Environmental Enrichment and Social Isolation Mediate Neuroplasticity of Medium Spiny Neurons Through the GSK3 Pathway

Overview

Journal Cell Rep

Publisher Cell Press

Specialties Biology
Cell Biology
Molecular Biology

Date 2018 Apr 12

PMID 29642012

Citations 31

Authors

Federico Scala

Miroslav N Nenov

Elizabeth J Crofton

Aditya K Singh

Oluwarotimi Folorunso

Yafang Zhang

Brent C Chesson

Norelle C Wildburger

Thomas F James

Musaad A Alshammari

Tahani K Alshammari

Hannah Elfrink

Claudio Grassi

James M Kasper

Ashley E Smith

Jonathan D Hommel

Cheryl F Lichti

Jai S Rudra

Marcello DAscenzo

Thomas A Green

Fernanda Laezza

Affiliations

Soon will be listed here.

Abstract

Resilience and vulnerability to neuropsychiatric disorders are linked to molecular changes underlying excitability that are still poorly understood. Here, we identify glycogen-synthase kinase 3β (GSK3β) and voltage-gated Na channel Nav1.6 as regulators of neuroplasticity induced by environmentally enriched (EC) or isolated (IC) conditions-models for resilience and vulnerability. Transcriptomic studies in the nucleus accumbens from EC and IC rats predicted low levels of GSK3β and SCN8A mRNA as a protective phenotype associated with reduced excitability in medium spiny neurons (MSNs). In vivo genetic manipulations demonstrate that GSK3β and Nav1.6 are molecular determinants of MSN excitability and that silencing of GSK3β prevents maladaptive plasticity of IC MSNs. In vitro studies reveal direct interaction of GSK3β with Nav1.6 and phosphorylation at Nav1.6 by GSK3β. A GSK3β-Nav1.6 competing peptide reduces MSNs excitability in IC, but not EC rats. These results identify GSK3β regulation of Nav1.6 as a biosignature of MSNs maladaptive plasticity.

Citing Articles

Axin-binding domain of glycogen synthase kinase 3β facilitates functional interactions with voltage-gated Na+ channel Na1.6.

Baumgartner T, Baumgartner T, Dvorak N, Dvorak N, Goode N, Goode N J Biol Chem. 2025; 301(2):108162.

PMID: 39793889 PMC: 11847078. DOI: 10.1016/j.jbc.2025.108162.

Crosstalk among WEE1 Kinase, AKT, and GSK3 in Nav1.2 Channelosome Regulation.

Singh A, Singh J, Goode N, Laezza F Int J Mol Sci. 2024; 25(15).

PMID: 39125637 PMC: 11311446. DOI: 10.3390/ijms25158069.

TNFR1 signaling converging on FGF14 controls neuronal hyperactivity and sickness behavior in experimental cerebral malaria.

Dvorak N, Domingo N, Tapia C, Wadsworth P, Marosi M, Avchalumov Y J Neuroinflammation. 2023; 20(1):306.

PMID: 38115011 PMC: 10729485. DOI: 10.1186/s12974-023-02992-7.

Fibroblast growth factor 13-mediated regulation of medium spiny neuron excitability and cocaine self-administration.

Dvorak N, Di Re J, Vasquez T, Marosi M, Shah P, Marmol Contreras Y Front Neurosci. 2023; 17:1294567.

PMID: 38099204 PMC: 10720079. DOI: 10.3389/fnins.2023.1294567.

Voltage-Gated Na Channels in Alzheimer's Disease: Physiological Roles and Therapeutic Potential.

Baumgartner T, Haghighijoo Z, Goode N, Dvorak N, Arman P, Laezza F Life (Basel). 2023; 13(8).

PMID: 37629512 PMC: 10455313. DOI: 10.3390/life13081655.

References

Shavkunov A, Wildburger N, Nenov M, James T, Buzhdygan T, Panova-Elektronova N . The fibroblast growth factor 14·voltage-gated sodium channel complex is a new target of glycogen synthase kinase 3 (GSK3). J Biol Chem. 2013; 288(27):19370-85. PMC: 3707642. DOI: 10.1074/jbc.M112.445924. View

Ataman B, Ashley J, Gorczyca M, Ramachandran P, Fouquet W, Sigrist S . Rapid activity-dependent modifications in synaptic structure and function require bidirectional Wnt signaling. Neuron. 2008; 57(5):705-18. PMC: 2435264. DOI: 10.1016/j.neuron.2008.01.026. View

Nishi A, Snyder G, Greengard P . Bidirectional regulation of DARPP-32 phosphorylation by dopamine. J Neurosci. 1997; 17(21):8147-55. PMC: 6573760. View

Scala F, Fusco S, Ripoli C, Piacentini R, Li Puma D, Spinelli M . Intraneuronal Aβ accumulation induces hippocampal neuron hyperexcitability through A-type K(+) current inhibition mediated by activation of caspases and GSK-3. Neurobiol Aging. 2014; 36(2):886-900. PMC: 4801354. DOI: 10.1016/j.neurobiolaging.2014.10.034. View

Royeck M, Horstmann M, Remy S, Reitze M, Yaari Y, Beck H . Role of axonal NaV1.6 sodium channels in action potential initiation of CA1 pyramidal neurons. J Neurophysiol. 2008; 100(4):2361-80. DOI: 10.1152/jn.90332.2008. View

Hu X, Dong Y, Zhang X, White F . Dopamine D2 receptor-activated Ca2+ signaling modulates voltage-sensitive sodium currents in rat nucleus accumbens neurons. J Neurophysiol. 2004; 93(3):1406-17. DOI: 10.1152/jn.00771.2004. View

Osorio N, Cathala L, Meisler M, Crest M, Magistretti J, Delmas P . Persistent Nav1.6 current at axon initial segments tunes spike timing of cerebellar granule cells. J Physiol. 2010; 588(Pt 4):651-70. PMC: 2828138. DOI: 10.1113/jphysiol.2010.183798. View

Baek J, Cerda O, Trimmer J . Mass spectrometry-based phosphoproteomics reveals multisite phosphorylation on mammalian brain voltage-gated sodium and potassium channels. Semin Cell Dev Biol. 2010; 22(2):153-9. PMC: 3043121. DOI: 10.1016/j.semcdb.2010.09.009. View

Hu W, Tian C, Li T, Yang M, Hou H, Shu Y . Distinct contributions of Na(v)1.6 and Na(v)1.2 in action potential initiation and backpropagation. Nat Neurosci. 2009; 12(8):996-1002. DOI: 10.1038/nn.2359. View

10.

Hur E, Zhou F . GSK3 signalling in neural development. Nat Rev Neurosci. 2010; 11(8):539-51. PMC: 3533361. DOI: 10.1038/nrn2870. View

11.

Li Y, Gao W . GSK-3β activity and hyperdopamine-dependent behaviors. Neurosci Biobehav Rev. 2010; 35(3):645-54. PMC: 2997336. DOI: 10.1016/j.neubiorev.2010.08.001. View

12.

Crofton E, Zhang Y, Green T . Inoculation stress hypothesis of environmental enrichment. Neurosci Biobehav Rev. 2014; 49:19-31. PMC: 4305384. DOI: 10.1016/j.neubiorev.2014.11.017. View

13.

Li X, Jope R . Is glycogen synthase kinase-3 a central modulator in mood regulation?. Neuropsychopharmacology. 2010; 35(11):2143-54. PMC: 3055312. DOI: 10.1038/npp.2010.105. View

14.

Onwuli D, Beltran-Alvarez P . An update on transcriptional and post-translational regulation of brain voltage-gated sodium channels. Amino Acids. 2015; 48(3):641-651. PMC: 4752963. DOI: 10.1007/s00726-015-2122-y. View

15.

Bessa J, Morais M, Marques F, Pinto L, Palha J, Almeida O . Stress-induced anhedonia is associated with hypertrophy of medium spiny neurons of the nucleus accumbens. Transl Psychiatry. 2013; 3:e266. PMC: 3693402. DOI: 10.1038/tp.2013.39. View

16.

Yan H, Wang C, Marx S, Pitt G . Calmodulin limits pathogenic Na+ channel persistent current. J Gen Physiol. 2017; 149(2):277-293. PMC: 5299624. DOI: 10.1085/jgp.201611721. View

17.

Dunleavy M, Provenzano G, Henshall D, Bozzi Y . Kainic acid-induced seizures modulate Akt (SER473) phosphorylation in the hippocampus of dopamine D2 receptor knockout mice. J Mol Neurosci. 2012; 49(1):202-10. PMC: 3532719. DOI: 10.1007/s12031-012-9927-x. View

18.

Lichti C, Fan X, English R, Zhang Y, Li D, Kong F . Environmental enrichment alters protein expression as well as the proteomic response to cocaine in rat nucleus accumbens. Front Behav Neurosci. 2014; 8:246. PMC: 4104784. DOI: 10.3389/fnbeh.2014.00246. View

19.

Ochs S, Dorostkar M, Aramuni G, Schon C, Filser S, Poschl J . Loss of neuronal GSK3β reduces dendritic spine stability and attenuates excitatory synaptic transmission via β-catenin. Mol Psychiatry. 2014; 20(4):482-9. PMC: 4378257. DOI: 10.1038/mp.2014.55. View

20.

Wilkinson M, Dias C, Magida J, Mazei-Robison M, Lobo M, Kennedy P . A novel role of the WNT-dishevelled-GSK3β signaling cascade in the mouse nucleus accumbens in a social defeat model of depression. J Neurosci. 2011; 31(25):9084-92. PMC: 3133937. DOI: 10.1523/JNEUROSCI.0039-11.2011. View