Transient focal cerebral ischemia induces long-term cognitive function deficit in an experimental ischemic stroke model

Highlights

• tMCAO induced a progressive decline in spatial learning and memory.

• tMCAO induced bilateral hippocampal LTP suppression.

• tMCAO increased hippocampal GABAergic neurotransmission.

• tMCAO decreased hippocampal ERK activation.

Abstract

Vascular dementia ranks as the second leading cause of dementia in the United States. However, its underlying pathophysiological mechanism is not fully understood and no effective treatment is available. The purpose of the current study was to evaluate long-term cognitive deficits induced by transient middle cerebral artery occlusion (tMCAO) in rats and to investigate the underlying mechanism. Sprague–Dawley rats were subjected to tMCAO or sham surgery. Behavior tests for locomotor activity and cognitive function were conducted at 7 or 30 days after stroke. Hippocampal long term potentiation (LTP) and involvement of GABAergic neurotransmission were evaluated at 30 days after sham surgery or stroke. Immunohistochemistry and Western blot analyses were conducted to determine the effect of tMCAO on cell signaling in the hippocampus. Transient MCAO induced a progressive deficiency in spatial performance. At 30 days after stroke, no neuron loss or synaptic marker change in the hippocampus were observed. LTP in both hippocampi was reduced at 30 days after stroke. This LTP impairment was prevented by blocking GABA_A receptors. In addition, ERK activity was significantly reduced in both hippocampi. In summary, we identified a progressive decline in spatial learning and memory after ischemic stroke that correlates with suppression of hippocampal LTP, elevation of GABAergic neurotransmission, and inhibition of ERK activation. Our results indicate that the attenuation of GABAergic activity or enhancement of ERK/MAPK activation in the hippocampus might be potential therapeutic approaches to prevent or attenuate cognitive impairment after ischemic stroke.

Introduction

Stroke ranks as the fourth leading cause of death in the United States, with ischemic stroke comprising more than 80% of total stroke. The stroke patients must not only survive the acute stages of infarction, but they must then cope with the ongoing neurological impairment. Stroke is the most common cause of permanent disability among people in the United States and is associated with a high incidence of deficits in both sensorimotor function as well as cognitive ability (Phipps, 1991). Epidemiological studies have shown that the prevalence of dementia in ischemic stroke patients is nine-fold higher than controls at 3 months (Tatemichi et al., 1992), and 4–12 times higher than in controls 4 years after a lacuna infarct (Loeb et al., 1992). Many of these dementias developed progressively after stroke, and thus cannot be interpreted as direct consequence of the primary ischemic damage (Tatemichi et al., 1994).

Middle cerebral artery occlusion (MCAO) in rodents is considered to be a convenient, reproducible, and reliable model of cerebral ischemia in humans. MCAO typically results in extensive damage in the cortex and caudate putamen, and sensorimotor behavior impairment has been extensively studied in ischemic stroke models. Spontaneous partial or complete recovery of sensorimotor function has been reported consistently over time after ischemic stroke (DeVries et al., 2001, Markgraf et al., 1992, Yonemori et al., 1999). On the other hand, the assessment of the cognitive impairment after MCAO has yielded conflicting results (Bingham et al., 2012, Bland et al., 2000, DeVries et al., 2001). Characterization of long-term cognitive outcome after stroke will be critical for discovery of therapeutic approaches and evaluating efficacies of potential therapeutic agents.

In the present study, the progression of impaired spatial learning and memory performance after ischemic stroke was evaluated in a rat model of transient focal cerebral ischemia. Then, potential underlying mechanisms of the progressive impairments were studied in the hippocampus, a brain region recognized to play a vital role in spatial information processing and memory formation. Our study demonstrated a progressive decline in capacity to acquire spatial learning after ischemic stroke, which could be attributed to functional changes in the hippocampus distal to the primary infarct area.