Microglia activation related to neuronal malformation in developing cerebellar cortex of drug-induced autistic model rat

Identification: Yoshida, Sachiko


Microglia activation related to neuronal malformation in developing cerebellar cortex of drug-induced autistic model rat
*Sachiko Yoshida1, Naohiro Hozumi1, Yukiko Fueta2, Susumu Ueno2, Yoko Sekino3, Yasunari Kanda4 1Toyohashi University of Technology; 2University of Occupational and Environmental Health; 3 University of; 4National Institute of Health Sciences, Japan
Valproate (VPA), the popular anticonvulsant and mood stabilizer, is known as an inducer of autism. It has many kinds of physiological properties, including the inhibition of histone deacetylase (HDAC). Recently we reported VPA administration to rat fetus caused developmental changes and malformation in cerebellar cortex. In VPA-administrated cerebellum, the dendrites of Purkinje cells were elongated earlier than in vehicles and immature granule cells were left in the external germinal layer even in P16. Our hypothesis is VPA would activate microglia in the EGL and make immature granule cells suppress their differentiation and migration.
600mg/mother body kg VPA was administrated to embryonic day 16 p.o., and the offspring were observed for 3 weeks after birth. Some pups were treated 33 mg/kg Oxytocin from postnatal day 3 to 7 to observe its recovery effect.

 In the surrounding area of the remaining granules cells in the VPA-rat EGL of postnatal day (P) 10, Iba-1 positive cells were more distributed than that in vehicle cerebellum, whereas in P 14 they were decreased and less observed in vehicle. Activated microglia might be distributed in the VPA-rat EGL and control granule cell migration. Additionally the excess folds and irregular expanding of astrocytes were observed on lobule V - VII in the vermis of the VPA-rat. These malformations in the VPA-rat cerebellum suggest astrocyte development might be altered by inflammation signals from microglia. Oxytocin administration to the VPA-rat showed recovery effects from neuronal malformation. We suggest Oxytocin might suppress neuroinflammation in the VPA-rat.   
VPA administration to embryo showed cerebellar developmental malformation with microglia activation. This irregular neuronal formation was recovered by additional administration of oxytocin after birth. Cerebellar irregular formation in autistic model rat would be regulated by microglia activation.


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