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

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.

Hyperexcitability and plasticity induced by sustained hypoxia on rectus abdominis motoneurons

“…On the other hand, increased soma area was associated with decreases in R n in hippocampal neurons from mice (Santos et al . ), as well as in motoneurons from the oculomotor nucleus of rats (Torres‐Torrelo et al . ).…”

“…In pyramidal cells, for example, dendritic hypercomplexity is associated with altered neuronal activity as a result of a reduction in spike frequency adaptation episodes (van der Velden et al 2012). On the other hand, increased soma area was associated with decreases in R n in hippocampal neurons from mice (Santos et al 2017), as well as in motoneurons from the oculomotor nucleus of rats (Torres-Torrelo et al 2014). In the present study, we observed that SH increases the morphological complexity and somatic surface area and also decreases the R n of tonically active RA motoneurons.…”

PTEN in Autism and Neurodevelopmental Disorders

“…PTEN-ASD subjects and mice often develop (or are prone to) seizures, a condition of synchronized pathological firing, and it is accepted that neuronal hyperexcitability is a driving force for epileptogenesis. Aberrant circuitry of the dentate gyrus because of ectopic migration, hypertrophy, and hyperexcitability has been shown to result in increased spontaneous EPSCs, fewer iPSCs, and multiple population spikes and is also a wellknown factor for temporal lobe epilepsy (Nadler 2003;Pun et al 2012;LaSarge et al 2016;Santos et al 2017). From a molecular point of view, an involvement of potassium channels in hippocampal hyperexcitability of 8-week-old Pten f/f ; Gfap-cre mice has been implicated (Lugo et al 2014;Nguyen and Anderson 2018).…”

Signaling Pathways and Cellular Mechanisms Regulating Mossy Fiber Sprouting in the Development of Epilepsy

“…Deletion of PTEN from 2- to 4-week-old mice produces epilepsy in Nestin- and Gli1-Cre lines ( 88 , 89 ). PTEN deletion leads to granule cell mossy fiber axon abnormalities, with evidence for increased axon collateralization in the hilus and stratum lucidum ( 91 ) and the development of recurrent excitation in acute hippocampal slices ( 92 , 93 ). Epilepsy can develop in these animals, however, without robust mossy fiber sprouting ( 89 ).…”