Astrocyte-derived ATP modulates depressive-like behaviors.
TL;DR: It is found that stimulating endogenous ATP release from astrocytes induced antidepressant- like effects in mouse models of depression, and P2X2 receptors in the medial prefrontal cortex mediated the antidepressant-like effects of ATP.
Abstract: Major depressive disorder (MDD) is a cause of disability that affects approximately 16% of the world's population; however, little is known regarding the underlying biology of this disorder. Animal studies, postmortem brain analyses and imaging studies of patients with depression have implicated glial dysfunction in MDD pathophysiology. However, the molecular mechanisms through which astrocytes modulate depressive behaviors are largely uncharacterized. Here, we identified ATP as a key factor involved in astrocytic modulation of depressive-like behavior in adult mice. We observed low ATP abundance in the brains of mice that were susceptible to chronic social defeat. Furthermore, we found that the administration of ATP induced a rapid antidepressant-like effect in these mice. Both a lack of inositol 1,4,5-trisphosphate receptor type 2 and transgenic blockage of vesicular gliotransmission induced deficiencies in astrocytic ATP release, causing depressive-like behaviors that could be rescued via the administration of ATP. Using transgenic mice that express a Gq G protein-coupled receptor only in astrocytes to enable selective activation of astrocytic Ca(2+) signaling, we found that stimulating endogenous ATP release from astrocytes induced antidepressant-like effects in mouse models of depression. Moreover, we found that P2X2 receptors in the medial prefrontal cortex mediated the antidepressant-like effects of ATP. These results highlight astrocytic ATP release as a biological mechanism of MDD.
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TL;DR: How the immune system regulates mood and the potential causes of the dysregulated inflammatory responses in depressed patients are described, and inflammation is likely a critical disease modifier, promoting susceptibility to depression.
604 citations
TL;DR: This review summarizes the recent research regarding the process of adult neurogenesis from different perspectives, with particular emphasis on the differentiation and development of new neurons, the regulation of the process by extrinsic and intrinsic factors, and their ultimate function in the hippocampus circuit.
Abstract: Adult neurogenesis in the hippocampus is a notable process due not only to its uniqueness and potential impact on cognition but also to its localized vertical integration of different scales of neu...
523 citations
TL;DR: This review summarizes the most recent discoveries and insights for which parallel findings have been obtained in human depressed subjects and rodent models of mood disorders in order to examine the potential etiology of depression.
348 citations
TL;DR: This review will review classical models along with new methods that will enrich knowledge of this disorder to elucidate the physiopathology underlying depression and to treat depressive symptoms.
Abstract: Major depressive disorder is a serious mental disorder that profoundly affects an individual's quality of life. Although the aetiologies underlying this disorder remain unclear, an increasing attention has been focused on the influence imposed by psychological stress over depression. Despite limited animal models of psychological stress, significant progress has been made as to be explicated in this review to elucidate the physiopathology underlying depression and to treat depressive symptoms. Therefore, we will review classical models along with new methods that will enrich our knowledge of this disorder.
330 citations
Cites background from "Astrocyte-derived ATP modulates dep..."
...The ATP abundance in interstitial fluid derived from the hippocampus and PFC of the mice vulnerable to chronic social defeat stress was lower than that from the resilient mice [36]....
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...The antidepressant action of ATP was evidenced to be modulated by P2X2 receptors in PFC [36]....
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TL;DR: Investigations are in progress for the use of purinergic agents for the treatment of osteoporosis, myocardial infarction, irritable bowel syndrome, epilepsy, atherosclerosis, depression, autism, diabetes, and cancer.
Abstract: Purinergic signalling, i.e. the role of nucleotides as extracellular signalling molecules, was proposed in 1972. However, this concept was not well accepted until the early 1990’s when receptor subtypes for purines and pyrimidines were cloned and characterised, which includes 4 subtypes of the P1 (adenosine) receptor, 7 subtypes of P2X ion channel receptors and 8 subtypes of the P2Y G protein-coupled receptor. Early studies were largely concerned with the physiology, pharmacology and biochemistry of purinergic signalling. More recently, the focus has been on the pathophysiology and therapeutic potential. There was early recognition of the use of P1 receptor agonists for the treatment of supraventicular tachycardia and A2A receptor antagonists are promising for the treatment of Parkinson’s disease. Clopidogrel, a P2Y¬12 antagonist, is widely used for the treatment of thrombosis and stroke, blocking P2Y¬12 receptor-mediated platelet aggregation. Diquafasol, a long acting P2Y¬2 receptor agonist, is being used for the treatment of dry eye. P2X3 receptor antagonists have been developed that are orally bioavailable and stable in vivo and are currently in clinical trials for the treatment of chronic cough, bladder incontinence, visceral pain and hypertension. Antagonists to P2X7 receptors are being investigated for the treatment of inflammatory disorders, including neurodegenerative diseases. Other investigations are in progress for the use of purinergic agents for the treatment of osteoporosis, myocardial infarction, irritable bowel syndrome, epilepsy, atherosclerosis, depression, autism, diabetes and cancer.
279 citations
Cites background from "Astrocyte-derived ATP modulates dep..."
...P2X2R in the medial prefrontal cortex mediate the antidepressant-like actions of ATP released from astrocytes (Cao et al., 2013)....
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References
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TL;DR: Notably, major depressive disorder is a common disorder, widely distributed in the population, and usually associated with substantial symptom severity and role impairment, and while the recent increase in treatment is encouraging, inadequate treatment is a serious concern.
Abstract: ContextUncertainties exist about prevalence and correlates of major depressive
disorder (MDD).ObjectiveTo present nationally representative data on prevalence and correlates
of MDD by Diagnostic and Statistical Manual of Mental Disorders,
Fourth Edition (DSM-IV) criteria, and on study
patterns and correlates of treatment and treatment adequacy from the recently
completed National Comorbidity Survey Replication (NCS-R).DesignFace-to-face household survey conducted from February 2001 to December
2002.SettingThe 48 contiguous United States.ParticipantsHousehold residents ages 18 years or older (N = 9090) who responded
to the NCS-R survey.Main Outcome MeasuresPrevalence and correlates of MDD using the World Health Organization's
(WHO) Composite International Diagnostic Interview (CIDI), 12-month severity
with the Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR),
the Sheehan Disability Scale (SDS), and the WHO disability assessment scale
(WHO-DAS). Clinical reinterviews used the Structured Clinical Interview for DSM-IV.ResultsThe prevalence of CIDI MDD for lifetime was 16.2% (95% confidence interval
[CI], 15.1-17.3) (32.6-35.1 million US adults) and for 12-month was 6.6% (95%
CI, 5.9-7.3) (13.1-14.2 million US adults). Virtually all CIDI 12-month cases
were independently classified as clinically significant using the QIDS-SR,
with 10.4% mild, 38.6% moderate, 38.0% severe, and 12.9% very severe. Mean
episode duration was 16 weeks (95% CI, 15.1-17.3). Role impairment as measured
by SDS was substantial as indicated by 59.3% of 12-month cases with severe
or very severe role impairment. Most lifetime (72.1%) and 12-month (78.5%)
cases had comorbid CIDI/DSM-IV disorders, with MDD
only rarely primary. Although 51.6% (95% CI, 46.1-57.2) of 12-month cases
received health care treatment for MDD, treatment was adequate in only 41.9%
(95% CI, 35.9-47.9) of these cases, resulting in 21.7% (95% CI, 18.1-25.2)
of 12-month MDD being adequately treated. Sociodemographic correlates of treatment
were far less numerous than those of prevalence.ConclusionsMajor depressive disorder is a common disorder, widely distributed in
the population, and usually associated with substantial symptom severity and
role impairment. While the recent increase in treatment is encouraging, inadequate
treatment is a serious concern. Emphasis on screening and expansion of treatment
needs to be accompanied by a parallel emphasis on treatment quality improvement.
7,706 citations
TL;DR: It is shown that viral-mediated, mesolimbic dopamine pathway–specific knockdown of brain-derived neurotrophic factor is required for the development of experience-dependent social aversion in mice experiencing repeated aggression.
Abstract: Mice experiencing repeated aggression develop a long-lasting aversion to social contact, which can be normalized by chronic, but not acute, administration of antidepressant. Using viral-mediated, mesolimbic dopamine pathway-specific knockdown of brain-derived neurotrophic factor (BDNF), we showed that BDNF is required for the development of this experience-dependent social aversion. Gene profiling in the nucleus accumbens indicates that local knockdown of BDNF obliterates most of the effects of repeated aggression on gene expression within this circuit, with similar effects being produced by chronic treatment with antidepressant. These results establish an essential role for BDNF in mediating long-term neural and behavioral plasticity in response to aversive social experiences.
1,873 citations
TL;DR: It is shown that molecular recapitulations of three prototypical adaptations associated with the unsusceptible phenotype are each sufficient to promote resistant behavior and validate a multidisciplinary approach to examine the neurobiological mechanisms of variations in stress resistance.
1,863 citations
TL;DR: This review is focused on purinergic neurotransmission, i.e., ATP released from nerves as a transmitter or cotransmitter to act as an extracellular signaling molecule on both pre- and postjunctional membranes at neuroeffector junctions and synapses, as well as acting as a trophic factor during development and regeneration.
Abstract: This review is focused on purinergic neurotransmission, i.e., ATP released from nerves as a transmitter or cotransmitter to act as an extracellular signaling molecule on both pre- and postjunctional membranes at neuroeffector junctions and synapses, as well as acting as a trophic factor during development and regeneration. Emphasis is placed on the physiology and pathophysiology of ATP, but extracellular roles of its breakdown product, adenosine, are also considered because of their intimate interactions. The early history of the involvement of ATP in autonomic and skeletal neuromuscular transmission and in activities in the central nervous system and ganglia is reviewed. Brief background information is given about the identification of receptor subtypes for purines and pyrimidines and about ATP storage, release, and ectoenzymatic breakdown. Evidence that ATP is a cotransmitter in most, if not all, peripheral and central neurons is presented, as well as full accounts of neurotransmission and neuromodulation in autonomic and sensory ganglia and in the brain and spinal cord. There is coverage of neuron-glia interactions and of purinergic neuroeffector transmission to nonmuscular cells. To establish the primitive and widespread nature of purinergic neurotransmission, both the ontogeny and phylogeny of purinergic signaling are considered. Finally, the pathophysiology of purinergic neurotransmission in both peripheral and central nervous systems is reviewed, and speculations are made about future developments.
1,482 citations
TL;DR: The cellular composition of area sg24 in two different sets of brains was examined to identify a biological marker associated with familial mood disorders that may provide important clues regarding the pathogenesis of these common psychiatric conditions.
Abstract: Mood disorders are among the most common neuropsychiatric illnesses, yet little is known about their neurobiology. Recent neuroimaging studies have found that the volume of the subgenual part of Brodmann's area 24 (sg24) is reduced in familial forms of major depressive disorder (MDD) and bipolar disorder (BD). In this histological study, we used unbiased stereological techniques to examine the cellular composition of area sg24 in two different sets of brains. There was no change in the number or size of neurons in area sg24 in mood disorders. In contrast, the numbers of glia were reduced markedly in both MDD and BD. The reduction in glial number was most prominent in subgroups of subjects with familial MDD (24%, P = 0.01) or BD (41%, P = 0.01). The glial reduction in subjects without a clear family history was lower in magnitude and not statistically significant. Consistent with neuroimaging findings, cortical volume was reduced in area sg24 in subjects with familial mood disorders. Schizophrenic brains studied as psychiatric controls had normal neuronal and glial numbers and cortical volume. Glial and neuronal numbers also were counted in area 3b of the somatosensory cortex in the same group of brains and were normal in all psychiatric groups. Glia affect several processes, including regulation of extracellular potassium, glucose storage and metabolism, and glutamate uptake, all of which are crucial for normal neuronal activity. We thus have identified a biological marker associated with familial mood disorders that may provide important clues regarding the pathogenesis of these common psychiatric conditions.
1,435 citations