Status Epilepticus-Induced Somatostatinergic Hilar Interneuron Degeneration Is Regulated by Striatal Enriched Protein Tyrosine Phosphatase

Abstract

Excitotoxic cell death is one of the precipitating events in the development of temporal lobe epilepsy. Of particular prominence is the loss of GABAergic hilar neurons. Although the molecular mechanisms responsible for the selective vulnerability of these cells are not well understood, activation of the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) pathway has been implicated in neuroprotective responses to excitotoxicity in other neuronal populations. Here, we report that high levels of the striatalenriched protein tyrosine phosphatase (STEP), a key regulator of ERK/MAPK signaling, are found in vulnerable somatostatinimmunoreactive hilar interneurons. Under both control conditions and after pilocarpine-induced status epilepticus (SE), ERK/MAPK activation was repressed in STEP-immunoreactive hilar neurons. This contrasts with robust SE-induced ERK/MAPK activation in the granule cell layer of the dentate gyrus, a cell region that does not express STEP. During pilocarpine-induced SE, in vivo disruption of STEP activity allowed activation of the MAPK pathway, leading to immediate-early gene expression and significant rescue from cell death. Thus, STEP increases the sensitivity of neurons to SE-induced excitotoxicity by specifically blocking a latent neuroprotective response initiated by the MAPK pathway. These findings identify a key set of signaling events that render somatostatinergic hilar interneurons vulnerable to SE-induced cell death.

Somatostatin: An endogenous antiepileptic

“…Shortly thereafter, this specific pattern of neuron loss was confirmed in humans with temporal lobe epilepsy (de Lanerolle et al, 1989), and an upregulation of SST binding sites in human tissue was also noted (Robbins et al, 1991). Since these first reports, the loss of SST-containing hilar interneurons has been observed in many animal models, including kainate Sperk et al, 1992) and pilocarpine (Choi et al, 2007;Kobayashi and Buckmaster, 2003), and is now considered a hallmark of epileptic hippocampus. In as little as 2 days after kainate injection, SST-positive neurons were dramatically decreased in the inner part of the hilus, while the number of SST-positive neurons remained unchanged in nearby polymorphic cell areas .…”

“…Furthermore, injection of the inhibitor was associated with an increase in phospho-ERK expression in hilar SST neurons, suggesting activation of ERK1/2. These observations, although intriguing, do not fully explain the differences in vulnerabililty of hilar SST neurons to seizure-induced death, since seizure-resistant SST neurons in CA1 also express STEP (Choi et al, 2007).…”

“…Another recent study points to a signaling cascade impacting the vulnerability of hilar SST neurons to seizure-induced death (Choi et al, 2007). Activation of the MAP kinase ERK1/2 has been shown to be neuroprotective (Hetman et al, 1999).…”

IGF‐1 receptor‐mediated ERK/MAPK signaling couples status epilepticus to progenitor cell proliferation in the subgranular layer of the dentate gyrus

“…7. Thus, SE-evoked glutamate release induces rapid neuronal injury, gliosis (Rizzi et al, 2003;Borges et al, 2003;Choi et al, 2007;Lee et al, 2007), and the induction of CREBdependent transcription in both neurons and glial populations . As a CREBtarget gene, IGF-1 expression is upregulated, and actuates cell proliferation via a MAPKdependent mechanism.…”

Future clinical prospects in somatostatin/cortistatin/somatostatin receptor field

“…Comparable results were found in animal models for epilepsy (Mitchell et al, 1995;Sloviter, 1987) in which SS containing neuronal loss can extend beyond the hilus to the rest of the hippocampus (Lahtinen et al, 1993). Recent studies have investigated the pathways involved in SS neuron loss in epilepsy, and it seems that the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) pathway may be involved (Choi et al, 2007). The function of these SS neurons and the consequences of their loss are unknown.…”