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In rats, neurodevelopmental disorders induced by maternal hypoxia are associated with attenuated excitatory
Kentaro Tokudome1,2, Masaaki Ueki1,3, Takujiro Homma1
1Department of Pharmacology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan.
Background And Purpose:
Maternal hypoxia is a recognised risk factor for neurodevelopmental disorders in offspring. Although rodent models of hypoxia have been reported, the detailed pathogenesis of maternal hypoxia-induced neurodevelopmental disorders remains unclear. The objectives of this study are to understand the pathophysiological mechanisms underlying maternal hypoxia-related neurodevelopmental disorders and to identify new drug targets for these pathologies.
Experimental Approach:
A newly generated rat model exhibiting maternal hypoxia-induced neurodevelopmental disorder-like phenotypes was employed for behavioural assessments. Immunohistochemical analysis was performed on foetal and adult rat brain sections to characterise structural alterations. Furthermore, synaptic transmission and microstructural changes resulting from maternal hypoxia were examined utilising extracellular electrophysiological recordings and transmission electron microscopy.
Key Results:
A rat model of maternal hypoxia-induced neurodevelopmental disorders was established. Immunohistochemical analysis showed a reduction in the density of excitatory pyramidal neurones in layer II/III of the anterior cingulate cortex. Moreover, excitatory neurogenesis was disrupted following gestational exposure to hypoxia. Extracellular electrophysiological recordings in the anterior cingulate cortex region demonstrated decreased synaptic responsiveness, potentially attributable to a reduction in presynaptic vesicle density. Remarkably, pharmacological antagonism of mGlu2/3 receptors with LY341495 abolished the neurodevelopmental disorder-like phenotypes in the experimental animals.
Conclusion And Implications:
Maternal hypoxia-induced neurodevelopmental disorder-like behaviours point to morphological and/or functional deficits in excitatory pyramidal neurones, potentially causing excitatory/inhibitory imbalance in the anterior cingulate cortex. Enhancing excitatory synaptic response may represent a novel therapeutic strategy for hypoxia-related neurodevelopmental disorders.
