PTEN deletion increases hippocampal granule cell excitability in male and female mice

Neurobiol Dis. 2017 Dec;108:339-351. doi: 10.1016/j.nbd.2017.08.014. Epub 2017 Sep 21.

Abstract

Deletion of the mTOR pathway inhibitor PTEN from postnatally-generated hippocampal dentate granule cells causes epilepsy. Here, we conducted field potential, whole cell recording and single cell morphology studies to begin to elucidate the mechanisms by which granule cell-specific PTEN-loss produces disease. Cells from both male and female mice were recorded to identify sex-specific effects. PTEN knockout granule cells showed altered intrinsic excitability, evident as a tendency to fire in bursts. PTEN knockout granule cells also exhibited increased frequency of spontaneous excitatory synaptic currents (sEPSCs) and decreased frequency of inhibitory currents (sIPSCs), further indicative of a shift towards hyperexcitability. Morphological studies of PTEN knockout granule cells revealed larger dendritic trees, more dendritic branches and an impairment of dendrite self-avoidance. Finally, cells from both female control and female knockout mice received more sEPSCs and more sIPSCs than corresponding male cells. Despite the difference, the net effect produced statistically equivalent EPSC/IPSC ratios. Consistent with this latter observation, extracellularly evoked responses in hippocampal slices were similar between male and female knockouts. Both groups of knockouts were abnormal relative to controls. Together, these studies reveal a host of physiological and morphological changes among PTEN knockout cells likely to underlie epileptogenic activity.

Significance statement: Hyperactivation of the mTOR pathway is associated with numerous neurological diseases, including autism and epilepsy. Here, we demonstrate that deletion of the mTOR negative regulator, PTEN, from a subset of hippocampal dentate granule impairs dendritic patterning, increases excitatory input and decreases inhibitory input. We further demonstrate that while granule cells from female mice receive more excitatory and inhibitory input than males, PTEN deletion produces mostly similar changes in both sexes. Together, these studies provide new insights into how the relatively small number (≈200,000) of PTEN knockout granule cells instigates the development of the profound epilepsy syndrome evident in both male and female animals in this model.

Keywords: Dentate gyrus; Electrophysiology; Epilepsy; Epileptogenesis; Hippocampus; Mouse models; Neuroanatomy; mTOR.

MeSH terms

  • Animals
  • Cell Count
  • Epilepsy / metabolism
  • Epilepsy / pathology
  • Female
  • Hippocampus / metabolism*
  • Hippocampus / pathology*
  • Immunohistochemistry
  • Male
  • Membrane Potentials / physiology
  • Mice, Knockout
  • Microscopy, Confocal
  • Neural Inhibition / physiology
  • Neurons / metabolism*
  • Neurons / pathology*
  • PTEN Phosphohydrolase / deficiency*
  • PTEN Phosphohydrolase / genetics
  • Patch-Clamp Techniques
  • Sex Characteristics*
  • Tissue Culture Techniques

Substances

  • PTEN Phosphohydrolase
  • Pten protein, mouse