Cognitive, Behavioral, and Systems NeuroscienceResearch PaperDeletion of selenoprotein P results in impaired function of parvalbumin interneurons and alterations in fear learning and sensorimotor gating
Highlights
▶The receptor for selenoprotein P (Sepp1), ApoER2, is highly expressed on parvalbumin (PV)-interneurons. ▶Sepp1−/− mice have reduced numbers of PV-interneurons in the inferior colliculus, which corresponds with a regional increase in oxidative stress. ▶Sepp1−/− mice display deficits in contextual fear extinction, latent inhibition, and sensorimotor gating.
Section snippets
Animals
Sepp1−/− mice and Sepp1+/+ littermates were generated from crosses of heterozygous Sepp1+/− mice on a C57BL/6 background at the University of Hawaii Animal Facility. Mice were fed a selenium-adequate (0.25 mg Se/kg) diet and housed on a 12/12-h light/dark cycle. Animals were group housed until 10–12 weeks of age and then single-housed for 7–10 days to acclimatize before behavioral experiments. All behavioral experiments were conducted on single-housed adult mice aged 12–16 weeks during the
ApoER2 is highly expressed on PV-interneurons
There is evidence that PV-interneurons are particularly sensitive to oxidative stress (Behrens et al., 2007, Behrens et al., 2008, Wang et al., 2011) and recently selenoprotein synthesis has been implicated as a critical factor for the function of this important class of interneurons (Wirth et al., 2010). However, the functional relationship between the putative selenium transport protein, Sepp1, and PV-interneurons has not been clearly defined. Therefore, using immunohistochemistry, we mapped
Discussion
In summary, our main findings are as follows: first, the Sepp1 receptor, ApoER2, is highly expressed on PV-interneurons. Second, Sepp1 deletion results in elevated oxidative damage and diminished PV expression in the inferior colliculus. Finally, behavioral studies showed that Sepp1−/− mice exhibit impairments in contextual fear extinction, latent inhibition, and sensorimotor gating.
ApoER2 is a multifunctional member of the low-density lipoprotein (LDL) receptor family that binds apolipoprotein
Conclusion
This report details the neuroprotective role of ApoER2-mediated uptake of Sepp1 on PV-interneurons. We hypothesize that the behavioral deficits we observed, as well as those previously reported (Hill et al., 2004, Peters et al., 2006), are largely due to diminished integrity of PV-interneuron networks. Previous studies (Valentine et al., 2008) and our findings together indicate that ApoER2-mediated uptake of Sepp1 serves an important neuroprotective role in the inferior colliculus. Yet, the
Acknowledgments
This work was supported by National Institute of Health grants DK47320, NS40302, and RR003061.
References (45)
- et al.
Does schizophrenia arise from oxidative dysregulation of parvalbumin-interneurons in the developing cortex?
Neuropharmacology
(2009) - et al.
Oxidative stress in schizophrenia: an integrated approach
Neurosci Biobehav Rev
(2011) - et al.
GABAergic regulation of the neural organization of fear in the midbrain tectum
Neurosci Biobehav Rev
(2005) - et al.
Defense reaction induced by microinjections of bicuculline into the inferior colliculus
Physiol Behav
(1988) - et al.
Selenoprotein P—expression, functions, and roles in mammals
Biochim Biophys Acta
(2009) - et al.
Progression of neurodegeneration and morphologic changes in the brains of juvenile mice with selenoprotein P deleted
Brain Res
(2011) - et al.
Expression and alternate splicing of apolipoprotein receptor 2 in brain
Neuroscience
(1999) - et al.
Redox dysregulation, neurodevelopment, and schizophrenia
Curr Opin Neurobiol
(2009) Role of GABA abnormalities in the inferior colliculus pathophysiology—audiogenic seizures
Hear Res
(2002)- et al.
Loss of intensity-induced inhibition in inferior colliculus neurons leads to audiogenic seizure susceptibility in behaving genetically epilepsy-prone rats
Exp Neurol
(1991)