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The pathogenesis of hypertension-related cognitive impairment has not been sufficiently clarified, new molecular targets are needed. Synaptic plasticity is the neurobiological basis of learning and memory. p38 MAPK signalling pathway plays an important role in hypertensive target organ damage and synaptic plasticity. To examine whether there is a link between p38 MAPK and hypertension- related cognitive dysfunction. And to determine the impact this link may have on hippocampal synaptic plasticity.
We used p38 heterozygous knockdown mouse (p38KI/+). 2 month old p38KI/+ and wild type (WT) mice were infused via minipump with angiotensin II or saline solution as a control. Long-term potentiation (LTP) was measured by vitro electrophysiology on hippocampal slices at the Schaffer-CA1 pathway, the density of the dendritic spines on the CA1 pyramidal cells was examined by Golgi staining, spatial memory was assessed using the Morris water maze test, and hippocampal p38 MAPK and p-p38 MAPK protein expression were detected by western-blotting.
The treatment of angiotensin II significantly raised the systolic blood pressure constant throughout the experiment in p38KI/+ and WT mice (p<0.01). We found that LTP of hippocampal CA1 was decreased, the density of the dendritic spines on the CA1 pyramidal cells was reduced, the p-p38 protein expression in hippocampus was elevated, and cognitive function was impaired in angiotensin II-dependent hypertensive mice. Using p38KI/+ model, we showed that knockdown of p38 MAPK in hippocampus leads to the improvement of cognitive function and hippocampal synaptic plasticity in angiotensin II-dependent p38KI/+ hypertensive mice.
Knockdown of p38 MAPK improves synaptic plasticity and memory in angiotensin II-dependent hypertensive mice. p38 MAPK inhibition may provide a new target for the treatment of hypertension-related cognitive dysfunction.