PMID- 35628400
OWN - NLM
STAT- MEDLINE
DCOM- 20220531
LR  - 20220716
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 23
IP  - 10
DP  - 2022 May 17
TI  - Seizures in PPT1 Knock-In Mice Are Associated with Inflammatory Activation of 
      Microglia.
LID - 10.3390/ijms23105586 [doi]
LID - 5586
AB  - Infantile neuronal ceroid lipofuscinosis (INCL), the most severe form of neuronal 
      ceroid lipofuscinoses, is caused by mutations in the lysosomal enzyme palmitoyl 
      protein thioesterase 1 (PPT1). Typical symptoms of this disease include 
      progressive psychomotor developmental retardation, visual failure, seizures, and 
      premature death. Here, we investigated seizure activity and relevant pathological 
      changes in PPT1 knock-in mice (PPT1 KI). The behavior studies in this study 
      demonstrated that PPT1 KI mice had no significant seizure activity until 7 months 
      of age, and local field potentials also displayed epileptiform activity at the 
      same age. The expression levels of Iba-1 and CD68 demonstrated, by Western blot 
      analysis, the inflammatory cytokine TNF-alpha content measured with enzyme-linked 
      immunosorbent assay, and the number of microglia demonstrated by 
      immunohistochemistry (IHC) were significantly increased at age of 7 months, all 
      of which indicate microglia activation at an age of seizure onset. The increased 
      expression of GFAP were seen at an earlier age of 4 months, and such an increase 
      reached its peak at age of 6 months, indicating that astrocyte activation 
      precedes microglia. The purinergic P2X7 receptor (P2X7R) is an ATP-sensitive 
      ionic channel that is highly expressed in microglia and is fundamental to 
      microglial activation, proliferation, cytokines release and epilepsy. We show 
      that the ATP concentration in hippocampal tissue in PPT1 KI mice was increased 
      using an enhanced ATP assay kit and demonstrated that the antagonist of P2X7R, 
      A-438079, significantly reduced seizures in PPT1 KI mice. In contrast to glial 
      cell activation and proliferation, a significant reduction in synaptic proteins 
      GABA(A)R was seen in PPT1 KI mice. These results indicate that seizure in PPT1 KI 
      mice may be associated with microglial activation involved in ATP-sensitive P2X7R 
      signaling and impaired inhibitory neurotransmission.
FAU - Zhang, Xusheng
AU  - Zhang X
AD  - Institute of Psychiatry and Neuroscience, Xinxiang Medical University, Xinxiang 
      453003, China.
FAU - Wang, Mengting
AU  - Wang M
AD  - Institute of Psychiatry and Neuroscience, Xinxiang Medical University, Xinxiang 
      453003, China.
FAU - Feng, Bingyan
AU  - Feng B
AD  - Henan International Joint Laboratory of Non-Invasive Neuromodulation, Department 
      of Physiology and Pathophysiology, Xinxiang Medical University, Xinxiang 453003, 
      China.
FAU - Zhang, Qiuyu
AU  - Zhang Q
AD  - Institute of Psychiatry and Neuroscience, Xinxiang Medical University, Xinxiang 
      453003, China.
FAU - Tong, Jia
AU  - Tong J
AUID- ORCID: 0000-0003-1835-7385
AD  - Institute of Psychiatry and Neuroscience, Xinxiang Medical University, Xinxiang 
      453003, China.
FAU - Wang, Mingyong
AU  - Wang M
AD  - Xinxiang Key Laboratory of Immunoregulation and Molecular Diagnostics, School of 
      Laboratory Medicine, Xinxiang Medical University, Xinxiang 453003, China.
FAU - Lu, Chengbiao
AU  - Lu C
AD  - Henan International Joint Laboratory of Non-Invasive Neuromodulation, Department 
      of Physiology and Pathophysiology, Xinxiang Medical University, Xinxiang 453003, 
      China.
FAU - Peng, Shiyong
AU  - Peng S
AD  - Institute of Psychiatry and Neuroscience, Xinxiang Medical University, Xinxiang 
      453003, China.
LA  - eng
PT  - Journal Article
DEP - 20220517
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (Cytokines)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
RN  - EC 3.1.2.- (Thiolester Hydrolases)
RN  - EC 3.1.2.22 (palmitoyl-protein thioesterase)
SB  - IM
MH  - Adenosine Triphosphate
MH  - Animals
MH  - Cytokines/metabolism
MH  - Disease Models, Animal
MH  - Inflammation/metabolism/pathology
MH  - Mice
MH  - Mice, Knockout
MH  - *Microglia/metabolism/pathology
MH  - *Neuronal Ceroid-Lipofuscinoses/pathology
MH  - Seizures/genetics
MH  - *Thiolester Hydrolases/genetics/metabolism
PMC - PMC9144763
OTO - NOTNLM
OT  - A 438079
OT  - PPT1 KI mice
OT  - hippocampus
OT  - microglia
OT  - seizures
COIS- The authors report no conflict of interest. The authors alone are responsible for 
      the content and writing of the paper.
EDAT- 2022/05/29 06:00
MHDA- 2022/06/01 06:00
PMCR- 2022/05/17
CRDT- 2022/05/28 01:22
PHST- 2022/03/26 00:00 [received]
PHST- 2022/05/08 00:00 [revised]
PHST- 2022/05/11 00:00 [accepted]
PHST- 2022/05/28 01:22 [entrez]
PHST- 2022/05/29 06:00 [pubmed]
PHST- 2022/06/01 06:00 [medline]
PHST- 2022/05/17 00:00 [pmc-release]
AID - ijms23105586 [pii]
AID - ijms-23-05586 [pii]
AID - 10.3390/ijms23105586 [doi]
PST - epublish
SO  - Int J Mol Sci. 2022 May 17;23(10):5586. doi: 10.3390/ijms23105586.