STEP regulation of seizure thresholds in the hippocampus

Abstract

SUMMARYPurpose: To investigate whether striatal enriched protein tyrosine phosphatase (STEP) influences ictogenesis. Methods: STEP knockout mice were compared to wildtype (WT) mice in pilocarpine-induced seizures. Hippocampal slices were also prepared from these two mouse populations, allowing the examination of ictal-like stimulation in these slices using calcium imaging and electrophysiologic recordings. Key Findings: To examine seizure thresholds, increasing doses of pilocarpine were administered to adult mice and seizures were scored behaviorally. Significantly fewer STEP knockout mice developed seizures that progressed to the stage of status epilepticus compared to WT mice.To examine potential differences in neural circuits that might account for this finding, seizure-like activity was induced in hippocampal slices. Electrical stimulation of the hippocampal-entorhinal cortex pathway in STEP knockout mice resulted in less activation of the dentate gyrus granule cell layer (GCL), but greater activation of the hilus in STEP knockouts, compared with heterozygous slices. Significance: STEP deficiency is associated with higher seizure thresholds. The locus of these effects appears to include the dentate gyrus granule cell layer and hilus.

Therapeutic Implications for Striatal-Enriched Protein Tyrosine Phosphatase (STEP) in Neuropsychiatric Disorders

“…Extensive colocalization of STEP with GAD65/67, a marker for GABAergic neurons, is found in hilar and stratum oriens interneurons of the hippocampus, where STEP modulates ERK1/2 activity (Choi et al, 2007). Moreover, loss of STEP reduces excitability of granule cell neurons and enhances excitability of hilar interneurons (Briggs et al, 2011). Taken together, these findings suggest that STEP contributes to the summation of excitatory and inhibitory input to control neuronal homeostasis.…”

“…Genetic ablation of STEP consistently renders mice more resistant to pilocarpine-induced SE than WT or heterozygous mice (Briggs et al, 2011). Using calcium imaging and cell-attached recordings, Briggs et al (2011) discovered that the basis for these findings is fold.…”

“…Using calcium imaging and cell-attached recordings, Briggs et al (2011) discovered that the basis for these findings is fold. During repetitive ictal-like stimulation, STEP KO granule cell neurons have reduced excitability, and inhibitory hilar interneurons show increased excitability.…”

“…Expanding upon the observation that STEP KO mice are more resistant to pilocarpine-induced seizures (Briggs et al, 2011), STEP/Fmr1 double KO mice exhibit fewer audiogenic seizures and fewer seizure-induced c-Fos-positive neurons in the periaqueductal gray relative to Fmr1 KOs (Goebel-Goody et al, 2010). Although a major thrust of drug discovery in FXS has focused on inhibitors of mGluRs, our findings implicate STEP as a potential target downstream of mGluR stimulation.…”

“…(SZ), fragile X syndrome (FXS), epileptogenesis, and alcohol-induced memory loss (Snyder et al, 2005;Choi et al, 2007;Correa et al, 2009;Carty et al, 2010;GoebelGoody et al, 2010;Kurup et al, 2010;Zhang et al, 2010;Briggs et al, 2011;Hicklin et al, 2011). On the other hand, too little STEP protein and/or activity can also negatively affect neuronal function and has been recently implicated in Huntington's disease (HD), drug abuse, stroke/ischemia, and inflammatory pain (Valjent et al, 2005;Braithwaite et al, 2008;Tashev et al, 2009;Xu et al, 2009;Saavedra et al, 2011;Yang et al, 2011).…”