Disruption of Striatal-Enriched Protein Tyrosine Phosphatase Signaling Might Contribute to Memory Impairment in a Mouse Model of Sepsis-Associated Encephalopathy

Neurochem Res. 2019 Dec;44(12):2832-2842. doi: 10.1007/s11064-019-02905-2. Epub 2019 Nov 6.

Abstract

Sepsis-associated encephalopathy (SAE) is a potentially irreversible acute cognitive dysfunction with unclear mechanism. Striatal-enriched protein tyrosine phosphatase (STEP) is a brain-specific phosphatase which normally opposes synaptic strengthening by regulating key signaling molecules involved in synaptic plasticity and neuronal function. Thus, we hypothesized that abnormal STEP signaling pathway was involved in sepsis-induced cognitive impairment evoked by lipopolysaccharides (LPS) injection. The levels of STEP, phosphorylation of GluN2B (pGluN2B), the kinases extracellular signal-regulated kinase 1/2 (pERK), cAMP-response element binding protein (CREB), synaptophysin, brain derived neurotrophic factor (BDNF), and post-synaptic density protein 95 (PSD95) in the hippocampus, prefrontal cortex, and striatum were determined at the indicated time points. In the present study, we found that STEP levels were significantly increased in the hippocampus, prefrontal cortex, and striatum following LPS injection, which might resulted from the disruption of the ubiquitin-proteasome system. Notably, a STEP inhibitor TC-2153 treatment alleviated sepsis-induced memory impairment by increasing phosphorylation of GluN2B and ERK1/2, CREB/BDNF, and PSD95. In summary, our results support the key role of STEP in sepsis-induced memory impairment in a mouse model of SAE, whereas inhibition of STEP may provide a novel therapeutic approach for this disorder and possible other neurodegenerative diseases.

Keywords: Cognition; LPS; Striatal-enriched protein tyrosine phosphatase; Synaptic plasticity.

MeSH terms

  • Animals
  • Benzothiepins / pharmacology
  • Brain-Derived Neurotrophic Factor / chemistry
  • Brain-Derived Neurotrophic Factor / metabolism
  • Corpus Striatum / metabolism
  • Cyclic AMP Response Element-Binding Protein / chemistry
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Disks Large Homolog 4 Protein / chemistry
  • Disks Large Homolog 4 Protein / metabolism
  • Hippocampus / metabolism
  • Lipopolysaccharides
  • Male
  • Memory / drug effects
  • Memory / physiology
  • Memory Disorders / chemically induced
  • Memory Disorders / physiopathology*
  • Mice, Inbred C57BL
  • Mitogen-Activated Protein Kinase 1 / chemistry
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / chemistry
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Phosphorylation / drug effects
  • Prefrontal Cortex / metabolism
  • Protein Tyrosine Phosphatases, Non-Receptor / antagonists & inhibitors
  • Protein Tyrosine Phosphatases, Non-Receptor / metabolism*
  • Receptors, N-Methyl-D-Aspartate / chemistry
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Sepsis-Associated Encephalopathy / chemically induced
  • Sepsis-Associated Encephalopathy / physiopathology*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*

Substances

  • 8-(trifluoromethyl)-1,2,3,4,5-benzopentathiepin-6-amine
  • Bdnf protein, mouse
  • Benzothiepins
  • Brain-Derived Neurotrophic Factor
  • Creb1 protein, mouse
  • Cyclic AMP Response Element-Binding Protein
  • Disks Large Homolog 4 Protein
  • Dlg4 protein, mouse
  • Lipopolysaccharides
  • NR2B NMDA receptor
  • Receptors, N-Methyl-D-Aspartate
  • Mapk1 protein, mouse
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Protein Tyrosine Phosphatases, Non-Receptor
  • Ptpn5 protein, mouse