The role of neurotrophic factors in adult hippocampal neurogenesis, antidepressant treatments and animal models of depressive-like behavior.
ABSTRACT Major depressive disorder (MDD) is characterized by structural and neurochemical changes in limbic structures, including the hippocampus, that regulate mood and cognitive functions. Hippocampal atrophy is observed in patients with depression and this effect is blocked or reversed by antidepressant treatments. Brain-derived neurotrophic factor and other neurotrophic/growth factors are decreased in postmortem hippocampal tissue from suicide victims, which suggests that altered trophic support could contribute to the pathophysiology of MDD. Preclinical studies demonstrate that exposure to stress leads to atrophy and cell loss in the hippocampus as well as decreased expression of neurotrophic/growth factors, and that antidepressant administration reverses or blocks the effects of stress. Accumulating evidence suggests that altered neurogenesis in the adult hippocampus mediates the action of antidepressants. Chronic antidepressant administration upregulates neurogenesis in the adult hippocampus and this cellular response is required for the effects of antidepressants in certain animal models of depression. Here, we review cellular (e.g. adult neurogenesis) and behavioral studies that support the neurotrophic/neurogenic hypothesis of depression and antidepressant action. Aberrant regulation of neuronal plasticity, including neurogenesis, in the hippocampus and other limbic nuclei may result in maladaptive changes in neural networks that underlie the pathophysiology of MDD.
SourceAvailable from: Noriko Osumi[Show abstract] [Hide abstract]
ABSTRACT: Human genetic data on psychiatric disorders repeatedly demonstrate the involvement of various genes that are associated with neural development and neurogenesis. Neurogenesis is a biological process that is critical in brain development and continues throughout life. Neurogenesis is a multi-step process starting from the division of neural stem cells/progenitor cells, leading to self-renewal and simultaneously to the production of lineage-committed cells, including neurons and glial cells. Minor defects in the neurogenesis process, such as production of fewer new neurons and malformation of neural circuits, could represent phenotypes of psychiatric disorders at molecular and cellular levels in animal models (here termed as " microphenotypes "). However, microphenotypes are not easily used as biomarkers. We have focused on a physiological condition, sensorimotor gating deficits, that can be scored by a prepulse inhibition (PPI) test. Impaired PPI is considered to be one of the compelling endophenotypes (biological markers) of mental disorders such as schizophrenia, autism, and other neurodevelopmental disorders. Because the neural circuit for PPI involves the hippocampus, a unique brain region where neurogenesis occurs postnatally, we hypothesize that an impairment of preadolescent neurogenesis is critical for the onset of sensorimotor gating defects. To test this hypothesis, we investigated a critical period of neurogenesis that can affect PPI. In this paradigm, we introduced an enriched environment to restore neurogenesis, thereby recovering PPI deficits in mice. We noted impairments in the maturation of newborn neurons in the hippocampal dentate gyrus (DG) and GABAergic neurons in the hippocampus, which could be considered as microphenotypes associated with PPI defects. More precise genetically controlled neurogenesis models (with precise time points or periods) are needed to be studied in further investigation to support our hypothesis.Current Molecular Medicine 03/2015; 15:1-9. · 3.61 Impact Factor
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ABSTRACT: Thyroid hormone disorders have long been linked to depression, but the causal relationship between them remains controversial. To address this question, we established rat models of hypothyroidism using 131iodine (131I) and hyperthyroidism using levothyroxine (LT4). Serum free thyroxine (FT4) and triiodothyronine (FT3) significantly decreased in the hypothyroid of rats with single injections of 131I (5 mCi/kg). These rats exhibited decreased depression-like behaviors in forced swimming test and sucrose preference tests, as well as decreased anxiety-like behaviors in an elevated plus maze. Diminished levels of brain serotonin (5-HT) and increased levels of hippocampal brain-derived neurotrophic factor (BDNF) were found in the hypothyroid rats compared to the control saline-vehicle administered rats. LT4 treatment reversed the decrease in thyroid hormones and depression-like behaviors. In contrast, hyperthyroidism induced by weekly injections of LT4 (15 μg/kg) caused a greater than 10-fold increase in serum FT4 and FT3 levels. The hyperthyroid rats exhibited higher anxiety- and depression-like behaviors, higher brain 5-HT level, and lower hippocampal BDNF levels than the controls. Treatment with the antidepressant imipramine (15 mg/kg) diminished serum FT4 levels as well as anxiety- and depression-like behaviors in the hyperthyroid rats but led to a further increase in brain 5-HT levels, compared with the controls or the hypothyroid rats. Together, our results suggest that hypothyroidism and hyperthyroidism have bidirectional effects on anxiety- and depression-like behaviors in rats, possibly by modulating hippocampal BDNF levels.Hormones and Behavior 01/2015; 69C. DOI:10.1016/j.yhbeh.2015.01.003 · 4.51 Impact Factor
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ABSTRACT: Major depression is a common, recurrent mental illness that affects millions of people worldwide. Recently, a unique fast neuroprotective and antidepressant treatment effect has been observed by ketamine, which acts via the glutamatergic system. Hence, a steady accumulation of evidence supporting a role for the excitatory amino acid neurotransmitter (EAA) glutamate in the treatment of depression has been observed in the last years. Emerging evidence indicates that N-methyl-D-aspartate (NMDA), group 1 metabotropic glutamate receptor antagonists and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) agonists have antidepressant properties. Indeed, treatment with NMDA receptor antagonists has shown the ability to sprout new synaptic connections and reverse stress-induced neuronal changes. Based on glutamatergic signaling, a number of therapeutic drugs might gain interest in the future. Several compounds such as ketamine, memantine, amantadine, tianeptine, pioglitazone, riluzole, lamotrigine, AZD6765, magnesium, zinc, guanosine, adenosine aniracetam, traxoprodil (CP-101,606), MK-0657, GLYX-13, NRX-1047, Ro25-6981, LY392098, LY341495, D-cycloserine, D-serine, dextromethorphan, sarcosine, scopolamine, pomaglumetad methionil, LY2140023, LY404039, MGS0039, MPEP, 1-Aminocyclopropanecarboxylic acid all of which target this system have already been brought up, some of them recently. Drugs targeting the glutamatergic system might open up a promising new territory for the development of drugs to meet the needs of patients with major depression. Copyright © 2015. Published by Elsevier Inc.Progress in Neuro-Psychopharmacology and Biological Psychiatry 03/2015; DOI:10.1016/j.pnpbp.2015.02.015 · 4.03 Impact Factor