A Novel Role for Phospholamban in the Thalamic Reticular Nucleus

Overview

Journal Sci Rep

Specialty Science

Date 2024 Mar 17

PMID 38493225

Authors

Benjamin Klocke

Aikaterini Britzolaki

Joseph Saurine

Hayden Ott

Kylie Krone

Kiara Bahamonde

Connor Thelen

Christos Tzimas

Despina Sanoudou

Evangelia G Kranias

Pothitos M Pitychoutis

Affiliations

Soon will be listed here.

Abstract

The thalamic reticular nucleus (TRN) is a brain region that influences vital neurobehavioral processes, including executive functioning and the generation of sleep rhythms. TRN dysfunction underlies hyperactivity, attention deficits, and sleep disturbances observed across various neurodevelopmental disorders. A specialized sarco-endoplasmic reticulum calcium (Ca) ATPase 2 (SERCA2)-dependent Ca signaling network operates in the dendrites of TRN neurons to regulate their bursting activity. Phospholamban (PLN) is a prominent regulator of SERCA2 with an established role in myocardial Ca-cycling. Our findings suggest that the role of PLN extends beyond the cardiovascular system to impact brain function. Specifically, we found PLN to be expressed in TRN neurons of the adult mouse brain, and utilized global constitutive and innovative conditional genetic knockout mouse models in concert with electroencephalography (EEG)-based somnography and the 5-choice serial reaction time task (5-CSRTT) to investigate the role of PLN in sleep and executive functioning, two complex behaviors that map onto thalamic reticular circuits. The results of the present study indicate that perturbed PLN function in the TRN results in aberrant TRN-dependent phenotypes in mice (i.e., hyperactivity, impulsivity and sleep deficits) and support a novel role for PLN as a critical regulator of SERCA2 in the TRN neurocircuitry.

References

Wolff M, Savova M, Malleret G, Segu L, Buhot M . Differential learning abilities of 129T2/Sv and C57BL/6J mice as assessed in three water maze protocols. Behav Brain Res. 2002; 136(2):463-74. DOI: 10.1016/s0166-4328(02)00192-4. View

Maclennan D, Brandl C, Korczak B, Green N . Amino-acid sequence of a Ca2+ + Mg2+-dependent ATPase from rabbit muscle sarcoplasmic reticulum, deduced from its complementary DNA sequence. Nature. 1985; 316(6030):696-700. DOI: 10.1038/316696a0. View

Wang Y, He J, Kastin A, Hsuchou H, Pan W . Hypersomnolence and reduced activity in pan-leptin receptor knockout mice. J Mol Neurosci. 2013; 51(3):1038-45. PMC: 3797855. DOI: 10.1007/s12031-013-0093-6. View

Chu G, Luo W, Slack J, Tilgmann C, Sweet W, Spindler M . Compensatory mechanisms associated with the hyperdynamic function of phospholamban-deficient mouse hearts. Circ Res. 1996; 79(6):1064-76. DOI: 10.1161/01.res.79.6.1064. View

Chu G, Kerr J, Mitton B, Egnaczyk G, Vazquez J, Shen M . Proteomic analysis of hyperdynamic mouse hearts with enhanced sarcoplasmic reticulum calcium cycling. FASEB J. 2004; 18(14):1725-7. DOI: 10.1096/fj.04-2025fje. View

Van Den Bosch L, Wuytack F, Raeymaekers L, Casteels R . Regulation of the sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA) 2 gene transcript in neuronal cells. Brain Res Mol Brain Res. 1998; 55(1):92-100. DOI: 10.1016/s0165-3806(98)80015-6. View

Houser C, Vaughn J, Barber R, Roberts E . GABA neurons are the major cell type of the nucleus reticularis thalami. Brain Res. 1980; 200(2):341-54. DOI: 10.1016/0006-8993(80)90925-7. View

Coulon P, Herr D, Kanyshkova T, Meuth P, Budde T, Pape H . Burst discharges in neurons of the thalamic reticular nucleus are shaped by calcium-induced calcium release. Cell Calcium. 2009; 46(5-6):333-46. DOI: 10.1016/j.ceca.2009.09.005. View

Boutrel B, Franc B, Hen R, Hamon M, Adrien J . Key role of 5-HT1B receptors in the regulation of paradoxical sleep as evidenced in 5-HT1B knock-out mice. J Neurosci. 1999; 19(8):3204-12. PMC: 6782285. View

10.

Nensa F, Neumann M, Schrotter A, Przyborski A, Mastalski T, Susdalzew S . Amyloid beta a4 precursor protein-binding family B member 1 (FE65) interactomics revealed synaptic vesicle glycoprotein 2A (SV2A) and sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2) as new binding proteins in the human brain. Mol Cell Proteomics. 2013; 13(2):475-88. PMC: 3916648. DOI: 10.1074/mcp.M113.029280. View

11.

Raeymaekers L, Wuytack F, de Greef C, Missiaen L, Casteels R . Distribution of the organellar Ca2+ transport ATPase SERCA2 isoforms in the cat brain. Brain Res. 1996; 743(1-2):141-53. DOI: 10.1016/s0006-8993(96)01037-2. View

12.

Britzolaki A, Cronin C, Flaherty P, Rufo R, Pitychoutis P . Chronic but not acute pharmacological activation of SERCA induces behavioral and neurochemical effects in male and female mice. Behav Brain Res. 2020; 399:112984. PMC: 7855138. DOI: 10.1016/j.bbr.2020.112984. View

13.

Uhlen M, Fagerberg L, Hallstrom B, Lindskog C, Oksvold P, Mardinoglu A . Proteomics. Tissue-based map of the human proteome. Science. 2015; 347(6220):1260419. DOI: 10.1126/science.1260419. View

14.

Belarbi K, Burnouf S, Fernandez-Gomez F, Laurent C, Lestavel S, Figeac M . Beneficial effects of exercise in a transgenic mouse model of Alzheimer's disease-like Tau pathology. Neurobiol Dis. 2011; 43(2):486-94. DOI: 10.1016/j.nbd.2011.04.022. View

15.

Haeussler M, Schonig K, Eckert H, Eschstruth A, Mianne J, Renaud J . Evaluation of off-target and on-target scoring algorithms and integration into the guide RNA selection tool CRISPOR. Genome Biol. 2016; 17(1):148. PMC: 4934014. DOI: 10.1186/s13059-016-1012-2. View

16.

Pitychoutis P, Pallis E, Mikail H, Papadopoulou-Daifoti Z . Individual differences in novelty-seeking predict differential responses to chronic antidepressant treatment through sex- and phenotype-dependent neurochemical signatures. Behav Brain Res. 2011; 223(1):154-68. DOI: 10.1016/j.bbr.2011.04.036. View

17.

Gerfen C, Surmeier D . Modulation of striatal projection systems by dopamine. Annu Rev Neurosci. 2011; 34:441-66. PMC: 3487690. DOI: 10.1146/annurev-neuro-061010-113641. View

18.

Zhang Y, Chen K, Sloan S, Bennett M, Scholze A, OKeeffe S . An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J Neurosci. 2014; 34(36):11929-47. PMC: 4152602. DOI: 10.1523/JNEUROSCI.1860-14.2014. View

19.

McKee S, Grissom N, Herdt C, Reyes T . Methyl donor supplementation alters cognitive performance and motivation in female offspring from high-fat diet-fed dams. FASEB J. 2017; 31(6):2352-2363. PMC: 5434647. DOI: 10.1096/fj.201601172R. View

20.

Cederlof M, Bergen S, Langstrom N, Larsson H, Boman M, Craddock N . The association between Darier disease, bipolar disorder, and schizophrenia revisited: a population-based family study. Bipolar Disord. 2014; 17(3):340-4. DOI: 10.1111/bdi.12257. View