-127, a selective delta opioid receptor agonist, shows beneficial effects in the hippocampal dentate gyrus of a chronic vicarious social defeat stress mouse model.

Delta opioid receptors (DOPs) play an important role in depression and other mood disorders. However, little is known about the underlying physiological mechanisms. The hypothalamic-pituitary-adrenal axis, adult hippocampal neurogenesis, and neuroinflammation are regarded as key pathophysiological factors in depression. In this study, we investigated the influence of DOP activation on those factors in a valid animal model of depression, chronic vicarious social defeat stress (cVSDS) mice. cVSDS mice (male C57BL/6J mice) were produced following a 10-day exposure to witness of social defeat stress, and each evaluation was performed more than 28 days after the stress period. Repeated administrations to cVSDS mice with a selective DOP agonist, KNT-127, both during (10 days) and after (28 days) the stress period respectively improved their decreased social interaction behaviors and increased serum corticosterone levels. When administered during the stress period, KNT-127 suppressed decreases in the hippocampal newborn neuron survival rate in cVSDS mice. Moreover, in both administration paradigms, KNT-127 reduced the number of Iba-1- and CD11b-positive cells in the subgranular zone and the granule cell layer of the hippocampal dentate gyrus, indicating a suppression of cVSDS-induced microglial overactivation. These results suggest that KNT-127 acts over the hypothalamic-pituitary-adrenal axis and regulates neurogenesis and neuroinflammation resulting in anti-stress effects, and the antidepressant-like effects of the DOP agonist are implicated in the suppression of the neuroinflammation. This study presents a new finding on the effects of repeated DOP activations on the pathophysiological states of depression.

Overexpression of NT-3 in the hippocampus suppresses the early phase of the adult neurogenic process.

The dentate gyrus (DG) of the hippocampus regulates stress-related emotional behaviors and ensures neurogenesis throughout life. Neurotrophin-3 (NT-3) is a neurotrophic factor that regulates neuronal differentiation, survival, and synaptic formation in both the peripheral and central nervous systems. NT-3 is expressed in the adult DG of the hippocampus; several chronic stress conditions enhance NT-3 expression in rodents. However, functional modulation of the adult DG by NT-3 signaling remains unclear. To directly investigate the impact of NT-3 on DG function, NT-3 was overexpressed in the hippocampal ventral DG by an adeno-associated virus carrying NT-3 (AAV-NT-3). Four weeks following the AAV-NT-3 injection, high NT-3 expression was observed in the ventral DG. We examined the influence of NT-3 overexpression on the neuronal responses and neurogenic processes in the ventral DG. NT-3 overexpression significantly increased the expression of the mature DG neuronal marker calbindin and immediate early genes, such as Fos and Fosb, thereby suggesting DG neuronal activation. During neurogenesis, the number of proliferating cells and immature neurons in the subgranular zone of the DG significantly decreased in the AAV-NT-3 group. Among the neurogenesis-related factors, Vegfd, Lgr6, Bmp7, and Drd1 expression significantly decreased. These results demonstrated that high NT-3 levels in the hippocampus regulate the activation of mature DG neurons and suppress the early phase of neurogenic processes, suggesting a possible role of NT-3 in the regulation of adult hippocampal function under stress conditions.

Prostacyclin-IP signaling and prostaglandin E2-EP2/EP4 signaling both mediate joint inflammation in mouse collagen-induced arthritis.

Prostaglandin (PG)I2 (prostacyclin [PGI]) and PGE2 are abundantly present in the synovial fluid of rheumatoid arthritis (RA) patients. Although the role of PGE2 in RA has been well studied, how much PGI2 contributes to RA is little known. To examine this issue, we backcrossed mice lacking the PGI receptor (IP) to the DBA/1J strain and subjected them to collagen-induced arthritis (CIA). IP-deficient (IP-/-) mice exhibited significant reduction in arthritic scores compared with wild-type (WT) mice, despite anti-collagen antibody production and complement activation similar to WT mice. IP-/- mice also showed significant reduction in contents of proinflammatory cytokines, such as interleukin (IL)-6 in arthritic paws. Consistently, the addition of an IP agonist to cultured synovial fibroblasts significantly enhanced IL-6 production and induced expression of other arthritis-related genes. On the other hand, loss or inhibition of each PGE receptor subtype alone did not affect elicitation of inflammation in CIA. However, a partial but significant suppression of CIA was achieved by the combined inhibition of EP2 and EP4. Our results show significant roles of both PGI2-IP and PGE2-EP2/EP4 signaling in the development of CIA, and suggest that inhibition of PGE2 synthesis alone may not be sufficient for suppression of RA symptoms.

Regulation of adult-born and mature neurons in stress response and antidepressant action in the dentate gyrus of the hippocampus.

The dentate gyrus (DG) of the hippocampus has been implicated in the regulation of stress responses, and in the pathophysiology and treatment of depression. This review discusses the cellular changes caused by chronic stress and the cellular role of the DG in stress-induced behavioral changes and its antidepressant-like effects. Regarding adult-born neurogenic processes in the DG, chronic stress, such as repeated social defeat, suppresses cell proliferation during and immediately after stress; however, this effect is transient. The subsequent differentiation and survival processes are differentially regulated depending on the timing and sensitivity of stress. The activation of young adult-born neurons during stress contributes to stress resilience, while the transient increase in the survival of adult-born neurons after the cessation of stress seems to promote stress susceptibility. In mature granule neurons, the predominant cells in the DG, synaptic plasticity is suppressed by chronic stress. However, a group of mature granule neurons is activated by chronic stress. Chronic antidepressant treatment can transform mature granule neurons to a phenotype resembling that of immature neurons, characterized as "dematuration". Adult-born neurons suppress the activation of mature granule neurons during stress, indicating that local neural interactions within the DG are important for the stress response. Elucidating the stress-associated context- and timing-dependent cellular changes and functions in the DG will provide insights into stress-related psychiatric diseases.

Chronic vicarious social defeat stress attenuates new-born neuronal cell survival in mouse hippocampus.

Increasing evidence has shown that adult hippocampal neurogenesis is closely related to the pathophysiological condition of depressive disorders. Recently, chronic social defeat stress paradigms have been regarded as important animal models of depression, accompanied with neural plastic changes in the hippocampus. However, little is known about influences of non-physical stress on neurogenesis. In the present study, we focused on the chronic vicarious social defeat stress paradigm and examined the effect of psychological stress on mouse hippocampal neurogenesis. Immediately after the chronic psychological stress, the cell survival rate in the dentate gyrus of the hippocampus was significantly diminished without modifying the cell proliferation rate. The decreased ratio in cell survival persisted for 4 weeks after the stress-loading period, while the differentiation and maturity of new-born neurons were identical to control groups. Furthermore, treatment with the chronic antidepressant fluoxetine reversed the social behavioral deficits and promoted new-born neurons survival. These results demonstrate that emotional stress in the vicarious social defeat stress paradigm influences neuronal cell survival in the hippocampus, which reinforces its validity as an animal model of depression.

Prostaglandin E2-EP4 signaling suppresses adipocyte differentiation in mouse embryonic fibroblasts via an autocrine mechanism.

The prostaglandin (PG) receptors EP4 and FP have the potential to exert negative effects on adipogenesis, but the exact contribution of endogenous PG-driven receptor signaling to this process is not fully understood. In this study, we employed an adipocyte differentiation system from mouse embryonic fibroblasts (MEF) and compared the effects of each PG receptor-deficiency on adipocyte differentiation. In wild-type (WT) MEF cells, inhibition of endogenous PG synthesis by indomethacin augmented the differentiation, whereas exogenous PGE2, as well as an FP agonist, reversed the effect of indomethacin. In EP4-deficient cells, basal differentiation was upregulated to the levels in indomethacin-treated WT cells, and indomethacin did not further enhance differentiation. Differentiation in FP-deficient cells was equivalent to WT and was still sensitive to indomethacin. PGE2 or indomethacin treatment of WT MEF cells for the first two days was enough to suppress or enhance transcription of the Pparg2 gene as well as the subsequent differentiation, respectively. Differentiation stimuli induced COX-2 gene and protein expression, as well as PGE2 production, in WT MEF cells. These results suggest that PGE2-EP4 signaling suppresses adipocyte differentiation by affecting Pparg2 expression in an autocrine manner and that FP-mediated inhibition is not directly involved in adipocyte differentiation in the MEF system.

Exploration of new molecular mechanisms for antidepressant actions of electroconvulsive seizure.

Electroconvulsive seizure (ECS) therapy 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. Here, I review studies that show molecular, cellular, and behavioral changes by ECS treatment, and discuss the functions of ECS to underlie the action of antidepressant effects. In hippocampus, these changes cover gene induction, increased adult neurogenesis, and electrophysiological reactivity. Especially, the role of vascular endothelial growth factor (VEGF) in neurogenesis is discussed. Among other gene expression changes in hippocampus, a role of cyclooxygenase (COX)-2, an inducible type of the rate-limiting enzyme of prostanoid synthesis, is focused. ECS-induced changes in other brain regions such as prefrontal cortex and hypothalamus, and ECS-induced behavioral changes are also reviewed. Understanding the molecular, cellular, and behavioral changes by ECS will provide a new view to find potential targets for novel antidepressant design that are highlighted by these findings.

Electroconvulsive seizure and VEGF increase the proliferation of neural stem-like cells in rat hippocampus.

All classes of antidepressants increase hippocampal cell proliferation and neurogenesis, which contributes, in part, to the behavioral actions of these treatments. Among antidepressant treatments, electroconvulsive seizure (ECS) is the most robust stimulator of hippocampal cell proliferation and the most efficacious treatment for depression, but the cellular mechanisms underlying the actions of ECS are unknown. To address this question, we investigated the effect of ECS on proliferation of neural stem-like and/or progenitor cells in the subgranular zone of rat dentate gyrus. We define the neural differentiation cascade from stem-like cells to early neural progenitors (also referred to as quiescent and amplifying neural progenitors, respectively) by coexpression of selective cellular and mitotic activity markers. We find that at an early mitotic phase ECS increases the proliferation of quiescent progenitors and then at a later phase increases the proliferation of amplifying progenitors. We further demonstrate that vascular endothelial growth factor (VEGF) signaling is necessary for ECS induction of quiescent neural progenitor cell proliferation and is sufficient to produce this effect. These findings demonstrate that ECS and subsequent induction of VEGF stimulates the proliferation of neural stem-like cells and neural progenitor cells, thereby accounting for the superior neurogenic actions of ECS compared with chemical antidepressants.