Franklin Sarah L, Love Seth, Greene J Richard T, Betmouni Samar
MRC Centre for Synaptic Plasticity, University of Bristol, Bristol, United Kingdom.
J Neuropathol Exp Neurol. 2008 Mar;67(3):189-99. doi: 10.1097/NEN.0b013e3181654386.
Microglial activation and behavioral abnormalities occur before neuronal loss in experimental murine prion disease; the behavioral changes coincide with a reduction in synaptic plasticity. Because synaptic plasticity depends on an intact perineuronal net (PN), a specialized extracellular matrix that surrounds parvalbumin (PV)-positive GABAergic (gamma-aminobutyric acid [GABA]) inhibitory interneurons, we investigated the temporal relationships between microglial activation and loss of PN and PV-positive neurons in ME7 murine prion disease. Anesthetized C57Bl/6J mice received bilateral intracerebral microinjections of ME7-infected or normal brain homogenate into the dorsal hippocampus. Microglial activation, PrP accumulation, the number of PV-positive interneurons, and Wisteria floribunda agglutinin-positive neurons (i.e. those with an intact PN) were assessed in the ventral CA1 and subiculum at 4, 8, 12, 16, and 20 weeks postinjection. Hippocampal areas and total neuron numbers in the ventral CA1 and subiculum were also determined. Loss of PN coincided with early microglial activation and with a reduction in synaptic plasticity. No significant loss of PV-positive interneurons was observed. Our findings suggest that the substrate of the earliest synaptic and behavioral abnormalities in murine prion disease may be inflammatory microglia-mediated degradation of the PN.
在实验性鼠朊病毒病中，小胶质细胞激活和行为异常在神经元丧失之前就已出现；行为变化与突触可塑性降低相一致。由于突触可塑性依赖于完整的神经元周围网（PN），这是一种围绕小白蛋白（PV）阳性γ-氨基丁酸（GABA）能抑制性中间神经元的特殊细胞外基质，我们研究了ME7鼠朊病毒病中小胶质细胞激活与PN和PV阳性神经元丧失之间的时间关系。将麻醉的C57Bl/6J小鼠双侧脑内微量注射ME7感染的或正常的脑匀浆到背侧海马体。在注射后4、8、12、16和20周，评估腹侧CA1和海马下托中的小胶质细胞激活、PrP积累、PV阳性中间神经元数量以及紫藤凝集素阳性神经元（即具有完整PN的神经元）数量。还测定了腹侧CA1和海马下托的海马区域和总神经元数量。PN的丧失与早期小胶质细胞激活以及突触可塑性降低相一致。未观察到PV阳性中间神经元有明显丧失。我们的研究结果表明，鼠朊病毒病中最早的突触和行为异常的底物可能是炎症性小胶质细胞介导的PN降解。
