Recognition memory impairments after subcortical white matter stroke in mice.
OBJECTIVE
Small subcortical white matter infarcts are a common stroke subtype often associated with cognitive deficits. The lack of relevant models confined to white matter has limited the investigation of its pathophysiology. Here, we examine tissue and functional outcome after an ischemic lesion within corpus callosum in wild-type (WT) mice and in mice null for a gene, NOTCH3, linked to white matter ischemic injury in patients.


METHODS
WT and NOTCH3 knockout mice were subjected to stereotactic microinjections of the potent vasoconstrictor endothelin-1 at the level of periventricular white matter to induce a focal ischemic lesion. Infarct location was confirmed by MRI, and brains were examined for lesion size and histology; behavioral deficits were assessed ≤1 month in WT mice.


RESULTS
Ischemic damage featured an early cerebral blood flow deficit, blood-brain barrier opening, and a lesion largely confined to white matter. At later stages, myelin and axonal degeneration and microglial/macrophage infiltration were found. WT mice displayed prolonged cognitive deficit when tested using a novel object recognition task. NOTCH3 mutants showed larger infarcts and greater cognitive deficit at 7 days post stroke.


CONCLUSIONS
Taken together, these data show the usefulness of microinjections of endothelin-1 into periventricular white matter to study focal infarcts and cognitive deficit in WT mice. In short-term studies, stroke outcome was worse in NOTCH3 null mice, consistent with the notion that the lack of the NOTCH3 receptor affects white matter stroke susceptibility.
From the Stroke and Neurovascular Research Laboratory, Department of Radiology (F.B., Y.W., M.B., C.A., M.A.M.), Stroke Service and Neuroscience Intensive Care Unit, Department of Neurology (C.A.), Department of Cell Biology (S.T.), and Department of Radiology, Martinos Center for Biomedical Imaging (J.B.M.), Massachusetts General Hospital, Harvard Medical School, Boston; and Department of Pharmacology, School of Pharmacy, University College Cork, Cork, Ireland (C.W.).
Francesco
F
Blasi
Ying
Y
Wei
Mustafa
M
Balkaya
Saara
S
Tikka
Joseph B
JB
Mandeville
Christian
C
Waeber
Cenk
C
Ayata
Michael A
MA
Moskowitz
D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D002544:Cerebral Infarction / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D003337:Corpus Callosum / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000008:administration & dosage / Q000494:pharmacology; D020022:Genetic Predisposition to Disease / Q000235:genetics; D056784:Leukoencephalopathies / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D008569:Memory Disorders / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011897:Random Allocation; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000172:deficiency* / Q000235:genetics; D021641:Recognition, Psychology / Q000502:physiology*
D019332:Endothelin-1; C499373:Notch3 protein, mouse; D000071656:Receptor, Notch3; D051880:Receptors, Notch
mild cognitive impairment; models, animal; stroke, lacunar; white matter diseases