Elsevier

Neuroscience

Volume 208, 19 April 2012, Pages 58-68
Neuroscience

Cognitive, Behavioral, and Systems Neuroscience
Research Paper
Deletion of selenoprotein P results in impaired function of parvalbumin interneurons and alterations in fear learning and sensorimotor gating

https://doi.org/10.1016/j.neuroscience.2012.02.017Get rights and content

Abstract

One of the primary lines of defense against oxidative stress is the selenoprotein family, a class of proteins that contain selenium in the form of the 21st amino acid, selenocysteine. Within this class of proteins, selenoprotein P (Sepp1) is unique, as it contains multiple selenocysteine residues and is postulated to act in selenium transport. Recent findings have demonstrated that neuronal selenoprotein synthesis is required for the development of parvalbumin (PV)-interneurons, a class of GABAergic neurons involved in the synchronization of neural activity. To investigate the potential influence of Sepp1 on PV-interneurons, we first mapped the distribution of the Sepp1 receptor, ApoER2, and parvalbumin in the mouse brain. Our results indicate that ApoER2 is highly expressed on PV-interneurons in multiple brain regions. Next, to determine whether PV-interneuron populations are affected by Sepp1 deletion, we performed stereology on several brain regions in which we observed ApoER2 expression on PV-interneurons, comparing wild-type and Sepp1−/− mice. We observed reduced numbers of PV-interneurons in the inferior colliculus of Sepp1−/− mice, which corresponded with a regional increase in oxidative stress. Finally, as impaired PV-interneuron function has been implicated in several neuropsychiatric conditions, we performed multiple behavioral tests on Sepp1−/− mice. Our behavioral results indicate that Sepp1−/− mice have impairments in contextual fear extinction, latent inhibition, and sensorimotor gating. In sum, these findings demonstrate the important supporting role of Sepp1 on ApoER2-expressing PV-interneurons.

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.

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