Remodeling of axo-spinous synapses in the pathophysiology and treatment of depression

Licznerski, Pawel; Duman, Ronald S.

doi:10.1016/j.neuroscience.2012.09.057

Cited by 137 publications

(95 citation statements)

References 253 publications

(289 reference statements)

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“…Concomitantly, both dendrite shrinkage and spine loss were induced by restraint stress in the hippocampus, whereas dendrite growth and increase of spine density were induced in the basolateral amygdala [29,30]. These contrasting structural changes were also reported in the hippocampus and amygdala of patients suffering from major depressive and anxiety disorders [31,32]. The present study showed that hypergravity down-regulated the expression of BNDF mRNA in the ventral hippocampus but had no effect in the amygdala.…”

Section: Discussionmentioning

confidence: 99%

Effects of gravity changes on gene expression of BDNF and serotonin receptors in the mouse brain

Ishikawa

Ogura

et al. 2017

PLoS ONE

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Spaceflight entails various stressful environmental factors including microgravity. The effects of gravity changes have been studied extensively on skeletal, muscular, cardiovascular, immune and vestibular systems, but those on the nervous system are not well studied. The alteration of gravity in ground-based animal experiments is one of the approaches taken to address this issue. Here we investigated the effects of centrifugation-induced gravity changes on gene expression of brain-derived neurotrophic factor (BDNF) and serotonin receptors (5-HTRs) in the mouse brain. Exposure to 2g hypergravity for 14 days showed differential modulation of gene expression depending on regions of the brain. BDNF expression was decreased in the ventral hippocampus and hypothalamus, whereas increased in the cerebellum. 5-HT1BR expression was decreased in the cerebellum, whereas increased in the ventral hippocampus and caudate putamen. In contrast, hypergravity did not affect gene expression of 5-HT1AR, 5-HT2AR, 5-HT2CR, 5-HT4R and 5-HT7R. In addition to hypergravity, decelerating gravity change from 2g hypergravity to 1g normal gravity affected gene expression of BDNF, 5-HT1AR, 5-HT1BR, and 5-HT2AR in various regions of the brain. We also examined involvement of the vestibular organ in the effects of hypergravity. Surgical lesions of the inner ear’s vestibular organ removed the effects induced by hypergravity on gene expression, which suggests that the effects of hypergravity are mediated through the vestibular organ. In summary, we showed that gravity changes induced differential modulation of gene expression of BDNF and 5-HTRs (5-HT1AR, 5-HT1BR and 5-HT2AR) in some brain regions. The modulation of gene expression may constitute molecular bases that underlie behavioral alteration induced by gravity changes.

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Section: Discussionmentioning

confidence: 99%

Effects of gravity changes on gene expression of BDNF and serotonin receptors in the mouse brain

Ishikawa

Ogura

et al. 2017

PLoS ONE

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“…Estrogen influences neurotransmitter activity, neurogenesis, and neurotrophic factor expression, as well as many aspects of glial function 58,61,62 . Notably, BDNF levels fluctuate with the estrous cycle and estrogen administration can increase the expression of BDNF in the PFC and hippocampus 63–66 .…”

Section: Sex Differences In Susceptibility To Depressionmentioning

confidence: 99%

Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants

Duman

Aghajanian

Sanacora

et al. 2016

Nat Med

1,207

911

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Depression is a common, devastating illness. Current pharmacotherapies help many patients, but there are high rates of partial- or non-response and the delayed onset of the effects of antidepressant leave many patients inadequately treated. However, new insights into the neurobiology of stress and human mood disorders have shed light on mechanisms underlying the vulnerability of individuals to depression and have pointed to novel antidepressants. Environmental events and other risk factors contribute to depression through converging molecular and cellular mechanisms that disrupt neuronal function and morphology, resulting in dysfunction of the circuitry essential for mood regulation and cognitive function. Although current antidepressants such as serotonin reuptake inhibitors produce subtle changes that take effect in weeks or months, new agents have recently shown improvement in mood ratings within hours of dosing in patients resistant to typical antidepressants. These new agents have also been shown to reverse the synaptic deficits caused by stress within a similar time scale.

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“…There is evidence of vmPFC gray matter loss in mood disorders 7,115,116 , which implies dendritic atrophy. However, there have been no direct studies of changes in spine numbers in these circuits.…”

Section: Potential Relevance To Spine Loss In Mental Disordersmentioning

confidence: 99%

Stress weakens prefrontal networks: molecular insults to higher cognition

2015

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A variety of cognitive disorders are worsened by stress exposure and involve dysfunction of the newly evolved prefrontal cortex (PFC). Exposure to acute, uncontrollable stress increases catecholamine release in PFC, reducing neuronal firing and impairing cognitive abilities. High levels of noradrenergic α1-adrenoceptor and dopaminergic D1 receptor stimulation activate feedforward calcium–protein kinase C and cyclic AMP–protein kinase A signaling, which open potassium channels to weaken synaptic efficacy in spines. In contrast, high levels of catecholamines strengthen the primary sensory cortices, amygdala and striatum, rapidly flipping the brain from reflective to reflexive control of behavior. These mechanisms are exaggerated by chronic stress exposure, where architectural changes lead to persistent loss of PFC function. Understanding these mechanisms has led to the successful translation of prazosin and guanfacine for treating stress-related disorders. Dysregulation of stress signaling pathways by genetic insults likely contributes to PFC deficits in schizophrenia, while age-related insults initiate interacting vicious cycles that increase vulnerability to Alzheimer’s degeneration.

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Remodeling of axo-spinous synapses in the pathophysiology and treatment of depression

Cited by 137 publications

References 253 publications

Effects of gravity changes on gene expression of BDNF and serotonin receptors in the mouse brain

Effects of gravity changes on gene expression of BDNF and serotonin receptors in the mouse brain

Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants

Stress weakens prefrontal networks: molecular insults to higher cognition

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