Targeted disruption of layer 4 during development increases GABA<sub>A</sub>receptor neurotransmission in the neocortex

Abbah, J.; Braga, Maria F. M.; Juliano, Sharon L.

doi:10.1152/jn.00652.2012

Cited by 8 publications

(5 citation statements)

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“…We also observed that interneurons migrating into the neocortex from the ganglionic eminence specifically altered their speed and pattern of movement after MAM treatment [6]. Furthermore, MAM-treated brains have increased levels of GABA Aα receptors and KCC2 protein at neonatal ages [6], and GABA Aα receptors in older animals [17].…”

Section: Introductionmentioning

confidence: 61%

“…After treatment with MAM in pregnant ferrets during corticogenesis, although the offspring are relatively normal in appearance, a number of features in their cortical architecture and function are altered. These include laminar disorganization [14], altered response profiles through neocortical layers [15], specific displacement of GABAergic neurons in the mature neocortex [14,16], and increased levels of GABA A receptors [6,17]. We also observed that interneurons migrating into the neocortex from the ganglionic eminence specifically altered their speed and pattern of movement after MAM treatment [6].…”

Section: Introductionmentioning

confidence: 70%

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Distribution and Cellular Localization of KCC2 in the Ferret Neocortex

Djankpa¹,

Akinola

Juliano³

2018

Dev Neurosci

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KCC2 (a brain-specific potassium-chloride cotransporter) affects development of the cerebral cortex, including aspects of neuronal migration and cellular maturation and differentiation. KCC2 also modulates chloride homeostasis by influencing the switch of GABA from depolarizing in young neurons to hyperpolarizing in mature neurons. We describe the expression pattern, regional distribution, and cellular colocalization of KCC2 in the ferret cortex in normal kits and those treated with methylazoxymethanol acetate (MAM). We earlier developed a model of impaired cortical development by injecting MAM during mid-cortical gestation, which briefly interferes with neuronal production and additionally results in increased levels of KCC2 at P0. Using immunohistochemistry, we show a shift in KCC2 expression during development, being high in the subplate at P0, repositioning into a subtle laminar pattern in the neocortex at P7-P14, and becoming homogeneous at P35. KCC2 colocalizes with neuronal markers in the developing and mature cerebral cortex of normal ferrets and those treated with MAM, but shows a differential pattern of expression at different ages and locates in distinct cellular compartments during development. Subcellular localization shows that KCC2 predominantly situates in the membrane fraction of neocortical samples. These findings reveal that KCC2 colocalizes differentially with neurons and its expression pattern alters during development.

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Section: Introductionmentioning

confidence: 61%

Section: Introductionmentioning

confidence: 70%

Distribution and Cellular Localization of KCC2 in the Ferret Neocortex

Djankpa¹,

Akinola

Juliano³

2018

Dev Neurosci

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“…Rat pups treated with MAM on gestational day 15 (GD-15) or GD-17 develop neuropathological and behavioral changes consistent with focal cortical dysplasia ( Paredes et al, 2006 ; Wong, 2009 ; Kim et al, 2017 ) or schizophrenia ( Moore et al, 2006 ; Lodge and Grace, 2009 ; Du et al, 2020 ; Sonnenschein and Grace, 2020 ), respectively. A cortical dysplasia animal model can also be produced by administering MAM to pregnant ferrets (GD-33) resulting in reduced migration of cortical neurons ( Schaefer et al, 2008 ) and increased GABA A receptor expression ( Abbah et al, 2014 ). Studies by Schaefer et al (2008) suggest that the effect of MAM on the migration of cortical neurons in the GD-33 ferret model is due to reductions in reelin , a gene that undergoes epigenetic regulation and encodes a protein with an important role in the migration of cortical neurons in the brains of subjects with various psychiatric disorders (e.g., schizophrenia) ( Ibi et al, 2020 ).…”

Section: Cycad Genotoxins and Neurodevelopmentmentioning

confidence: 99%

Genotoxic Damage During Brain Development Presages Prototypical Neurodegenerative Disease

Kisby

Spencer

2021

Front. Neurosci.

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Western Pacific Amyotrophic Lateral Sclerosis and Parkinsonism-Dementia Complex (ALS/PDC) is a disappearing prototypical neurodegenerative disorder (tau-dominated polyproteinopathy) linked with prior exposure to phytogenotoxins in cycad seed used for medicine and/or food. The principal cycad genotoxin, methylazoxymethanol (MAM), forms reactive carbon-centered ions that alkylate nucleic acids in fetal rodent brain and, depending on the timing of systemic administration, induces persistent developmental abnormalities of the cortex, hippocampus, cerebellum, and retina. Whereas administration of MAM prenatally or postnatally can produce animal models of epilepsy, schizophrenia or ataxia, administration to adult animals produces little effect on brain structure or function. The neurotoxic effects of MAM administered to rats during cortical brain development (specifically, gestation day 17) are used to model the histological, neurophysiological and behavioral deficits of human schizophrenia, a condition that may precede or follow clinical onset of motor neuron disease in subjects with sporadic ALS and ALS/PDC. While studies of migrants to and from communities impacted by ALS/PDC indicate the degenerative brain disorder may be acquired in juvenile and adult life, a proportion of indigenous cases shows neurodevelopmental aberrations in the cerebellum and retina consistent with MAM exposure in utero. MAM induces specific patterns of DNA damage and repair that associate with increased tau expression in primary rat neuronal cultures and with brain transcriptional changes that parallel those associated with human ALS and Alzheimer’s disease. We examine MAM in relation to neurodevelopment, epigenetic modification, DNA damage/replicative stress, genomic instability, somatic mutation, cell-cycle reentry and cellular senescence. Since the majority of neurodegenerative disease lacks a solely inherited genetic basis, research is needed to explore the hypothesis that early-life exposure to genotoxic agents may trigger or promote molecular events that culminate in neurodegeneration.

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“…Alteration in KCC2 expression during development can have dire consequences on cortical formation because it influences the final laminar position of interneurons to reach the neocortex (Fishell & Kriegstein, 2005) and determines the developmental switch of GABAergic neurons from depolarizing to hyperpolarizing (Ben‐Ari, 2014; Ben‐Ari et al, 1989; Kahle et al, 2008; Mueller et al, 1984). There is evidence that common chemicals such as bisphenol A can alter KCC2 expression during brain development and cause neurodevelopmental disorders (Abbah et al, 2014; Abbah & Juliano, 2014; Djankpa et al, 2019). Hence, we hypothesise that MSG can alter KCC2 expression and affect behaviour.…”

Section: Introductionmentioning

confidence: 99%

Effects of in utero exposure to monosodium glutamate on locomotion, anxiety, depression, memory and KCC2 expression in offspring

Biney

Djankpa

Osei

et al. 2021

Intl J of Devlp Neuroscience

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In pregnancy, there is a significant risk for developing embryos to be adversely affected by everyday chemicals such as food additives and environmental toxins. In recent times, several studies have documented the detrimental effect of exposure to such chemicals on the behaviour and neurodevelopment of the offspring. This study evaluated the influence of the food additive, monosodium glutamate (MSG), on behaviour and development in mice. Pregnant dams were exposed to MSG 2 or 4 g/kg or distilled water from gestation day 10–20. On delivery, postnatal day 1 (PN 1), 3 pups were sacrificed and whole brain samples assayed for KCC2 expression by western blot. The remaining pups were housed until PN 43 before commencing behavioural assessment. Their weights were measured at birth and at 3 days intervals until PN 42. The impact of prenatal exposure to MSG on baseline exploratory, anxiety and depression behaviours as well as spatial and working memory was assessed. In utero exposure to 4 g/kg MSG significantly reduced exploratory drive and increased depression‐like behaviours but did not exert any significant impact on anxiety‐like behaviours (p < 0.01). Additionally, there was a two‐fold increase in KCC2 expression in both 2 and 4 g/kg MSG‐exposed offspring. Conclusion This study indicates that, in utero exposure to MSG increases the expression of KCC2 and causes significant effect on locomotion and depression‐like behaviours but only marginally affects memory function.

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Targeted disruption of layer 4 during development increases GABA_Areceptor neurotransmission in the neocortex

Abstract: Abbah J, Braga MF, Juliano SL. Targeted disruption of layer 4 during development increases GABA A receptor neurotransmission in the neocortex.

Cited by 8 publications

References 99 publications

Distribution and Cellular Localization of KCC2 in the Ferret Neocortex

Distribution and Cellular Localization of KCC2 in the Ferret Neocortex

Genotoxic Damage During Brain Development Presages Prototypical Neurodegenerative Disease

Effects of in utero exposure to monosodium glutamate on locomotion, anxiety, depression, memory and KCC2 expression in offspring

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Targeted disruption of layer 4 during development increases GABAAreceptor neurotransmission in the neocortex

Abstract: Abbah J, Braga MF, Juliano SL. Targeted disruption of layer 4 during development increases GABA A receptor neurotransmission in the neocortex.

Cited by 8 publications

References 99 publications

Distribution and Cellular Localization of KCC2 in the Ferret Neocortex

Distribution and Cellular Localization of KCC2 in the Ferret Neocortex

Genotoxic Damage During Brain Development Presages Prototypical Neurodegenerative Disease

Effects of in utero exposure to monosodium glutamate on locomotion, anxiety, depression, memory and KCC2 expression in offspring

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Targeted disruption of layer 4 during development increases GABA_Areceptor neurotransmission in the neocortex