Single bilateral injection of endothelin‐1 leads to temporary deficits in memory and synaptic dysfunction

Background Cerebral small vessel disease (SVD) has gained prominence worldwide as a major factor for cognitive impairment seen in dementia. Micro infracts causing elusive changes in cognitive function clinically will not get diagnosed are found to be the main risk factor for SVD. We were interested in creating micro infarcts rather than a severe insult to replicate small vessel damage, so we opted for Intra cerebroventricular (ICV) bilateral stereotaxic injection of endothelin‐1 (ET‐1) into lateral ventricles. Sub cortical injections of ET‐1 in brain has been used in many studies to accomplish long lasting vasoconstriction and gradual reperfusion causing lesion. Therefore, we tried to overcome this by injecting into lateral ventricles allowing it to spread through cerebrospinal fluid. Method ET‐1 (Endothelin‐ 1) a 21 amino acid vasoconstricting peptide was injected bilaterally into lateral ventricles of C57 mice. Some animals were injected unilaterally to see whether there are any motor deficits. Expression of CD31, a marker of endothelial cells was done by immunohistochemistry to assess vasoconstriction. Contextual fear conditioning, object recognition and Morris water maze task was performed to examine associative learning and spatial memory deficits. Gait and rotarod was performed to examine if there are any motor deficits. Synaptic plasticity was evaluated as activity dependent protein translation was measured in synaptoneurosomes prepared from hippocampus. Result The obstruction in cerebral blood flow due to vasoconstriction caused by ET‐1 injection leads to deficits in associative learning and spatial memory after 7 days. There was no change in gait or rotarod performance indicating no effect on motor function. However, the behavioral dysfunction was temporary and reversed after 30 days of ET‐1 treatment once the blood flow was restored. These changes were demonstrated as drop in the activity dependent protein translation after 7 days of ET‐1 injection and raise after 30 days of treatment as it is an indicator for synaptic plasticity. Conclusion Bilateral injection of ET‐1 leads to prominent associative and spatial memory deficit and decline in activity dependent protein translation in hippocampus. Still these defects are reversible once the blood flow is restored. Unilateral injection of ET‐1 did not show any motor dysfunction.