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Simvastatin impairs hippocampal synaptic plasticity and cognitive function in mice.

Yujun Guo1, Guichang Zou1, Keke Qi2

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Long-term simvastatin use impairs hippocampal synaptic plasticity and memory in mice by reducing brain cholesterol. These cognitive effects are reversible upon drug discontinuation, suggesting a link to neurological side effects.

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Area of Science:

  • Neuroscience
  • Pharmacology
  • Biochemistry

Background:

  • Lipophilic statins can cross the blood-brain barrier (BBB), potentially impacting central nervous system cholesterol synthesis and neural functions.
  • The specific effects of BBB-permeable statins on hippocampal cholesterol levels, synaptic plasticity, and cognitive function remain largely unelucidated.

Purpose of the Study:

  • To investigate the in vivo effects of chronic simvastatin administration on hippocampal cholesterol levels, synaptic plasticity, and memory in mice.
  • To determine the reversibility of simvastatin-induced neurological changes upon drug discontinuation.

Main Methods:

  • Long-term subcutaneous simvastatin treatment in mice.
  • Electrophysiological recordings to assess hippocampal long-term potentiation (LTP).
  • Behavioral tests for recognition, spatial memory, motor ability, and anxiety.
  • Mass spectrometry imaging to quantify hippocampal cholesterol levels.

Main Results:

  • Chronic simvastatin significantly impaired hippocampal synaptic plasticity (attenuated LTP) and caused deficits in recognition and spatial memory.
  • Motor ability and anxiety behaviors were unaffected by simvastatin treatment.
  • Mass spectrometry imaging revealed a significant decrease in hippocampal cholesterol intensity in simvastatin-treated mice.
  • Discontinuation of simvastatin treatment led to the restoration of hippocampal cholesterol levels, synaptic plasticity, and memory function.

Conclusions:

  • Long-term use of BBB-permeable simvastatin can impair hippocampal cholesterol homeostasis, synaptic plasticity, and cognitive functions in mice.
  • The observed neurological side effects, particularly cognitive impairment, are transient and reversible.
  • These findings highlight potential mechanisms underlying neurological adverse effects associated with chronic use of lipophilic statins.