Prenatal Inflammation Dampens Neurogenesis and Enhances Serotonin Transporter Expression in the Hippocampus of Adult Female Rats

Mouihate, Abdeslam; Kalakh, Samah; Almutairi, Rawan; AlAshqar, Abdelrahman

doi:10.1159/000499658

Cited by 7 publications

(4 citation statements)

References 31 publications

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“…Images were processed and analyzed using a package of self-written programs for image processing and data analysis: “Image Processing and Data Analyzing Software” (IPDAS, SynoSoft, Kuwait) (Henkel et al, 2014; Mouihate et al, 2019).…”

Section: Methodsmentioning

confidence: 99%

Differential Release of Exocytosis Marker Dyes Indicates Stimulation-Dependent Regulation of Synaptic Activity

2019

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There is a general consensus that synaptic vesicular release by a full collapse process is the primary machinery of synaptic transmission. However, competing view suggests that synaptic vesicular release operates via a kiss-and-run mechanism. By monitoring the release dynamics of a synaptic vesicular marker, FM1-43 from individual synapses in hippocampal neurons, we found evidence that the release of synaptic vesicle was delayed by several seconds after the start of field stimulation. This phenomenon was associated with modified opening kinetics of fusion pores. Detailed analysis revealed that some synapses were completely inactive for a few seconds after stimulation, despite immediate calcium influx. This delay in vesicular release was modulated by various stimulation protocols and different frequencies, indicating an activity-dependent regulation mechanism for neurotransmitter exocytosis. Staurosporine, a drug known to induce “kiss-and-run” exocytosis, increased the proportion of delayed synapses as well as the delay duration, while fluoxetine acted contrarily. Besides being a serotonin reuptake inhibitor, it directly enhanced vesicle mobilization and reduced synaptic fatigue. Exocytosis was never delayed, when it was monitored with pH-sensitive probes, synaptopHlourin and αSyt-CypHerE5 antibody, indicating an instantaneous formation of a fusion pore that allowed rapid equilibration of vesicular lumenal pH but prevented FM1-43 release because of its slow dissociation from the inner vesicular membrane. Our observations suggest that synapses operate via a sequential “kiss-and-run” and “full-collapse” exocytosis mechanism. The initially narrow vesicular pore allows the equilibration of intravesicular pH which then progresses toward full fusion, causing FM1-43 release.

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Section: Methodsmentioning

confidence: 99%

Differential Release of Exocytosis Marker Dyes Indicates Stimulation-Dependent Regulation of Synaptic Activity

2019

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“…Over the years, it has been well documented that maternal immune activation, mimed by LPS administration, among others, is a serious risk factor for developing neurological disorders such as neurodevelopmental disorders (Han et al, 2021). Indeed, in previous studies assessing LPS activation during gestation, doses usually needed to range from 0.02 to 0.1 mg/kg in order to induce neurodevelopmental disorders (Hsueh et al, 2017(Hsueh et al, , 2018Mouihate et al, 2019). However, at these higher doses, there are significant side effects on litter size, due to abortion, fetal death, or behavioral sickness in dams (Kirsten et al, 2010a,b).…”

Section: Discussionmentioning

confidence: 99%

The herbicides glyphosate and glufosinate and the cyanotoxin β-N-methylamino-l-alanine induce long-term motor disorders following postnatal exposure: the importance of prior asymptomatic maternal inflammatory sensitization

Oummadi¹,

Menuet²,

Méresse³

et al. 2023

Front. Neurosci.

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BackgroundPrenatal maternal immune activation (MIA) and/or perinatal exposure to various xenobiotics have been identified as risk factors for neurological disorders, including neurodegenerative diseases. Epidemiological data suggest an association between early multi-exposures to various insults and neuropathologies. The “multiple-hit hypothesis” assumes that prenatal inflammation makes the brain more susceptible to subsequent exposure to several kinds of neurotoxins. To explore this hypothesis and its pathological consequences, a behavioral longitudinal procedure was performed after prenatal sensitization and postnatal exposure to low doses of pollutants.MethodsMaternal exposure to an acute immune challenge (first hit) was induced by an asymptomatic lipopolysaccharide (LPS) dose (0.008 mg/kg) in mice. This sensitization was followed by exposing the offspring to environmental chemicals (second hit) postnatally, by the oral route. The chemicals used were low doses of the cyanotoxin β-N-methylamino-l-alanine (BMAA; 50 mg/kg), the herbicide glufosinate ammonium (GLA; 0.2 mg/kg) or the pesticide glyphosate (GLY; 5 mg/kg). After assessing maternal parameters, a longitudinal behavioral assessment was carried out on the offspring in order to evaluate motor and emotional abilities in adolescence and adulthood.ResultsWe showed that the low LPS immune challenge was an asymptomatic MIA. Even though a significant increase in systemic pro-inflammatory cytokines was detected in the dams, no maternal behavioral defects were observed. In addition, as shown by rotarod assays and open field tests, this prenatal LPS administration alone did not show any behavioral disruption in offspring. Interestingly, our data showed that offspring subjected to both MIA and post-natal BMAA or GLA exposure displayed motor and anxiety behavioral impairments during adolescence and adulthood. However, this synergistic effect was not observed in the GLY-exposed offspring.ConclusionThese data demonstrated that prenatal and asymptomatic immune sensitization represents a priming effect to subsequent exposure to low doses of pollutants. These double hits act in synergy to induce motor neuron disease-related phenotypes in offspring. Thus, our data strongly emphasize that multiple exposures for developmental neurotoxicity regulatory assessment must be considered. This work paves the way for future studies aiming at deciphering cellular pathways involved in these sensitization processes.

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“…The surface of the EPM was cleaned with 70% alcohol before each test. The time spent in the open and closed arms was obtained using SynoQuant 3.26 software, as previously described [19]. This software enables the extraction of the static features of the rat (e.g., white rat in a dark background) and its dynamic features (change of location over time), which allows tracking of the rat's movement.…”

Section: The Elevated Plus Mazementioning

confidence: 99%

Maternal Interleukin-6 Hampers Hippocampal Neurogenesis in Adult Rat Offspring in a Sex-Dependent Manner

Mouihate

Kalakh

2021

Dev Neurosci

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Maternal immune activation (MIA) during pregnancy leads to long-lasting effects on brain development and function. Several lines of evidence suggest that the maternal inflammatory cytokine interleukin (IL)-6 plays a crucial role in the long-lasting effects of MIA on adult offspring. IL-6 is naturally produced during pregnancy in the absence of any underlying immune activation. The objective of this study was to assess whether this naturally occurring IL-6 has long-lasting effects on brain plasticity and function. Therefore, pregnant rats were given either an IL-6-neutralizing antibody (IL-6Ab) or vehicle during the third week of pregnancy. Newly born (doublecortin) and mature neurons (NeuN) were monitored in the hippocampus of adult male and female offspring. Prenatal IL-6Ab led to an enhanced number of newly born and mature neurons in the dentate gyrus of the hippocampus of male but not female adult offspring. This enhanced neurogenesis was associated with an increased propensity in memory acquisition in male offspring. Blunting the naturally occurring IL-6 during pregnancy did not have a significant long-lasting impact on astrocyte cell density (GFAP), or on anxiety-like behavior as assessed with elevated plus maze and open field tests. Taken together, these data suggest that maternal IL-6 contributes, at least in part, to the programming of the brain’s development in a sex-dependent manner.

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Prenatal Inflammation Dampens Neurogenesis and Enhances Serotonin Transporter Expression in the Hippocampus of Adult Female Rats

Cited by 7 publications

References 31 publications

Differential Release of Exocytosis Marker Dyes Indicates Stimulation-Dependent Regulation of Synaptic Activity

Differential Release of Exocytosis Marker Dyes Indicates Stimulation-Dependent Regulation of Synaptic Activity

The herbicides glyphosate and glufosinate and the cyanotoxin β-N-methylamino-l-alanine induce long-term motor disorders following postnatal exposure: the importance of prior asymptomatic maternal inflammatory sensitization

Maternal Interleukin-6 Hampers Hippocampal Neurogenesis in Adult Rat Offspring in a Sex-Dependent Manner

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