ABSTRACT
BACKGROUND: Morin is a flavonoid found in many edible fruits. The hippocampus and entorhinal cortex play crucial roles in memory formation and consolidation. This study aimed to characterize the effect of morin on recognition and space memory in healthy C57BL/6 adult mice and explore the underlying molecular mechanism. METHODS: Morin was administered i.p. at 1, 2.5, and 5 mg/kg/24 h for 10 days. The Morris water maze (MWM), novel object recognition, novel context recognition, and tasks were conducted 1 day after the last administration. The mice's brains underwent histological characterization, and their protein expression was examined using immunohistochemistry and Western blot techniques. RESULTS: In the MWM and novel object recognition tests, mice treated with 1 mg/kg of morin exhibited a significant recognition index increase compared to the control group. Besides, they demonstrated faster memory acquisition during MWM training. Additionally, the expression of pro-brain-derived neurotrophic factor (BDNF), BDNF, and postsynaptic density protein 95 proteins in the hippocampus of treated mice showed a significant increase. In the entorhinal cortex, only the pro-BDNF increased. Morin-treated mice exhibited a significant increase in the hippocampus's number and length of dendrites. CONCLUSION: This study shows that morin improves recognition memory and spatial memory in healthy adult mice.
Subject(s)
Brain-Derived Neurotrophic Factor , Flavones , Flavonoids , Mice , Animals , Brain-Derived Neurotrophic Factor/metabolism , Maze Learning , Mice, Inbred C57BL , Flavonoids/pharmacology , Flavonoids/metabolism , Hippocampus/metabolism , Spatial MemoryABSTRACT
Completion of neuronal migration is critical for brain development. Kif21b is a plus-end-directed kinesin motor protein that promotes intracellular transport and controls microtubule dynamics in neurons. Here we report a physiological function of Kif21b during radial migration of projection neurons in the mouse developing cortex. In vivo analysis in mouse and live imaging on cultured slices demonstrate that Kif21b regulates the radial glia-guided locomotion of newborn neurons independently of its motility on microtubules. We show that Kif21b directly binds and regulates the actin cytoskeleton both in vitro and in vivo in migratory neurons. We establish that Kif21b-mediated regulation of actin cytoskeleton dynamics influences branching and nucleokinesis during neuronal locomotion. Altogether, our results reveal atypical roles of Kif21b on the actin cytoskeleton during migration of cortical projection neurons.
Subject(s)
Kinesins , Neurons , Animals , Mice , Actin Cytoskeleton/metabolism , Cell Movement , Interneurons/metabolism , Kinesins/metabolism , Microtubules/metabolism , Neurons/metabolismABSTRACT
Kinesin Family Member 21B (KIF21B) encoded by KIF21B (MIM*608322), belongs to the Kinesin superfamily proteins, which play a key role in microtubule organisation in neuronal dendrites and axons. Recently, heterozygous variants in KIF21B were implicated as the cause of intellectual disability and brain malformations in four unrelated individuals. We report a 9-year-old male with delayed speech, hyperactivity, poor social interaction, and autistic features. A parent-offspring trio exome sequencing identified a novel de novo rare heterozygous variant, NM_001252102.2: c.1513A>C, p.(Ser505Arg) in exon 11 of KIF21B. In vivo functional analysis using in utero electroporation in mouse embryonic cortex revealed that the expression of Ser505Arg KIF21B protein in the cerebral cortex impaired the radial migration of projection neurons, thus confirming the pathogenicity of the variant. Our report further validates pathogenic variants in KIF21B as a cause of neurodevelopmental disorder.
Subject(s)
Intellectual Disability , Neurodevelopmental Disorders , Male , Animals , Mice , Kinesins/genetics , Neurons/metabolism , Neurodevelopmental Disorders/genetics , Neurodevelopmental Disorders/pathology , Axons , Cerebral Cortex/pathology , Intellectual Disability/pathologyABSTRACT
KIF21B is a kinesin protein that promotes intracellular transport and controls microtubule dynamics. We report three missense variants and one duplication in KIF21B in individuals with neurodevelopmental disorders associated with brain malformations, including corpus callosum agenesis (ACC) and microcephaly. We demonstrate, in vivo, that the expression of KIF21B missense variants specifically recapitulates patients' neurodevelopmental abnormalities, including microcephaly and reduced intra- and inter-hemispheric connectivity. We establish that missense KIF21B variants impede neuronal migration through attenuation of kinesin autoinhibition leading to aberrant KIF21B motility activity. We also show that the ACC-related KIF21B variant independently perturbs axonal growth and ipsilateral axon branching through two distinct mechanisms, both leading to deregulation of canonical kinesin motor activity. The duplication introduces a premature termination codon leading to nonsense-mediated mRNA decay. Although we demonstrate that Kif21b haploinsufficiency leads to an impaired neuronal positioning, the duplication variant might not be pathogenic. Altogether, our data indicate that impaired KIF21B autoregulation and function play a critical role in the pathogenicity of human neurodevelopmental disorder.
Subject(s)
Kinesins/genetics , Motor Activity , Mutation/genetics , Neurodevelopmental Disorders/genetics , Neurodevelopmental Disorders/physiopathology , Animals , Axons/metabolism , Cell Movement , Cell Proliferation , Cerebral Cortex/embryology , Cerebral Cortex/pathology , Cerebral Cortex/physiopathology , Female , Gene Expression Regulation, Developmental , HEK293 Cells , Humans , Male , Mice , Mutation, Missense/genetics , Nerve Net/pathology , Nerve Net/physiopathology , Neurons/metabolism , Organ Size , Organogenesis/genetics , Pedigree , RNA, Messenger/genetics , RNA, Messenger/metabolism , Zebrafish/anatomy & histology , Zebrafish/geneticsABSTRACT
La hepaticoyeyunostomía en Y de Roux con Asa de Baker modificada es una derivación bilioentérica que posee una Asa de yeyuno subcutánea que sirve para poderinstrumentar endoscópicamente el árbol biliar las veces que sea necesario. El presente trabajo presenta la experiencia de la 4a. Unidad de Cirugía del Hospital General San Juan de Dios de Guatemala en los últimos 11 años. Material y Métodos: De enero de 1992 a enero de 2003 se han efectuado 191 derivaciones bilio-entéricas, 24 coledocoduodenostomías L-L y 167 hepatico-yeyunostomía en Y de Roux con Asa de Barker Modificada a 154 mujeres y 37 hombres, entre las edades de 18 a 69 años. Resultados: Se han operado 93 pacientes por lesiones iatrogénicas al árbol biliar, 62 pacientes por obstrucción litiásica biliar, 7 por quistes del colédoco, 25 por cáncer y 4 por pseudoquistes de páncreas. De los 167 casos con hepaticoyeyunostomía en Y de Roux con Asa de Barker modificada 5 pacientes (3.03 por ciento) presentaron colangitis a repetición, todos aquellos pacientes post-iatrogenia. De éstos 5 casos 2 se resolvieron con tratamiento médico y a 3 se les efectuó instrumentación endoscópica del árbol biliar. Un caso no se pudo instrumentar por estrechez puntiforme se reintervino a ésta paciente y se le efectuó una nueva derivación. Las otras dos pacientes fueron instrumentadas, dilatadas y se colocaron endoprótesis biliares 10 Fr. temporal, a una de estas pacientes hubo necesidad de instrumentarla dos veces, resolviéndose la estrechez en los dos casos. Conclusión: La hepaticoyeyunostomía en Y de Roux con Asa de Barker Modificada es una derivación bilioentérica que permite el acceso permanente al árbol biliar pudiendo ser instrumentado endoscópicamente las veces que sea necesario
