Forebrain-specific ablation of phospholipase Cγ1 causes manic-like behavior

Abstract

Manic episodes are one of the major diagnostic symptoms in a spectrum of neuropsychiatric disorders that include schizophrenia, obsessive-compulsive disorder and bipolar disorder (BD). Despite a possible association between BD and the gene encoding phospholipase Cγ1 (PLCG1), its etiological basis remains unclear. Here, we report that mice lacking phospholipase Cγ1 (PLCγ1) in the forebrain (Plcg1f/f; CaMKII) exhibit hyperactivity, decreased anxiety-like behavior, reduced depressive-related behavior, hyperhedonia, hyperphagia, impaired learning and memory and exaggerated startle responses. Inhibitory transmission in hippocampal pyramidal neurons and striatal dopamine receptor D1-expressing neurons of Plcg1-deficient mice was significantly reduced. The decrease in inhibitory transmission is likely due to a reduced number of γ-aminobutyric acid (GABA)-ergic boutons, which may result from impaired localization and/or stabilization of postsynaptic CaMKII (Ca2+/calmodulin-dependent protein kinase II) at inhibitory synapses. Moreover, mutant mice display impaired brain-derived neurotrophic factor-tropomyosin receptor kinase B-dependent synaptic plasticity in the hippocampus, which could account for deficits of spatial memory. Lithium and valproate, the drugs presently used to treat mania associated with BD, rescued the hyperactive phenotypes of Plcg1f/f; CaMKII mice. These findings provide evidence that PLCγ1 is critical for synaptic function and plasticity and that the loss of PLCγ1 from the forebrain results in manic-like behavior.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

References

  1. 1

    Greer PL, Greenberg ME . From synapse to nucleus: calcium-dependent gene transcription in the control of synapse development and function. Neuron 2008; 59: 846–860.

    CAS  Article  Google Scholar 

  2. 2

    Rantamaki T, Hendolin P, Kankaanpaa A, Mijatovic J, Piepponen P, Domenici E et al. Pharmacologically diverse antidepressants rapidly activate brain-derived neurotrophic factor receptor TrkB and induce phospholipase-Cγ signaling pathways in mouse brain. Neuropsychopharmacology 2007; 32: 2152–2162.

    CAS  Article  Google Scholar 

  3. 3

    Gu B, Huang YZ, He XP, Joshi RB, Jang W, McNamara JO . A peptide uncoupling BDNF receptor TrkB from phospholipase Cγ1 prevents epilepsy induced by status epilepticus. Neuron 2015; 88: 484–491.

    CAS  Article  Google Scholar 

  4. 4

    Turecki G, Grof P, Cavazzoni P, Duffy A, Grof E, Ahrens B et al. Evidence for a role of phospholipase C-γ1 in the pathogenesis of bipolar disorder. Mol Psychiatry 1998; 3: 534–538.

    CAS  Article  Google Scholar 

  5. 5

    Lovlie R, Berle JO, Stordal E, Steen VM . The phospholipase C-γ1 gene (PLCG1) and lithium-responsive bipolar disorder: re-examination of an intronic dinucleotide repeat polymorphism. Psychiatr Genet 2001; 11: 41–43.

    CAS  Article  Google Scholar 

  6. 6

    Serretti A, Mandelli L . The genetics of bipolar disorder: genome 'hot regions,' genes, new potential candidates and future directions. Mol Psychiatry 2008; 13: 742–771.

    CAS  Article  Google Scholar 

  7. 7

    Nurnberger JI Jr, Koller DL, Jung J, Edenberg HJ, Foroud T, Guella I et al. Identification of pathways for bipolar disorder: a meta-analysis. JAMA Psychiatry 2014; 71: 657–664.

    CAS  Article  Google Scholar 

  8. 8

    Hou L, Heilbronner U, Degenhardt F, Adli M, Akiyama K, Akula N et al. Genetic variants associated with response to lithium treatment in bipolar disorder: a genome-wide association study. Lancet 2016; 387: 1085–1093.

    CAS  Article  Google Scholar 

  9. 9

    Radhakrishna U, Senol S, Herken H, Gucuyener K, Gehrig C, Blouin JL et al. An apparently dominant bipolar affective disorder (BPAD) locus on chromosome 20p11.2-q11.2 in a large Turkish pedigree. Eur J Hum Genet 2001; 9: 39–44.

    CAS  Article  Google Scholar 

  10. 10

    Berridge MJ, Downes CP, Hanley MR . Neural and developmental actions of lithium: a unifying hypothesis. Cell 1989; 59: 411–419.

    CAS  Article  Google Scholar 

  11. 11

    Park H, Poo MM . Neurotrophin regulation of neural circuit development and function. Nat Rev Neurosci 2013; 14: 7–23.

    CAS  Article  Google Scholar 

  12. 12

    Okada T, Hashimoto R, Numakawa T, Iijima Y, Kosuga A, Tatsumi M et al. A complex polymorphic region in the brain-derived neurotrophic factor (BDNF) gene confers susceptibility to bipolar disorder and affects transcriptional activity. Mol Psychiatry 2006; 11: 695–703.

    CAS  Article  Google Scholar 

  13. 13

    Sklar P, Gabriel SB, McInnis MG, Bennett P, Lim Y, Tsan G et al. Family-based association study of 76 candidate genes in bipolar disorder: BDNF is a potential risk locus. Brain-derived neutrophic factor. Mol Psychiatry 2002; 7: 579–593.

    CAS  Article  Google Scholar 

  14. 14

    Chen G, Henter ID, Manji HK . Translational research in bipolar disorder: emerging insights from genetically based models. Mol Psychiatry 2010; 15: 883–895.

    CAS  Article  Google Scholar 

  15. 15

    Minichiello L, Korte M, Wolfer D, Kuhn R, Unsicker K, Cestari V et al. Essential role for TrkB receptors in hippocampus-mediated learning. Neuron 1999; 24: 401–414.

    CAS  Article  Google Scholar 

  16. 16

    Tronche F, Kellendonk C, Kretz O, Gass P, Anlag K, Orban PC et al. Disruption of the glucocorticoid receptor gene in the nervous system results in reduced anxiety. Nat Genet 1999; 23: 99–103.

    CAS  Article  Google Scholar 

  17. 17

    Jia Y, Zhou J, Tai Y, Wang Y . TRPC channels promote cerebellar granule neuron survival. Nat Neurosci 2007; 10: 559–567.

    CAS  Article  Google Scholar 

  18. 18

    Trovo L, Ahmed T, Callaerts-Vegh Z, Buzzi A, Bagni C, Chuah M et al. Low hippocampal PI(4,5)P-2 contributes to reduced cognition in old mice as a result of loss of MARCKS. Nat Neurosci 2013; 16: 449–455.

    CAS  Article  Google Scholar 

  19. 19

    Ji QS, Winnier GE, Niswender KD, Horstman D, Wisdom R, Magnuson MA et al. Essential role of the tyrosine kinase substrate phospholipase C-γ1 in mammalian growth and development. Proc Natl Acad Sci USA 1997; 94: 2999–3003.

    CAS  Article  Google Scholar 

  20. 20

    Gruart A, Sciarretta C, Valenzuela-Harrington M, Delgado-Garcia JM, Minichiello L . Mutation at the TrkB PLCγ-docking site affects hippocampal LTP and associative learning in conscious mice. Learn Mem 2007; 14: 54–62.

    Article  Google Scholar 

  21. 21

    Minichiello L, Calella AM, Medina DL, Bonhoeffer T, Klein R, Korte M . Mechanism of TrkB-mediated hippocampal long-term potentiation. Neuron 2002; 36: 121–137.

    CAS  Article  Google Scholar 

  22. 22

    Bender RE, Alloy LB . Life stress and kindling in bipolar disorder: review of the evidence and integration with emerging biopsychosocial theories. Clin Psychol Rev 2011; 31: 383–398.

    Article  Google Scholar 

  23. 23

    Leussis MP, Berry-Scott EM, Saito M, Jhuang H, de Haan G, Alkan O et al. The ANK3 bipolar disorder gene regulates psychiatric-related behaviors that are modulated by lithium and stress. Biol Psychiatry 2013; 73: 683–690.

    CAS  Article  Google Scholar 

  24. 24

    Le-Niculescu H, McFarland MJ, Ogden CA, Balaraman Y, Patel S, Tan J et al. Phenomic, convergent functional genomic, and biomarker studies in a stress-reactive genetic animal model of bipolar disorder and co-morbid alcoholism. Am J Med Genet B 2008; 147B: 134–166.

    CAS  Article  Google Scholar 

  25. 25

    Kravitz AV, Freeze BS, Parker PR, Kay K, Thwin MT, Deisseroth K et al. Regulation of parkinsonian motor behaviours by optogenetic control of basal ganglia circuitry. Nature 2010; 466: 622–626.

    CAS  Article  Google Scholar 

  26. 26

    Knable MB, Barci BM, Webster MJ, Meador-Woodruff J, Torrey EF . Molecular abnormalities of the hippocampus in severe psychiatric illness: postmortem findings from the Stanley Neuropathology Consortium. Mol Psychiatry 2004; 9: 609–620.

    CAS  Article  Google Scholar 

  27. 27

    Hu H, Gan J, Jonas P . Interneurons. Fast-spiking, parvalbumin(+) GABAergic interneurons: from cellular design to microcircuit function. Science 2014; 345: 1255263.

    Article  Google Scholar 

  28. 28

    Korte M, Minichiello L, Klein R, Bonhoeffer T . SHC-binding site in the TRKB receptor is not required tor hippocampal long-term potentiation. Neuropharmacology 2000; 39: 717–724.

    CAS  Article  Google Scholar 

  29. 29

    Gartner A, Polnau DG, Staiger V, Sciarretta C, Minichiello L, Thoenen H et al. Hippocampal long-term potentiation is supported by presynaptic and postsynaptic tyrosine receptor kinase B-mediated phospholipase Cγ signaling. J Neurosci 2006; 26: 3496–3504.

    Article  Google Scholar 

  30. 30

    Kang H, Welcher AA, Shelton D, Schuman EM . Neurotrophins and time: different roles for TrkB signaling in hippocampal long-term potentiation. Neuron 1997; 19: 653–664.

    CAS  Article  Google Scholar 

  31. 31

    Patterson SL, Pittenger C, Morozov A, Martin KC, Scanlin H, Drake C et al. Some forms of cAMP-mediated long-lasting potentiation are associated with release of BDNF and nuclear translocation of phospho-MAP kinase. Neuron 2001; 32: 123–140.

    CAS  Article  Google Scholar 

  32. 32

    Ji Y, Lu Y, Yang F, Shen W, Tang TT, Feng L et al. Acute and gradual increases in BDNF concentration elicit distinct signaling and functions in neurons. Nat Neurosci 2010; 13: 302–309.

    CAS  Article  Google Scholar 

  33. 33

    Jang SW, Liu X, Yepes M, Shepherd KR, Miller GW, Liu Y et al. A selective TrkB agonist with potent neurotrophic activities by 7,8-dihydroxyflavone. Proc Natl Acad Sci USA 2010; 107: 2687–2692.

    CAS  Article  Google Scholar 

  34. 34

    Rose CR, Blum R, Pichler B, Lepier A, Kafitz KW, Konnerth A . Truncated TrkB-T1 mediates neurotrophin-evoked calcium signalling in glia cells. Nature 2003; 426: 74–78.

    CAS  Article  Google Scholar 

  35. 35

    Zimmerman L, Parr B, Lendahl U, Cunningham M, McKay R, Gavin B et al. Independent regulatory elements in the nestin gene direct transgene expression to neural stem cells or muscle precursors. Neuron 1994; 12: 11–24.

    CAS  Article  Google Scholar 

  36. 36

    van Rossum DB, Patterson RL, Sharma S, Barrow RK, Kornberg M, Gill DL et al. Phospholipase Cγ1 controls surface expression of TRPC3 through an intermolecular PH domain. Nature 2005; 434: 99–104.

    CAS  Article  Google Scholar 

  37. 37

    Houston CM, He Q, Smart TG . CaMKII phosphorylation of the GABA(A) receptor: receptor subtype- and synapse-specific modulation. J Physiol 2009; 587: 2115–2125.

    CAS  Article  Google Scholar 

  38. 38

    Klausberger T, Roberts JDB, Somogyi P . Cell type- and input-specific differences in the number and subtypes of synaptic GABA(A) receptors in the hippocampus. J Neurosci 2002; 22: 2513–2521.

    CAS  Article  Google Scholar 

  39. 39

    Brickley SG, Mody I . Extrasynaptic GABA(A) receptors: their function in the CNS and implications for disease. Neuron 2012; 73: 23–34.

    CAS  Article  Google Scholar 

  40. 40

    Hofmann T, Obukhov AG, Schaefer M, Harteneck C, Gudermann T, Schultz G . Direct activation of human TRPC6 and TRPC3 channels by diacylglycerol. Nature 1999; 397: 259–263.

    CAS  Article  Google Scholar 

  41. 41

    Scheffer RE . Concurrent ADHD and bipolar disorder. Curr Psychiatry Rep 2007; 9: 415–419.

    Article  Google Scholar 

  42. 42

    Barkley RA . Attention Deficit Hyperactivity Disorder in Adults: The Latest Assessment and Treatment Strategies, vol. vi. Jones and Bartlett Publishers: Sudbury, MA, USA, 2010, p 81.

    Google Scholar 

  43. 43

    Won H, Mah W, Kim E, Kim JW, Hahm EK, Kim MH et al. GIT1 is associated with ADHD in humans and ADHD-like behaviors in mice. Nat Med 2011; 17: 566–572.

    CAS  Article  Google Scholar 

  44. 44

    Anand A, Verhoeff P, Seneca N, Zoghbi SS, Seibyl JP, Charney DS et al. Brain SPECT imaging of amphetamine-induced dopamine release in euthymic bipolar disorder patients. Am J Psychiatry 2000; 157: 1108–1114.

    CAS  Article  Google Scholar 

  45. 45

    Shaltiel G, Maeng S, Malkesman O, Pearson B, Schloesser RJ, Tragon T et al. Evidence for the involvement of the kainate receptor subunit GluR6 (GRIK2) in mediating behavioral displays related to behavioral symptoms of mania. Mol psychiatry 2008; 13: 858–872.

    CAS  Article  Google Scholar 

  46. 46

    Engel SR, Creson TK, Hao Y, Shen Y, Maeng S, Nekrasova T et al. The extracellular signal-regulated kinase pathway contributes to the control of behavioral excitement. Mol Psychiatry 2009; 14: 448–461.

    CAS  Article  Google Scholar 

  47. 47

    Roybal K, Theobold D, Graham A, DiNieri JA, Russo SJ, Krishnan V et al. Mania-like behavior induced by disruption of CLOCK. Proc Natl Acad Sci USA 2007; 104: 6406–6411.

    CAS  Article  Google Scholar 

  48. 48

    Han K, Holder JL Jr, Schaaf CP, Lu H, Chen H, Kang H et al. SHANK3 overexpression causes manic-like behaviour with unique pharmacogenetic properties. Nature 2013; 503: 72–77.

    CAS  Article  Google Scholar 

  49. 49

    Ryan MM, Lockstone HE, Huffaker SJ, Wayland MT, Webster MJ, Bahn S . Gene expression analysis of bipolar disorder reveals downregulation of the ubiquitin cycle and alterations in synaptic genes. Mol Psychiatry 2006; 11: 965–978.

    CAS  Article  Google Scholar 

  50. 50

    Ting JT, Peca J, Feng G . Functional consequences of mutations in postsynaptic scaffolding proteins and relevance to psychiatric disorders. Annu Rev Neurosci 2012; 35: 49–71.

    CAS  Article  Google Scholar 

  51. 51

    Minichiello L . TrkB signalling pathways in LTP and learning. Nat Rev Neurosci 2009; 10: 850–860.

    CAS  Article  Google Scholar 

  52. 52

    Frerking M, Malenka RC, Nicoll RA . Brain-derived neurotrophic factor (BDNF) modulates inhibitory, but not excitatory, transmission in the CA1 region of the hippocampus. J Neurophysiol 1998; 80: 3383–3386.

    CAS  Article  Google Scholar 

  53. 53

    Marsden KC, Shemesh A, Bayer KU, Carroll RC . Selective translocation of Ca2+/calmodulin protein kinase IIalpha (CaMKIIalpha) to inhibitory synapses. Proc Natl Acad Sci USA 2010; 107: 20559–20564.

    CAS  Article  Google Scholar 

  54. 54

    Yizhar O, Fenno LE, Prigge M, Schneider F, Davidson TJ, O'Shea DJ et al. Neocortical excitation/inhibition balance in information processing and social dysfunction. Nature 2011; 477: 171–178.

    CAS  Article  Google Scholar 

  55. 55

    Uhlhaas PJ, Singer W . Neuronal dynamics and neuropsychiatric disorders: toward a translational paradigm for dysfunctional large-scale networks. Neuron 2012; 75: 963–980.

    CAS  Article  Google Scholar 

  56. 56

    Benes FM, Lim B, Matzilevich D, Walsh JP, Subburaju S, Minns M . Regulation of the GABA cell phenotype in hippocampus of schizophrenics and bipolars. Proc Natl Acad Sci USA 2007; 104: 10164–10169.

    CAS  Article  Google Scholar 

  57. 57

    Yong W, Zhang MM, Wang S, Ruan DY . Effects of sodium valproate on synaptic transmission and neuronal excitability in rat hippocampus. Clin Exp Pharmacol Physiol 2009; 36: 1062–1067.

    CAS  Article  Google Scholar 

  58. 58

    Lee SH, Sohn JW, Ahn SC, Park WS, Ho WK . Li+ enhances GABAergic inputs to granule cells in the rat hippocampal dentate gyrus. Neuropharmacology 2004; 46: 638–646.

    CAS  Article  Google Scholar 

  59. 59

    Mei L, Nave KA . Neuregulin-ERBB signaling in the nervous system and neuropsychiatric diseases. Neuron 2014; 83: 27–49.

    CAS  Article  Google Scholar 

  60. 60

    Thomson PA, Christoforou A, Morris SW, Adie E, Pickard BS, Porteous DJ et al. Association of neuregulin 1 with schizophrenia and bipolar disorder in a second cohort from the Scottish population. Mol Psychiatry 2007; 12: 94–104.

    CAS  Article  Google Scholar 

  61. 61

    Meier S, Strohmaier J, Breuer R, Mattheisen M, Degenhardt F, Muhleisen TW et al. Neuregulin 3 is associated with attention deficits in schizophrenia and bipolar disorder. Int J Neuropsychopharmacol 2013; 16: 549–556.

    CAS  Article  Google Scholar 

  62. 62

    Yang YR, Choi JH, Chang JS, Kwon HM, Jang HJ, Ryu SH et al. Diverse cellular and physiological roles of phospholipase C-γ1. Adv Biol Regul 2012; 52: 138–151.

    CAS  Article  Google Scholar 

Download references

Acknowledgements

This work was supported by a National Research Foundation of Korea (NRF) Grant, funded by the Korean Government (MOE) (2013R1A1A2064434) and a grant by the Korean Government (MSIP) (2010-0028684 and 2007-341-C00027; to P-GS), and by NRF Grants (2014051826, 2015R1A2A1A15054037 and 2015M3C7A1027351; to J-HK). We thank MP Kong at POSTECH for supporting generation of PLCγ1 conditional knockout mice, YH Lee at UNIST for maintaining mice and technical support, JH Hur at UNIST-Olympus Biomedical imaging Center (UOBC) for technical support and M Suh at the Korea Institute of Science and Technology (KIST) for experimental support for the behavior test. We also thank CH Bailey (Neuroscience, Columbia University) for critical reading and comments.

Author information

Affiliations

Authors

Corresponding authors

Correspondence to J-H Kim or P-G Suh.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Molecular Psychiatry website

Supplementary information

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Yang, Y., Jung, J., Kim, S. et al. Forebrain-specific ablation of phospholipase Cγ1 causes manic-like behavior. Mol Psychiatry 22, 1473–1482 (2017). https://doi.org/10.1038/mp.2016.261

Download citation

Further reading

Search