Comparison of inflammatory and behavioral responses to chronic stress in female and male mice.

Major depressive disorder (MDD) is a debilitating disease with a high worldwide prevalence. Despite its greater prevalence in women, male animals are used in most preclinical studies of depression even though there are many sex differences in key components of depression, such as stress responses and immune system functions. In the present study, we found that chronic restraint stress-induced depressive-like behaviors are quite similar in male and female mice, with both sexes displaying increased immobility time in the tail suspension test and reduced social interactions, and both sexes exhibited deficits in working and spatial memories.

Targeting the Adaptive Immune System in Depression: Focus on T Helper 17 Cells.

There is a vital need to understand mechanisms contributing to susceptibility to depression to improve treatments for the 11% of Americans who currently suffer from this debilitating disease. The adaptive immune system, comprising T and B cells, has emerged as a potential contributor to depression, as demonstrated in the context of lymphopenic mice. Overall, patients with depression have reduced circulating T and regulatory B cells, "immunosuppressed" T cells, and alterations in the relative abundance of T cell subtypes.

(+)-Naloxone blocks Toll-like receptor 4 to ameliorate deleterious effects of stress on male mouse behaviors.

Depression is a leading cause of disability worldwide and current treatments are often inadequate for many patients. Increasing evidence indicates that inflammation contributes to susceptibility to depression. We hypothesized that targeting Toll-like receptor 4 (TLR4), one of the main signaling pathways for triggering an inflammatory response, would lessen stress-induced depression-like behaviors in male mice.

Toll-like receptor 2 (TLR2)-deficiency impairs male mouse recovery from a depression-like state.

Major depression is a prevalent, debilitating disease, yet therapeutic interventions for depression are frequently inadequate. Many clinical and pre-clinical studies have demonstrated that depression is associated with aberrant activation of the inflammatory system, raising the possibility that reducing inflammation may provide antidepressant effects. Using the learned helplessness mouse model, we tested if susceptibility or recovery were affected by deficiency in either of two receptors that initiate inflammatory signaling, Toll-like receptor-4 (TLR4) and TLR2, using knockout male mice.

Brain Penetrable Histone Deacetylase 6 Inhibitor SW-100 Ameliorates Memory and Learning Impairments in a Mouse Model of Fragile X Syndrome.

Disease-modifying therapies are needed for Fragile X Syndrome (FXS), as at present there are no effective treatments or cures. Herein, we report on a tetrahydroquinoline-based selective histone deacetylase 6 (HDAC6) inhibitor SW-100, its pharmacological and ADMET properties, and its ability to improve upon memory performance in a mouse model of FXS, Fmr1 mice. This small molecule demonstrates good brain penetrance, low-nanomolar potency for the inhibition of HDAC6 (IC = 2.

Distinct characteristics of hippocampal pathogenic T17 cells in a mouse model of depression.

Increasing evidence indicates that multiple actions of the immune system are closely intertwined with the development of depression and subsequent recovery processes. One of these interactions is substantial evidence that the T17 subtype of CD4 T cells promotes susceptibility to depression-like behaviors in mice. Comparing subtypes of CD4 T cells, we found that administration of T17 cells, but not T1 cells or T, promoted susceptibility to learned-helplessness depressive-like behavior and accumulated in the hippocampus of learned helpless mice.

TNFα disrupts blood brain barrier integrity to maintain prolonged depressive-like behavior in mice.

Recovery from major depressive disorder is difficult, particularly in patients who are refractory to antidepressant treatments. To examine factors that regulate recovery, we developed a prolonged learned helplessness depression model in mice. After the induction of learned helplessness, mice were separated into groups that recovered or did not recover within 4 weeks.

Intranasal siRNA administration reveals IGF2 deficiency contributes to impaired cognition in Fragile X syndrome mice.

Molecular mechanisms underlying learning and memory remain imprecisely understood, and restorative interventions are lacking. We report that intranasal administration of siRNAs can be used to identify targets important in cognitive processes and to improve genetically impaired learning and memory. In mice modeling the intellectual deficiency of Fragile X syndrome, intranasally administered siRNA targeting glycogen synthase kinase-3β (GSK3β), histone deacetylase-1 (HDAC1), HDAC2, or HDAC3 diminished cognitive impairments.

Stressed and Inflamed, Can GSK3 Be Blamed?

Psychological stress has a pervasive influence on our lives. In many cases adapting to stress strengthens organisms, but chronic or severe stress is usually harmful. One surprising outcome of psychological stress is the activation of an inflammatory response that resembles inflammation caused by infection or trauma.

Cotinine administration improves impaired cognition in the mouse model of Fragile X syndrome.

Cotinine is the major metabolite of nicotine and has displayed some capacity for improving cognition in mouse models following chronic administration. We tested if acute cotinine treatment is capable of improving cognition in the mouse model of Fragile X syndrome, Fmr1 knockout mice, and if this is related to inhibition by cotinine treatment of glycogen synthase kinase-3β (GSK3β), which is abnormally active in Fmr1 mice. Acute cotinine treatment increased the inhibitory serine-phosphorylation of GSK3β and the activating phosphorylation of AKT, which can mediate serine-phosphorylation of GSK3β, in both wild-type and Fmr1 mouse hippocampus.

Ketamine-induced inhibition of glycogen synthase kinase-3 contributes to the augmentation of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor signaling.

Objectives: Sub-anesthetic doses of ketamine have been found to provide rapid antidepressant actions, indicating that the cellular signaling systems targeted by ketamine are potential sites for therapeutic intervention. Ketamine acts as an antagonist of N-methyl-D-aspartate (NMDA) receptors, and animal studies indicate that subsequent augmentation of signaling by α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors is critical for the antidepressant outcome.

Methods: In this study, we tested if the inhibitory effect of ketamine on glycogen synthase kinase-3 (GSK3) affected hippocampal cell-surface AMPA receptors using immunoblotting of membrane and synaptosomal extracts from wild-type and GSK3 knockin mice.

Ketamine up-regulates a cluster of intronic miRNAs within the serotonin receptor 2C gene by inhibiting glycogen synthase kinase-3.

Objectives: We examined mechanisms that contribute to the rapid antidepressant effect of ketamine in mice that is dependent on glycogen synthase kinase-3 (GSK3) inhibition.

Methods: We measured serotonergic (5HT)-2C-receptor (5HTR2C) cluster microRNA (miRNA) levels in mouse hippocampus after administering an antidepressant dose of ketamine (10 mg/kg) in wild-type and GSK3 knockin mice, after GSK3 inhibition with L803-mts, and in learned helpless mice.

Results: Ketamine up-regulated cluster miRNAs 448-3p, 764-5p, 1264-3p, 1298-5p and 1912-3p (2- to 11-fold).

Up-regulation of insulin-like growth factor 2 by ketamine requires glycogen synthase kinase-3 inhibition.

An antidepressant dose of the rapidly-acting ketamine inhibits glycogen synthase kinase-3 (GSK3) in mouse hippocampus, and this inhibition is required for the antidepressant effect of ketamine in learned helplessness depression-like behavior. Here we report that treatment with an antidepressant dose of ketamine (10mg/kg) increased expression of insulin-like growth factor 2 (IGF2) in mouse hippocampus, an effect that required ketamine-induced inhibition of GSK3. Ketamine also inhibited hippocampal GSK3 and increased expression of hippocampal IGF2 in mice when administered after the induction of learned helplessness.

Lithium to the Rescue.

Lithium, an element that Mother Nature has put in some drinking water sources, has been used for its curative powers for centuries. Today, it's given in capsule form as a mood stabilizer for bipolar disorder and depression. New research, however, reveals its role as a neuroprotector, and suggests that a better understanding of the role enzymes modulated by lithium play could lead to new treatments for Alzheimer's disease, Parkinson's disease, multiple sclerosis, and other neurodegenerative disorders.

Stress-induced neuroinflammation is mediated by GSK3-dependent TLR4 signaling that promotes susceptibility to depression-like behavior.

Most psychiatric and neurological diseases are exacerbated by stress. Because this may partially result from stress-induced inflammation, we examined factors involved in this stress response. After a paradigm of inescapable foot shock stress that causes learned helplessness depression-like behavior, eighteen cytokines and chemokines increased in mouse hippocampus, peaking 6-12h after stress.

GSK3β isoform-selective regulation of depression, memory and hippocampal cell proliferation.

Abnormally active glycogen synthase kinase-3 (GSK3) contributes to pathological processes in multiple psychiatric and neurological disorders. Modeled in mice, this includes increasing susceptibility to dysregulation of mood-relevant behaviors, impairing performance in several cognitive tasks and impairing adult hippocampal neural precursor cell (NPC) proliferation. These deficits are all evident in GSK3α/β knockin mice, in which serine-to-alanine mutations block the inhibitory serine phosphorylation regulation of both GSK3 isoforms, leaving GSK3 hyperactive.

A pre-conditioning stress accelerates increases in mouse plasma inflammatory cytokines induced by stress.

Background: Major depressive disorder is a prevalent disease that is inadequately treated with currently available interventions. Stress increases susceptibility to depression in patients and rodent models. Depression is also associated with aberrant activation of inflammation, such as increases in circulating levels of interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNFα).

Impairments in cognition and neural precursor cell proliferation in mice expressing constitutively active glycogen synthase kinase-3.

Brain glycogen synthase kinase-3 (GSK3) is hyperactive in several neurological conditions that involve impairments in both cognition and neurogenesis. This raises the hypotheses that hyperactive GSK3 may directly contribute to impaired cognition, and that this may be related to deficiencies in neural precursor cells (NPC). To study the effects of hyperactive GSK3 in the absence of disease influences, we compared adult hippocampal NPC proliferation and performance in three cognitive tasks in male and female wild-type (WT) mice and GSK3 knockin mice, which express constitutively active GSK3.

Glycogen synthase kinase-3 (GSK3): regulation, actions, and diseases.

Glycogen synthase kinase-3 (GSK3) may be the busiest kinase in most cells, with over 100 known substrates to deal with. How does GSK3 maintain control to selectively phosphorylate each substrate, and why was it evolutionarily favorable for GSK3 to assume such a large responsibility? GSK3 must be particularly adaptable for incorporating new substrates into its repertoire, and we discuss the distinct properties of GSK3 that may contribute to its capacity to fulfill its roles in multiple signaling pathways. The mechanisms regulating GSK3 (predominantly post-translational modifications, substrate priming, cellular trafficking, protein complexes) have been reviewed previously, so here we focus on newly identified complexities in these mechanisms, how each of these regulatory mechanism contributes to the ability of GSK3 to select which substrates to phosphorylate, and how these mechanisms may have contributed to its adaptability as new substrates evolved.

Astrocytes modulate the polarization of CD4+ T cells to Th1 cells.

T-cell characteristics are dynamic and influenced by multiple factors. To test whether cells and the environment in the central nervous system (CNS) can influence T-cells, we tested if culturing mouse CD4(+) T-cells on mouse primary astrocytes, compared with standard feeder cells, modified T-cell polarization to Th1 and Treg subtypes. Astrocytes supported the production of Th1 cells and Tregs, which was diminished by inflammatory activation of astrocytes, and glutamate accumulation that may result from impaired glutamate uptake by astrocytes strongly promoted Th1 production.

Glycogen synthase kinase-3 inhibitors reverse deficits in long-term potentiation and cognition in fragile X mice.

Background: Identifying feasible therapeutic interventions is crucial for ameliorating the intellectual disability and other afflictions of fragile X syndrome (FXS), the most common inherited cause of intellectual disability and autism. Hippocampal glycogen synthase kinase-3 (GSK3) is hyperactive in the mouse model of FXS (FX mice), and hyperactive GSK3 promotes locomotor hyperactivity and audiogenic seizure susceptibility in FX mice, raising the possibility that specific GSK3 inhibitors may improve cognitive processes.

Methods: We tested if specific GSK3 inhibitors improve deficits in N-methyl-D-aspartate receptor-dependent long-term potentiation at medial perforant path synapses onto dentate granule cells and dentate gyrus-dependent cognitive behavioral tasks.

Lithium treatment alleviates impaired cognition in a mouse model of fragile X syndrome.

Fragile X syndrome (FXS) is caused by suppressed expression of fragile X mental retardation protein (FMRP), which results in intellectual disability accompanied by many variably manifested characteristics, such as hyperactivity, seizures and autistic-like behaviors. Treatment of mice that lack FMRP, Fmr1 knockout (KO) mice, with lithium has been reported to ameliorate locomotor hyperactivity, prevent hypersensitivity to audiogenic seizures, improve passive avoidance behavior and attenuate sociability deficits. To focus on the defining characteristic of FXS, which is cognitive impairment, we tested if lithium treatment ameliorated impairments in four cognitive tasks in Fmr1 KO mice, tested if the response to lithium differed in adolescent and adult mice and tested if therapeutic effects persisted after discontinuation of lithium administration.

Glycogen synthase kinase-3 inhibitors: Rescuers of cognitive impairments.

Impairment of cognitive processes is a devastating outcome of many diseases, injuries, and drugs affecting the central nervous system (CNS). Most often, very little can be done by available therapeutic interventions to improve cognitive functions. Here we review evidence that inhibition of glycogen synthase kinase-3 (GSK3) ameliorates cognitive deficits in a wide variety of animal models of CNS diseases, including Alzheimer's disease, Fragile X syndrome, Down syndrome, Parkinson's disease, spinocerebellar ataxia type 1, traumatic brain injury, and others.

Regulation of Th1 cells and experimental autoimmune encephalomyelitis by glycogen synthase kinase-3.

Experimental autoimmune encephalomyelitis (EAE) is a rodent model of multiple sclerosis (MS), a debilitating autoimmune disease of the CNS, for which only limited therapeutic interventions are available. Because MS is mediated in part by autoreactive T cells, particularly Th17 and Th1 cells, in the current study, we tested whether inhibitors of glycogen synthase kinase-3 (GSK3), previously reported to reduce Th17 cell generation, also alter Th1 cell production or alleviate EAE. GSK3 inhibitors were found to impede the production of Th1 cells by reducing STAT1 activation.