Disruption of the Serotonergic System after Neonatal Hypoxia-Ischemia in a Rodent Model

Buller, Kathryn M.; Wixey, Julie A.; Reinebrant, Hanna E.

doi:10.1155/2012/650382

Cited by 18 publications

(22 citation statements)

References 158 publications

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“…In an endotoxin inflammatory perinatal rabbit model and using an enzyme-linked immunosorbent assay, decreased serotonin was found in cortical and hippocampal brain homogenates of P1 rabbit kits following lipopolysaccharide exposure at E28 (Kannan et al 2010) of cerebral palsy in rabbits. Similar decreases in cortical serotonin have been reported in a rat model of perinatal H-I (Buller et al 2012). In this model, a selective, significant decrease in numbers of 5-HT-positive neurons was noted in rostral raphe nuclei (dorsal raphe), while there was no change in the caudal raphe nuclei projecting to spinal cord, such as raphe magnus (Reinebrant et al 2010), similar to observation in a mouse model of neonatal asphyxia (Takeuchi et al 1992).…”

Section: Discussionsupporting

confidence: 85%

“…Depletion of serotonin levels in the brain has been reported in the rabbit antenatal H-I (Vasquez-Vivar et al 2009) and perinatal inflammation model of CP (Kannan et al 2010), along with injury to the brain serotonergic system after H-I injury in neonatal rats (Reinebrant et al 2013, Buller et al 2012). We hypothesized that a deficiency in the serotonergic input may underlie hypertonia in rabbits following antenatal H-I, as has been suggested in adult spastic conditions (Dentel et al 2013).…”

Section: Introductionmentioning

confidence: 99%

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Elevated spinal monoamine neurotransmitters after antenatal hypoxia–ischemia in rabbit cerebral palsy model

Drobyshevsky

Takada

Luo

et al. 2015

Journal of Neurochemistry

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We hypothesized that a deficiency in the descending serotonergic input to spinal cord may underlie postnatal muscle hypertonia after global antenatal hypoxic-ischemic injury in a rabbit model of cerebral palsy. Neurotransmitter content was determined by HPLC in the spinal cord of newborns with and without muscle hypertonia after fetal global hypoxic-ischemic brain injury and naïve controls. Contrary to our hypothesis, serotonin levels in both cervical and lumbar expansions and norepinephrine in cervical expansion were increased in hypertonic kits relative to non-hypertonic kits and controls, with unchanged number of serotonergic cells in caudal raphe by stereological count. Serotonergic fiber length per unit of volume was also increased in hypertonic kits’ cervical and lumbar spinal cord, both in dorsal and ventral horns. Gene expression of serotonin transporter was increased and 5-HTR2 receptors were decreased in hypertonic kits relative to controls in cervical and lumbar cord. Intrathecal administration of nonselective serotonin receptor inhibitor methysergide decreased muscle tone in hypertonic kits only. Conversely, intrathecal administration of serotonin solution increased muscle tone only in non-hypertonic kits. We speculate that maturation of serotonergic system in spinal cord may be directly affected by decreased corticospinal connectivity after antenatal hypoxic-ischemic brain injury.

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Section: Discussionsupporting

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Elevated spinal monoamine neurotransmitters after antenatal hypoxia–ischemia in rabbit cerebral palsy model

Drobyshevsky

Takada

Luo

et al. 2015

Journal of Neurochemistry

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“…Furthermore, hypoxia and prenatal nicotine reduce the number of raphe serotonergic neurons (49), which is the opposite of what is observed in SIDS. Fetal hypoxia and nicotine can reproduce other features of SIDS, such as the reduction of serotonin transporter expression and raphe neural projections, which might be responsible for the reduced serotonin content in rodent forebrain (7,49). It is likely that any explanation of a disparity in results from SIDS cases and prenatal mice treated with nicotine will require consideration of other concomitant contributors that could modify the response of the serotonergic system in humans.…”

Section: Discussionmentioning

confidence: 57%

“…The intensity of fetal hypoxia induced by cigarette smoking or nicotine injections is higher than that due to delivery by an osmotic minipump, because the steady-state plasma levels of nicotine attained with osmotic minipumps are lower than those that produce uterine flow reduction (48). Furthermore, hypoxia and prenatal nicotine reduce the number of raphe serotonergic neurons (49), which is the opposite of what is observed in SIDS. Fetal hypoxia and nicotine can reproduce other features of SIDS, such as the reduction of serotonin transporter expression and raphe neural projections, which might be responsible for the reduced serotonin content in rodent forebrain (7,49).…”

Section: Discussionmentioning

confidence: 95%

The Alteration of Neonatal Raphe Neurons by Prenatal–Perinatal Nicotine. Meaning for Sudden Infant Death Syndrome

Cerpa

Aylwin

Beltrán-Castillo

et al. 2015

Am J Respir Cell Mol Biol

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Nicotine may link maternal cigarette smoking with respiratory dysfunctions in sudden infant death syndrome (SIDS). Prenatal-perinatal nicotine exposure blunts ventilatory responses to hypercapnia and reduces central respiratory chemoreception in mouse neonates at Postnatal Days 0 (P0) to P3. This suggests that raphe neurons, which are altered in SIDS and contribute to central respiratory chemoreception, may be affected by nicotine. We therefore investigated whether prenatal-perinatal nicotine exposure affects the activity, electrical properties, and chemosensitivity of raphe obscurus (ROb) neurons in mouse neonates. Osmotic minipumps, implanted subcutaneously in 5-to 7-day-pregnant CF1 mice, delivered nicotine bitartrate (60 mg kg 21 d 21 ) or saline (control) for up to 28 days. In neonates, ventilation was recorded by head-out plethysmography, c-Fos (neuronal activity marker), or serotonin autoreceptors (5HT 1A R) were immunodetected using light microscopy, and patch-clamp recordings were made from raphe neurons in brainstem slices under normocarbia and hypercarbia. Prenatal-perinatal nicotine exposure decreased the hypercarbiainduced ventilatory responses at P1-P5, reduced both the number of c-Fos-positive ROb neurons during eucapnic normoxia at P1-P3 and their hypercapnia-induced recruitment at P3, increased 5HT 1A R immunolabeling of ROb neurons at P3-P5, and reduced the spontaneous firing frequency of ROb neurons at P3 without affecting their CO 2 sensitivity or their passive and active electrical properties. These findings reveal that prenatal-perinatal nicotine reduces the activity of neonatal ROb neurons, likely as a consequence of increased expression of 5HT 1A Rs. This hypoactivity may change the functional state of the respiratory neural network leading to breathing vulnerability and chemosensory failure as seen in SIDS.

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“…; Buller et al . ), we tested the effect of ischemia‐like condition on MAOA gene expression. Exposure of H9c2 and N2a cells expressing MAOA ‐pro‐975 promoter construct to ischemia‐like condition (serum deprivation plus hypoxia for 6 h) (Bonavita et al .…”

Section: Resultsmentioning

confidence: 99%

Molecular mechanism of monoamine oxidase A gene regulation under inflammation and ischemia‐like conditions: key roles of the transcription factors GATA2, Sp1 and TBP

Gupta

Khan

Sasi

et al. 2015

Journal of Neurochemistry

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Monoamine oxidase A (MAOA) plays important roles in the pathogenesis of several neurological and cardiovascular disorders. The mechanism of transcriptional regulation of MAOA under basal and pathological conditions, however, remains incompletely understood. Here, we report systematic identification and characterization of cis elements and transcription factors that govern the expression of MAOA gene. Extensive computational analysis of MAOA promoter, followed by 5 0 -promoter deletion/reporter assays, revealed that the À71/À40 bp domain was sufficient for its basal transcription. Gel-shift and chromatin immunoprecipitation assays provided evidence of interactions of the transcription factors GATAbinding protein 2 (GATA2), Sp1 and TATA-binding protein (TBP) with this proximal promoter region. Consistently, overexpression of GATA2, Sp1 and TBP augmented MAOA promoter activity in a coordinated manner. In corroboration, siRNA-mediated down-regulation of GATA2/Sp1/TBP repressed the endogenous MAOA expression as well as transfected MAOA promoter activity. Tumor necrosis factor-a and forskolin activated MAOA transcription that was reversed by Sp1 siRNA; in support, tumor necrosis factor-a-and forskolin-induced activities were enhanced by ectopic overexpression of Sp1. On the other hand, MAOA transcription was diminished upon exposure of neuroblasts or cardiac myoblasts to ischemia-like conditions because of reduced binding of GATA2/Sp1/TBP with MAOA promoter. In conclusion, this study revealed previously unknown roles of GATA2, Sp1 and TBP in modulating MAOA expression under basal as well as pathophysiological conditions such as inflammation and ischemia, thus providing new insights into the molecular basis of aberrant MAOA expression in neuronal/cardiovascular disease states.

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Disruption of the Serotonergic System after Neonatal Hypoxia-Ischemia in a Rodent Model

Cited by 18 publications

References 158 publications

Elevated spinal monoamine neurotransmitters after antenatal hypoxia–ischemia in rabbit cerebral palsy model

Elevated spinal monoamine neurotransmitters after antenatal hypoxia–ischemia in rabbit cerebral palsy model

The Alteration of Neonatal Raphe Neurons by Prenatal–Perinatal Nicotine. Meaning for Sudden Infant Death Syndrome

Molecular mechanism of monoamine oxidase A gene regulation under inflammation and ischemia‐like conditions: key roles of the transcription factors GATA2, Sp1 and TBP

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