Involvement of Innate and Adaptive Immune Systems Alterations in the Pathophysiology and Treatment of Depression

Major depressive disorder (MDD) is a prevalent and debilitating disorder, often fatal. Treatment options are few and often do not provide immediate relief to the patients. The increasing involvement of inflammation in the pathology of MDD has provided new potential therapeutic avenues. Cytokine levels are elevated in the blood and cerebrospinal fluid of MDD patients whereas immune cells often exhibit an immunosuppressed phenotype in MDD patients. Blocking cytokine actions in patients exhibiting MDD show some antidepressant efficacy. However, the role of cytokines, and the immune response in MDD patients remain to be determined. We reviewed here the roles of the innate and adaptive immune systems in MDD, as well as potential mechanisms whereby the immune response might be regulated in MDD

Altered Metabolism and Persistent Starvation Behaviors Caused by Reduced AMPK Function in Drosophila

Organisms must utilize multiple mechanisms to maintain energetic homeostasis in the face of limited nutrient availability. One mechanism involves activation of the heterotrimeric AMP-activated protein kinase (AMPK), a cell-autonomous sensor to energetic changes regulated by ATP to AMP ratios. We examined the phenotypic consequences of reduced AMPK function, both through RNAi knockdown of the gamma subunit (AMPKγ) and through expression of a dominant negative alpha (AMPKα) variant in Drosophila melanogaster. Reduced AMPK signaling leads to hypersensitivity to starvation conditions as measured by lifespan and locomotor activity. Locomotor levels in flies with reduced AMPK function were lower during unstressed conditions, but starvation-induced hyperactivity, an adaptive response to encourage foraging, was significantly higher than in wild type. Unexpectedly, total dietary intake was greater in animals with reduced AMPK function yet total triglyceride levels were lower. AMPK mutant animals displayed starvation-like lipid accumulation patterns in metabolically key liver-like cells, oenocytes, even under fed conditions, consistent with a persistent starved state. Measurements of O2 consumption reveal that metabolic rates are greater in animals with reduced AMPK function. Lastly, rapamycin treatment tempers the starvation sensitivity and lethality associated with reduced AMPK function. Collectively, these results are consistent with models that AMPK shifts energy usage away from expenditures into a conservation mode during nutrient-limited conditions at a cellular level. The highly conserved AMPK subunits throughout the Metazoa, suggest such findings may provide significant insight for pharmaceutical strategies to manipulate AMPK function in humans

The Actin-Binding Protein Capulet Genetically Interacts with the Microtubule Motor Kinesin to Maintain Neuronal Dendrite Homeostasis

BACKGROUND: Neurons require precise cytoskeletal regulation within neurites, containing microtubule tracks for cargo transport in axons and dendrites or within synapses containing organized actin. Due to the unique architecture and specialized function of neurons, neurons are particularly susceptible to perturbation of the cytoskeleton. Numerous actin-binding proteins help maintain proper cytoskeletal regulation. METHODOLOGY/PRINCIPAL FINDINGS: From a Drosophila forward genetic screen, we identified a mutation in capulet--encoding a conserved actin-binding protein--that causes abnormal aggregates of actin within dendrites. Through interaction studies, we demonstrate that simultaneous genetic inactivation of capulet and kinesin heavy chain, a microtubule motor protein, produces elongate cofilin-actin rods within dendrites but not axons. These rods resemble actin-rich structures induced in both mammalian neurodegenerative and Drosophila Alzheimer's models, but have not previously been identified by loss of function mutations in vivo. We further demonstrate that mitochondria, which are transported by Kinesin, have impaired distribution along dendrites in a capulet mutant. While Capulet and Cofilin may biochemically cooperate in certain circumstances, in neuronal dendrites they genetically antagonize each other. CONCLUSIONS/SIGNIFICANCE: The present study is the first molecularly defined loss of function demonstration of actin-cofilin rods in vivo. This study suggests that simultaneous, seemingly minor perturbations in neuronal dendrites can synergize producing severe abnormalities affecting actin, microtubules and mitochondria/energy availability in dendrites. Additionally, as >90% of Alzheimer's and Parkinson's cases are sporadic this study suggests mechanisms by which multiple mutations together may contribute to neurodegeneration instead of reliance on single mutations to produce disease

Inflammatory and neurodegenerative pathophysiology implicated in postpartum depression

Postpartum depression (PPD) is the most common psychiatric complication associated with pregnancy and childbirth with debilitating symptoms that negatively impact the quality of life of the mother as well as inflict potentially long-lasting developmental impairments to the child. Much of the theoretical pathophysiology put forth to explain the emergence of PPD overlaps with that of major depressive disorder (MDD) and, although not conventionally described in such terms, can be seen as neurodegenerative in nature. Framing the disorder from the perspective of the well-established inflammatory theory of depression, symptoms are thought to be driven by dysregulation, and subsequent hyperactivation of the body's immune response to stress. Compounded by physiological stressors such as drastic fluctuations in hormone signaling, physical and psychosocial stressors placed upon new mothers lay bare a number of significant vulnerabilities, or points of potential failure, in systems critical for maintaining healthy brain function. The inability to compensate or properly adapt to meet the changing demands placed upon these systems has the potential to damage neurons, hinder neuronal growth and repair, and disrupt neuronal circuit integrity such that essential functional outputs like mood and cognition are altered. The impact of this deterioration in brain function, which includes depressive symptoms, extends to the child who relies on the mother for critical life-sustaining care as well as important cognitive stimulation, accentuating the need for further research

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

•We describe a prolonged (>4 weeks) learned helplessness (LH) depression model in mice.•Prolonged LH was associated with elevated hippocampal TNFα, IL-17A and IL-23 levels.•Blood-brain barrier (BBB) disruption was evident in mice with prolonged LH.•Prolonged LH and elevated cytokines were rapidly reversed by Fingolimod or TNFα inhibitor treatment.•TNFα-mediated disruption of the BBB may contribute to impaired recovery from LH. 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. Comparisons were made between groups in hippocampal proteins, inflammatory cytokines, and blood brain barrier (BBB) permeability. Compared with mice that recovered and control mice, non-recovered mice displaying prolonged learned helplessness had greater hippocampal activation of glycogen synthase kinase-3 (GSK3), higher levels of tumor necrosis factor-α (TNFα), interleukin-17A, and interleukin-23, increased permeability of the blood brain barrier (BBB), and lower levels of the BBB tight junction proteins occludin, ZO1, and claudin-5. Treatment with the GSK3 inhibitor TDZD-8 reduced inflammatory cytokine levels, increased tight junction protein levels, and reversed impaired recovery from learned helplessness, demonstrating that prolonged learned helplessness is reversible and is maintained by abnormally active GSK3. In non-recovered mice with prolonged learned helpless, stimulation of sphingosine 1-phosphate receptors by Fingolimod or administration of the TNFα inhibitor etanercept repaired the BBB and reversed impaired recovery from prolonged learned helplessness. Thus, disrupted BBB integrity mediated in part by TNFα contributes to blocking recovery from prolonged learned helplessness depression-like behavior. Overall, this report describes a new model of prolonged depression-like behavior and demonstrates that stress-induced GSK3 activation contributes to disruption of BBB integrity mediated by inflammation, particularly TNFα, which contributes to impaired recovery from prolonged learned helplessness

Reduced <i>capulet</i> function leads to Kinesin aggregation in neuronal cell bodies.

<p>Kinesin heavy chain tagged with GFP (<i>Khc::EGFP</i>) expressed in a heterozygous <i>capulet</i> mutant background (capt/+) demonstrates aggregation in dorsal cluster sensory neuron cell bodies (arrows, B) but not in a wild type (for <i>capulet</i>) animal (A). Possibly, this phenotype is due to impaired transport of Khc::EGFP out of cell bodies (white arrows, B) and into dendrites. Note abundant Khc::EGFP expression in oenocytes in the same field to control for Khc::EGFP expression levels in other cell types. (All larvae contain <i>Gal4 109(2)80, UAS-Khc::EGFP</i> for visualization.)</p

Capulet modulates actin structure in neuronal dendrites.

<p>(A) PNS neurons expressing a rescuing transgene of mCherry::capulet (mCC, red) demonstrate co-localization within the soma, dendrites and axons (yellow) with actin::GFP but not within dendritic filopodia (green, arrows), which are enriched for F-actin. (B) Wild type PNS neuronal dendrites with abundant filopodia (arrows). (C) In contrast, overexpression of Capulet (<i>UAS-capt</i>), a monomeric actin-bindng protein, reduces the number of dendritic filopodia (arrows). (D–F) Time lapse analysis of the identical <i>capt</i>^K304 dendritic segment expressing actin::GFP demostrates that actin::GFP accumulations are dynamic in the <i>capulet</i> mutant. White arrows indicate disappearing actin::GFP accumulates while yellow arrows indicate the simultaneous appearance of actin::GFP accumulations within the same dendrite. Scale bar is 20 µm in A–C and 5 µm in D–F. (All larvae contain <i>Gal4 109(2)80</i> and <i>UAS-actin::GFP</i> (green) and/or UAS-mCC (red) for visualization.)</p

The <i>capulet</i> (<i>capt</i>) mutant demonstrates abnormal actin::GFP accumulation in neuronal dendrites.

<p>PNS neuronal dendrites in a live wild type (WT) larva (A) show dispersed labeling of actin::GFP in cell bodies (open arrow) and dendrites, while <i>capt</i>^K304 mutant dendrites display actin::GFP punctate-like accumulates within dendritic shafts (B, arrows). (C) A chromosomal deletion of <i>capt</i> produces a similar phenotype to the point mutant identified from the screen when transheterozygous. An independent allele of <i>capt</i> (<i>capt</i>^W145, D) that fails to complement <i>capt</i>^K304 lethality, produces a similar dendrite phenotype when transheterozygous (E). (F) The <i>capt</i>^K304 phenotype is rescued by a transgene encoding the <i>mCherry::capulet</i> (<i>mC-capt</i>) fusion protein. Arrows indicate abnormal actin::GFP accumulation in dendrites. Scale bar is 20 µm. (All larvae contain <i>Gal4 109(2)80</i>, <i>UAS-actin::GFP</i> (green signal) for visualization unless otherwise noted; in all figures the dorsal cluster of sensory neurons are shown with anterior toward the left and dorsal toward the top.)</p

<i>capulet</i> genetically interacts with <i>Kinesin heavy chain</i> (<i>khc</i>) to produce actin rod-like structures in dendrites.

<p>(A) The <i>khc</i> mutant phenotype demonstrates membrane swellings in dendrites (yellow arrows). (B) A genetic interaction between <i>khc</i> and <i>capt</i> revealed by the dendrite swelling phenotype (yellow arrows) in a trans-heterozygote not observed in either single heterozygote. (C) The simultaneous decrease of <i>khc</i> and <i>capt</i> function produces elongate actin rod-like structures in dendrites (white arrows) and smaller swellings (yellow arrow). The <i>capulet</i> actin puncta (white arrows-D, E) and the <i>capulet/khc</i> double mutant actin rods (H, I) do not produce membrane swellings like that observed with the single <i>khc</i> mutant (F, G). (The plasma membrane was visualized with myristoylated monomeric Red Fluorescent protein (red, D–I)). Yellow arrows indicate swellings, while white arrows indicate actin rods (C) or actin puncta (D, E). Scale bars are 20 µm in A and D, 5 µm in F. (All larvae contain <i>Gal4 109(2)80</i> and <i>UAS-actin::GFP</i> (green) or <i>UAS-myristoylated RFP</i> (red, membranes) for visualization.)</p