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J Neurosci. 2018 Dec 12;38(50):10672-10691. doi: 10.1523/JNEUROSCI.0825-17.2018. Epub 2018 Oct 31.

Characterization of Brain Dysfunction Induced by Bacterial Lipopeptides That Alter Neuronal Activity and Network in Rodent Brains.

Author information

1
Biomaterials and Advanced Drug Delivery Laboratory, Stanford University School of Medicine, Palo Alto, California 94304.
2
Department of Neurosurgery, Stanford University School of Medicine, Stanford, California 94305.
3
Department of Nuclear Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.
4
Department of Nuclear Medicine, Seoul National University, College of Medicine, Seoul, Korea.
5
Department of Biology, and.
6
Department of Molecular and Cellular Physiology, Stanford University, Stanford, California 94305.
7
Department of Nuclear Medicine, Seoul National University Bundang Hospital, Seongnam, Korea, jayraja@stanford.edu md1004@snu.ac.kr.
8
Biomaterials and Advanced Drug Delivery Laboratory, Stanford University School of Medicine, Palo Alto, California 94304, jayraja@stanford.edu md1004@snu.ac.kr.
9
Department of Bioengineering and Therapeutic Sciences, School of Pharmacy, University of California, San Francisco, California 94158.

Abstract

The immunopathological states of the brain induced by bacterial lipoproteins have been well characterized by using biochemical and histological assays. However, these studies have limitations in determining functional states of damaged brains involving aberrant synaptic activity and network, which makes it difficult to diagnose brain disorders during bacterial infection. To address this, we investigated the effect of Pam3CSK4 (PAM), a synthetic bacterial lipopeptide, on synaptic dysfunction of female mice brains and cultured neurons in parallel. Our functional brain imaging using PET with [18F]fluorodeoxyglucose and [18F] flumazenil revealed that the brain dysfunction induced by PAM is closely aligned to disruption of neurotransmitter-related neuronal activity and functional correlation in the region of the limbic system rather than to decrease of metabolic activity of neurons in the injection area. This finding was verified by in vivo tissue experiments that analyzed synaptic and dendritic alterations in the regions where PET imaging showed abnormal neuronal activity and network. Recording of synaptic activity also revealed that PAM reorganized synaptic distribution and decreased synaptic plasticity in hippocampus. Further study using in vitro neuron cultures demonstrated that PAM decreased the number of presynapses and the frequency of miniature EPSCs, which suggests PAM disrupts neuronal function by damaging presynapses exclusively. We also showed that PAM caused aggregation of synapses around dendrites, which may have caused no significant change in expression level of synaptic proteins, whereas synaptic number and function were impaired by PAM. Our findings could provide a useful guide for diagnosis and treatment of brain disorders specific to bacterial infection.SIGNIFICANCE STATEMENT It is challenging to diagnose brain disorders caused by bacterial infection because neural damage induced by bacterial products involves nonspecific neurological symptoms, which is rarely detected by laboratory tests with low spatiotemporal resolution. To better understand brain pathology, it is essential to detect functional abnormalities of brain over time. To this end, we investigated characteristic patterns of altered neuronal integrity and functional correlation between various regions in mice brains injected with bacterial lipopeptides using PET with a goal to apply new findings to diagnosis of brain disorder specific to bacterial infection. In addition, we analyzed altered synaptic density and function using both in vivo and in vitro experimental models to understand how bacterial lipopeptides impair brain function and network.

KEYWORDS:

PET; bacterial lipoprotein; brain infection; regional correlation; synaptic dysfunction

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