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Recurrent vascular insult leads to memory impairment and synaptic dysfunction detected as F‐actin loss
Author(s) -
Diwakar Latha,
Maurya Shashank Kumar,
Ravindranath Vijayalakshmi
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.042630
Subject(s) - vascular dementia , medicine , hippocampus , hippocampal formation , lesion , morris water navigation task , dementia , neuroscience , pathology , psychology , anesthesia , disease
Abstract Background Vascular dementia may begin as mild cognitive changes due to blockade of blood vessels that worsen gradually as a result of multiple minor strokes. Such vascular insults occurring in the aging human brain can induce various types of cerebral tissue lesions like hemorrhage, infarction, hippocampal sclerosis and white matter lesions leading to cognitive decline. Studies have shown that multi‐infarct dementia is accounted for most cases of vascular dementia. We wanted to develop an animal model to study the vascular pathology affecting synaptic function during such multiple vascular insult to pave way for better understanding of vascular dementia. Method Vasoconstriction was induced by ET‐1, a 21 amino acid peptide. C57/BL6J mice aged 4‐5 months was implanted with cannula on left side of the hemisphere. ET‐1 2ug/2ul was injected through guide cannula into the intracerebroventricular space of lateral ventricle. The animals were injected with 3 doses of ET‐1 at interval of three weeks for each dose for a period of 9 weeks, at the end of dosing mice were subjected behavioral task. Animals were sacrificed, different brain regions like cortex and hippocampus were dissected out to process for biochemical analysis. Result Animals were injected for a period of three weeks to make sure that animal completely recovers from first vascular insult. There was significant difference in novel object task, contextual fear conditioning test and Morris water maze in ET‐1 injected mice indicating memory deficits. Gait analysis demonstrated discrepancies in stride and stance length in chronic ET‐1 injected mice compared to vehicle control. Actin treadmilling plays important role in maintaining F/G‐actin equilibrium for optimal synaptic function. Hence, we wanted to know whether chronic vascular insult affects F/G‐actin equilibrium and our results demonstrated that synaptic dysfunction seen as F‐actin disassembly might be contributing to behavioral dysfunction. Conclusion Repeated vascular insult resulted in irreversible learning and memory deficits in ET‐1 injected mice compared to controls leading to vascular dementia. Gait analysis indicated changes in stride and stance length after three injections of ET‐1. We observed loss of F‐actin in synaptosomes prepared from cortex of mice with chronic dose of ET‐1.