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Investigations on Alterations of Hippocampal Circuit Function Following Mild Traumatic Brain Injury
Published on: November 19, 2012
Glial gap junctional communication involvement in hippocampal damage after middle cerebral artery occlusion
Minjie Xie1, Chenju Yi, Xiang Luo
1Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Insights
Middle cerebral artery occlusion (MCAO) causes hippocampal damage and cognitive impairment. Blocking astroglial gap junctional communication (GJC) protects neurons and improves memory, suggesting a therapeutic target for stroke patients.
Area of Science:
- Neuroscience
- Neurology
- Stroke Research
Background:
- Middle cerebral artery occlusion (MCAO) is a common cause of stroke, often leading to cognitive deficits.
- Cognitive impairment post-MCAO is typically attributed to cerebral cortex damage, with hippocampal involvement less understood.
- The precise mechanisms linking MCAO to hippocampal damage and subsequent cognitive decline require further investigation.
Purpose of the Study:
- To investigate hippocampal damage following exclusively unilateral MCAO.
- To determine the correlation between MCAO-induced hippocampal damage and cognitive deficits.
- To elucidate the underlying mechanisms of hippocampal damage after MCAO.
Main Methods:
- Utilized magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) to assess hippocampal damage in patients.
- Employed Mini Mental-Status Evaluation (MMSE) and Rey Auditory Verbal Learning Test (RAVLT) for cognitive function assessment.
- Investigated the role of gap junctional communication (GJC) and connexin43 (Cx43) in rodent MCAO models.
Main Results:
- Demonstrated infarct-size-independent hippocampal atrophy and altered metabolites in the ipsilateral hippocampus post-MCAO, correlating with cognitive impairment.
- Observed delayed neuronal death and spatial memory deficits in rodent MCAO models.
- Showed that blocking GJC or downregulating Cx43 enhanced neuronal survival and improved behavioral outcomes in MCAO models.
Conclusions:
- Astroglial GJC significantly contributes to MCAO-induced remote hippocampal damage and cognitive impairment.
- Targeting interastrocytic communication via gap junctions presents a potential therapeutic strategy for improving cognition in MCAO patients.
Objective:
Most patients with stroke caused by middle cerebral artery occlusion (MCAO) show cognitive deficit that is generally regarded as resulting from damage to the cerebral cortex rather than the hippocampus. Whether MCAO induces hippocampal damage and whether this contributes to the cognitive defects remains unclear. Here we investigate the hippocampal damage and its correlation to cognitive defects after exclusively unilateral MCAO and the underlying mechanism for that damage.
Methods:
Patients were assessed for hippocampal damage by magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA), and the Mini Mental-Status Evaluation (MMSE) and Rey Auditory Verbal Learning Test (RAVLT) were used to assess for cognitive defects.
Results:
We provide the first evidence that patients with exclusively unilateral MCAO showed hippocampal damage characterized by an infarct-size-independent atrophy and alterations in neuronal and glial metabolites in the ipsilateral hippocampus, in parallel with cognitive impairment. Rodent MCAO also induced delayed shrinkage and pyramidal neuronal death in the ipsilateral hippocampus and an impairment of hippocampal-dependent spatial memory. Blocking Gap junctional communication (GJC) with carbenoxolone or downregulation of connexin43 (Cx43) significantly increased the survival of the pyramidal neurons in the ipsilateral hippocampus and improved behavioral scores. Furthermore, Cx43 heterozygous mice showed reduced shrinkage and metabolite abnormality in ipsilateral hippocampus after MCAO.
Interpretation:
Astroglial GJC plays a significant role in MCAO-induced remote hippocampal damage and cognitive impairment. It might be possible to improve the cognition in patients with MCAO by manipulating interastrocytic communication via the gap junction channels.
