Increased amygdalar metabotropic glutamate receptor 7 mRNA in a genetic mouse model of impaired fear extinction
Post-traumatic stress disorder (PTSD) is a devastating anxiety-related disorder which develops subsequent to a severe psychologically traumatic event. Only ~ 9% of people who experience such a trauma develop PTSD. It is clear that a number of factors, including genetics, influence whether an individual will develop PTSD subsequent to a trauma. The 129S1/SvImJ (S1) inbred mouse strain displays poor fear extinction and may be useful to model this specific aspect of PTSD. The metabotropic glutamate receptor 7 (mGlu7 receptor) has previously been shown to be involved in cognitive processes and anxiety-like behaviour placing it in a key position to regulate fear extinction processes. We sought to compare mGlu7 receptor mRNA levels in the S1 strain with those in the robustly extinguishing C57BL/6J (B6) inbred strain using in situ hybridisation (ISH) in three brain regions associated with fear extinction: the amygdala, hippocampus and prefrontal cortex (PFC).
Compared to the B6 strain, S1 mice had increased mGlu7 receptor mRNA levels in the lateral amygdala (LA) and basolateral amygdala (BLA) subdivisions. An increase was also seen in the hippocampal CA1 and CA3 subregions of S1 mice. No difference in mGlu7 receptor levels were seen in the central nucleus (CeA) of the amygdala, dentate gyrus (DG) of the hippocampus or prefrontal cortex.
These data show altered mGlu7 receptor expression in key brain regions associated with fear extinction in two different inbred mouse strains which differ markedly in their fear extinction behaviour. Altered mGlu7 receptor levels may contribute to the deficit fear extinction processes seen in fear extinction in the S1 strain.
KeywordsmGlu7 receptor expression Post-traumatic stress disorder Trauma
JFC is supported by Science Foundation Ireland (SFI) (Grant Numbers 07/CE/BI368 and 12/RC/2273); the Irish Health Research Board. RMOC was supported by a postgraduate scholarship awarded by the Irish Research Council for Science Engineering and Technology (IRCSET). AH is supported by the NIAAA IRP. NS is supported by the Austrian Science Fund FWF SFB F4410.
Compliance with ethical standards
All experiments were conducted in accordance with the European Directive 86/609/EEC and the local Animal Care and Use Committees.
Conflict of interest
The authors declare that they have no conflict of interest.
- Bukalo O, Pinard CR, Silverstein S, Brehm C, Hartley ND, Whittle N, Colacicco G, Busch E, Patel S, Singewald N, Holmes A (2015) Prefrontal inputs to the amygdala instruct fear extinction memory formation. Sci Adv 1(6). https://doi.org/10.1126/sciadv.1500251
- Callaerts-Vegh Z, Beckers T, Ball SM, Baeyens F, Callaerts PF, Cryan JF, Molnar E, D'Hooge R (2006) Concomitant deficits in working memory and fear extinction are functionally dissociated from reduced anxiety in metabotropic glutamate receptor 7-deficient mice. J Neurosci 26:6573–6582CrossRefGoogle Scholar
- DSM-V (2013) Diagnostic and statistical manual of mental disorders: DSM-V. American Psychiatric Association, Washington D.CGoogle Scholar
- Fendt M, Schmid S, Thakker DR, Jacobson LH, Yamamoto R, Mitsukawa K, Maier R, Natt F, Husken D, Kelly PH, McAllister KH, Hoyer D, van der Putten H, Cryan JF, Flor PJ (2008) mGluR7 facilitates extinction of aversive memories and controls amygdala plasticity. Mol Psychiatry 13:970–979CrossRefGoogle Scholar
- Fisher NM, Gogliotti RG, Vermudez SAD, Stansley BJ, Conn PJ, Niswender CM (2017) Genetic reduction or negative modulation of mGlu7 does not impact anxiety and fear learning phenotypes in a mouse model of MECP2 duplication syndrome. ACS Chem Neurosci. https://doi.org/10.1021/acschemneuro.7b00414
- Gee CE, Peterlik D, Neuhauser C, Bouhelal R, Kaupmann K, Laue G, Uschold-Schmidt N, Feuerbach D, Zimmermann K, Ofner S, Cryan JF, van der Putten H, Fendt M, Vranesic I, Glatthar R, Flor PJ (2014) Blocking metabotropic glutamate receptor subtype 7 (mGlu7) via the Venus flytrap domain (VFTD) inhibits amygdala plasticity, stress, and anxiety-related behavior. J Biol Chem 289:10975–10987CrossRefGoogle Scholar
- Gunduz-Cinar O, Brockway E, Lederle L, Wilcox T, Halladay LR, Ding Y, Oh H, Busch EF, Kaugars K, Flynn S, Limoges A, Bukalo O, MacPherson KP, Masneuf S, Pinard C, Sibille E, Chesler EJ, Holmes A (2018) Identification of a novel gene regulating amygdala-mediated fear extinction. Mol Psychiatry. https://doi.org/10.1038/s41380-017-0003-3
- Mitsukawa K, Yamamoto R, Ofner S, Nozulak J, Pescott O, Lukic S, Stoehr N, Mombereau C, Kuhn R, McAllister KH, van der Putten H, Cryan JF, Flor PJ (2005) A selective metabotropic glutamate receptor 7 agonist: activation of receptor signaling via an allosteric site modulates stress parameters in vivo. Proc Natl Acad Sci U S A 102:18712–18717CrossRefGoogle Scholar
- Sukoff Rizzo SJ, Leonard SK, Gilbert A, Dollings P, Smith DL, Zhang MY, Di L, Platt BJ, Neal S, Dwyer JM, Bender CN, Zhang J, Lock T, Kowal D, Kramer A, Randall A, Huselton C, Vishwanathan K, Tse SY, Butera J, Ring RH, Rosenzweig-Lipson S, Hughes ZA, Dunlop J (2011) The metabotropic glutamate receptor 7 allosteric modulator AMN082: a monoaminergic agent in disguise? J Pharmacol Exp Ther 338:345–352CrossRefGoogle Scholar
- Toth I, Dietz M, Peterlik D, Huber SE, Fendt M, Neumann ID, Flor PJ, Slattery DA (2012) Pharmacological interference with metabotropic glutamate receptor subtype 7 but not subtype 5 differentially affects within- and between-session extinction of Pavlovian conditioned fear. Neuropharmacology 62:1619–1626CrossRefGoogle Scholar