Abstract
BackgroundCerebral microinfarcts (MIs) lead to progressive cognitive impairments in the elderly, and there is currently no effective preventative strategy due to uncertainty about the underlying pathogenic mechanisms. One possibility is the dysfunction of GABAergic transmission and ensuing excitotoxicity. Dysfunction of GABAergic transmission induces excitotoxicity, which contributes to stroke pathology, but the mechanism has kept unknown. The secreted leucine-rich repeat (LRR) family protein slit homologue 2 (Slit2) upregulates GABAergic activity and protects against global cerebral ischemia, but the neuroprotective efficacy of Slit2 against MIs has not been examined.MethodsMiddle-aged Wild type (WT) and Slit2-Tg mice were divided into sham and MI treatment groups. MIs were induced in parietal cortex by laser-evoked arteriole occlusion. Spatial memory was then compared between sham and MI groups using the Morris water maze (MWM) task. In addition, neuronal activity, blood brain barrier (BBB) permeability, and glymphatic clearance in peri-infarct areas were compared using two-photon imaging, while GABAergic transmission, microglial activation, neuronal loss, and altered cortical connectivity were compared by immunofluorescent staining or western blotting.ResultsMicroinfarcts increased the amplitude and frequency of spontaneous intracellular Ca2+ signals, reduced neuronal survival and connectivity within parietal cortex, decreased the number of GABAergic interneurons and expression of vesicular GABA transporter (VGAT), induced neuroinflammation, and impaired both glymphatic clearance and spatial memory. Alternatively, Slit2 overexpression attenuated dysfunctional neuronal Ca2+ signaling, protected against neuronal death in the peri-infarct area as well as loss of parietal cortex connectivity, increased GABAergic interneuron number and VGAT expression, attenuated neuroinflammation, and improved both glymphatic clearance and spatial memory.ConclusionOur results strongly suggest that overexpression of Slit2 protected against the dysfunction in MIs, which is a potential therapeutic target for cognition impairment in the elderly.
Highlights
Cerebral microinfarcts (MIs) are wedge-shaped ischemic lesions that result from occlusion of penetrating arterioles [1, 2]
MIs are common in the brains of patients with Alzheimer disease (AD) [3], mild cognitive impairment (MCI) [4], and vascular dementia (VaD) [5], and MI load is associated with the severity of cognitive impairment and dementia in the elderly [6]
slit homologue 2 (Slit2) was overexpressed in neurons and astrocytes but not in microglia/ macrophage of transgenic mice Western blotting was performed to confirm expression of the human Slit2 transgene protein in transgenic (Tg) mouse brain, and expression was significantly elevated in Slit2-Tg mice compared to Wild type (WT) mice (P < 0.001) (Supplementary Fig. 1a)
Summary
Cerebral microinfarcts (MIs) are wedge-shaped ischemic lesions that result from occlusion of penetrating arterioles [1, 2]. Augmenting GABAergic transmission can protect against ischemic damage [12, 13]. It is uncertain whether a glutamate/GABA imbalance and ensuing excitotoxicity contributes to MI pathology during aging. Cerebral microinfarcts (MIs) lead to progressive cognitive impairments in the elderly, and there is currently no effective preventative strategy due to uncertainty about the underlying pathogenic mechanisms. Dysfunction of GABAergic transmission induces excitotoxicity, which contributes to stroke pathology, but the mechanism has kept unknown. The secreted leucine-rich repeat (LRR) family protein slit homologue 2 (Slit2) upregulates GABAergic activity and protects against global cerebral ischemia, but the neuroprotective efficacy of Slit against MIs has not been examined
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