Cisplatin treatment induces attention deficits and impairs synaptic integrity in the prefrontal cortex in mice

Sci Rep. 2018 Nov 27;8(1):17400. doi: 10.1038/s41598-018-35919-x.

Abstract

Patients treated for cancer frequently experience chemobrain, characterized by impaired memory and reduced attention. These deficits often persist after treatment, and no preventive or curative interventions exist. In mice, we assessed the effect of cisplatin chemotherapy on attention using the 5-choice serial reaction time task and on synaptic integrity. We also assessed the capacity of mesenchymal stem cells to normalize the characteristics of chemobrain. Mice were trained in the 5-choice serial reaction time task. After reaching advancement criteria at a 4-second stimulus time, they were treated with cisplatin followed by nasal administration of mesenchymal stem cells. Cisplatin reduced the percentage of correct responses due to an increase in omissions, indicating attention deficits. Mesenchymal stem cell treatment reversed these cisplatin-induced deficits in attention. Cisplatin also induced abnormalities in markers of synaptic integrity in the prefrontal cortex. Specifically, cisplatin decreased expression of the global presynaptic marker synaptophysin and the glutamatergic presynaptic marker vGlut2. Expression of the presynaptic GABAergic marker vGAT increased. Nasal mesenchymal stem cell administration normalized these markers of synaptic integrity. In conclusion, cisplatin induces long-lasting attention deficits that are associated with decreased synaptic integrity in the prefrontal cortex. Nasal administration of mesenchymal stem cells reversed these behavioural and structural deficits.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / pharmacology*
  • Attention Deficit Disorder with Hyperactivity / etiology*
  • Attention Deficit Disorder with Hyperactivity / therapy
  • Cells, Cultured
  • Cisplatin / adverse effects
  • Cisplatin / pharmacology*
  • Male
  • Mesenchymal Stem Cell Transplantation / methods
  • Mice
  • Mice, Inbred C57BL
  • Prefrontal Cortex / drug effects*
  • Prefrontal Cortex / metabolism
  • Prefrontal Cortex / physiology
  • Synaptic Transmission*
  • Synaptotagmins / genetics
  • Synaptotagmins / metabolism
  • Vesicular Glutamate Transport Protein 2 / metabolism

Substances

  • Antineoplastic Agents
  • Slc17a6 protein, mouse
  • Vesicular Glutamate Transport Protein 2
  • Synaptotagmins
  • Cisplatin