Advertisement

Calcineurin Downregulation in the Amygdala Is Sufficient to Induce Anxiety-like and Depression-like Behaviors in C57BL/6J Male Mice

  • Yann S. Mineur
    Affiliations
    Division of Molecular Psychiatry and Interdepartmental Neuroscience Program, Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, Yale University School of Medicine, New Haven, Connecticut
    Search for articles by this author
  • Seth R. Taylor
    Affiliations
    Division of Molecular Psychiatry and Interdepartmental Neuroscience Program, Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, Yale University School of Medicine, New Haven, Connecticut
    Search for articles by this author
  • Marina R. Picciotto
    Correspondence
    Address correspondence to Marina R. Picciotto, Ph.D., Yale University School of Medicine, Department of Psychiatry, 34 Park Street-3rd Floor Research, New Haven, CT 06508
    Affiliations
    Division of Molecular Psychiatry and Interdepartmental Neuroscience Program, Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, Yale University School of Medicine, New Haven, Connecticut
    Search for articles by this author

      Background

      The calcium-dependent phosphatase calcineurin is highly expressed in the amygdala, a brain area important for behaviors related to mood disorders and anxiety. Organ transplant patients are administered the calcineurin inhibitor cyclosporine A (CsA) chronically and demonstrate an increased incidence of anxiety and mood disorders. It is therefore important to determine whether chronic blockade of calcineurin may contribute to symptoms of anxiety and depression in these patients.

      Methods

      Pharmacological (CSA) and viral-mediated gene transfer (adeno-associated viral expression of short hairpin RNA [shRNA]) approaches were used to inhibit calcineurin activity systemically or selectively in the amygdala of the mouse brain to determine the role of calcineurin in behaviors related to anxiety and depression.

      Results

      Systemic inhibition of calcineurin activity with CsA or local downregulation of calcineurin levels in the amygdala using adeno-associated viral-delivered shRNAs targeting calcineurin B increased measures of anxiety-like behavior in the elevated plus maze, the light/dark box, and the open field test. A decrease in locomotor activity was also observed in mice treated systemically with CsA. In the forced swim model of depression-like behavior, both systemic CsA treatment and shRNA-mediated calcineurin blockade in the amygdala significantly increased immobility.

      Conclusions

      Taken together, these data demonstrate that decreasing calcineurin activity in the amygdala increases anxiety-like behaviors and to some extent depression-like behaviors. These studies suggest that chronic administration of CsA to organ transplant patients could have significant effects on anxiety and mood and this should be recognized as a potential clinical consequence of treatment to prevent transplant rejection.

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Calne R.Y.
        • Rolles K.
        • White D.J.
        • Thiru S.
        • Evans D.B.
        • McMaster P.
        • et al.
        Cyclosporin A initially as the only immunosuppressant in 34 recipients of cadaveric organs: 32 kidneys, 2 pancreases, and 2 livers.
        Lancet. 1979; 2: 1033-1036
        • Calne R.Y.
        • White D.J.
        • Thiru S.
        • Evans D.B.
        • McMaster P.
        • Dunn D.C.
        • et al.
        Cyclosporin A in patients receiving renal allografts from cadaver donors.
        Lancet. 1978; 2: 1323-1327
        • Kahan B.D.
        • Flechner S.M.
        • Lorber M.I.
        • Golden D.
        • Conley S.
        • Van Buren C.T.
        Complications of cyclosporine-prednisone immunosuppression in 402 renal allograft recipients exclusively followed at a single center for from one to five years.
        Transplantation. 1987; 43: 197-204
        • de Groen P.C.
        • Aksamit A.J.
        • Rakela J.
        • Forbes G.S.
        • Krom R.A.
        Central nervous system toxicity after liver transplantation. The role of cyclosporine and cholesterol.
        N Engl J Med. 1987; 317: 861-866
        • Katon W.J.
        Clinical and health services relationships between major depression, depressive symptoms, and general medical illness.
        Biol Psychiatry. 2003; 54: 216-226
        • Ormel J.
        • Rijsdijk F.V.
        • Sullivan M.
        • van Sonderen E.
        • Kempen G.I.
        Temporal and reciprocal relationship between IADL/ADL disability and depressive symptoms in late life.
        J Gerontol B Psychol Sci Soc Sci. 2002; 57: P338-P347
        • Patten S.B.
        Long-term medical conditions and major depression in a Canadian population study at waves 1 and 2.
        J Affect Disord. 2001; 63: 35-41
        • van den Brink R.H.
        • van Melle J.P.
        • Honig A.
        • Schene A.H.
        • Crijns H.J.
        • Lambert F.P.
        • Ormel J.
        Treatment of depression after myocardial infarction and the effects on cardiac prognosis and quality of life: Rationale and outline of the Myocardial INfarction and Depression-Intervention Trial (MIND-IT).
        Am Heart J. 2002; 144: 219-225
        • Davis M.
        • Whalen P.J.
        The amygdala: Vigilance and emotion.
        Mol Psychiatry. 2001; 6: 13-34
        • Vyas A.
        • Mitra R.
        • Shankaranarayana Rao B.S.
        • Chattarji S.
        Chronic stress induces contrasting patterns of dendritic remodeling in hippocampal and amygdaloid neurons.
        J Neurosci. 2002; 22: 6810-6818
        • Drevets W.C.
        • Videen T.O.
        • Price J.L.
        • Preskorn S.H.
        • Carmichael S.T.
        • Raichle M.E.
        A functional anatomical study of unipolar depression.
        J Neurosci. 1992; 12: 3628-3641
        • Sheline Y.I.
        • Gado M.H.
        • Price J.L.
        Amygdala core nuclei volumes are decreased in recurrent major depression.
        Neuroreport. 1998; 9: 2023-2028
        • Drevets W.C.
        Neuroimaging and neuropathological studies of depression: Implications for the cognitive-emotional features of mood disorders.
        Curr Opin Neurobiol. 2001; 11: 240-249
        • Wolfensberger S.P.
        • Veltman D.J.
        • Hoogendijk W.J.
        • Boomsma D.I.
        • de Geus E.J.
        Amygdala responses to emotional faces in twins discordant or concordant for the risk for anxiety and depression.
        Neuroimage. 2008; 41: 544-552
        • Wallace T.L.
        • Stellitano K.E.
        • Neve R.L.
        • Duman R.S.
        Effects of cyclic adenosine monophosphate response element binding protein overexpression in the basolateral amygdala on behavioral models of depression and anxiety.
        Biol Psychiatry. 2004; 56: 151-160
        • Beck C.H.
        • Fibiger H.C.
        Chronic desipramine alters stress-induced behaviors and regional expression of the immediate early gene, c-fos.
        Pharmacol Biochem Behav. 1995; 51: 331-338
        • Mineur Y.S.
        • Picciotto M.R.
        • Sanacora G.
        Antidepressant-like effects of ceftriaxone in male C57BL/6J mice.
        Biol Psychiatry. 2007; 61: 250-252
        • Clark C.P.
        • Brown G.G.
        • Archibald S.L.
        • Fennema-Notestine C.
        • Braun D.R.
        • Thomas L.S.
        • et al.
        Does amygdalar perfusion correlate with antidepressant response to partial sleep deprivation in major depression?.
        Psychiatry Res. 2006; 146: 43-51
        • Clipstone N.A.
        • Fiorentino D.F.
        • Crabtree G.R.
        Molecular analysis of the interaction of calcineurin with drug-immunophilin complexes.
        J Biol Chem. 1994; 269: 26431-26437
        • Husi H.
        • Luyten M.A.
        • Zurini M.G.
        Mapping of the immunophilin-immunosuppressant site of interaction on calcineurin.
        J Biol Chem. 1994; 269: 14199-14204
        • Hashimoto Y.
        • Perrino B.A.
        • Soderling T.R.
        Identification of an autoinhibitory domain in calcineurin.
        J Biol Chem. 1990; 265: 1924-1927
        • Kissinger C.R.
        • Parge H.E.
        • Knighton D.R.
        • Lewis C.T.
        • Pelletier L.A.
        • Tempczyk A.
        • et al.
        Crystal structures of human calcineurin and the human FKBP12-FK506-calcineurin complex.
        Nature. 378. 1995: 641-644
        • Rusnak F.
        • Mertz P.
        Calcineurin: Form and function.
        Physiol Rev. 2000; 80: 1483-1521
        • Buttini M.
        • Limonta S.
        • Luyten M.
        • Boddeke H.
        Differential distribution of calcineurin A alpha isoenzyme mRNA’s in rat brain.
        Naunyn Schmiedebergs Arch Pharmacol. 1993; 348: 679-683
        • Polli J.W.
        • Billingsley M.L.
        • Kincaid R.L.
        Expression of the calmodulin-dependent protein phosphatase, calcineurin, in rat brain: Developmental patterns and the role of nigrostriatal innervation.
        Brain Res Dev Brain Res. 1991; 63: 105-119
        • Yakel J.L.
        Calcineurin regulation of synaptic function: From ion channels to transmitter release and gene transcription.
        Trends Pharmacol Sci. 1997; 18: 124-134
        • Zhu Y.
        • Yakel J.L.
        Calcineurin modulates G protein-mediated inhibition of N-type calcium channels in rat sympathetic neurons.
        J Neurophysiol. 1997; 78: 1161-1165
        • Victor R.G.
        • Thomas G.D.
        • Marban E.
        • O׳Rourke B.
        Presynaptic modulation of cortical synaptic activity by calcineurin.
        Proc Natl Acad Sci U S A. 1995; 92: 6269-6273
        • Mansuy I.M.
        Calcineurin in memory and bidirectional plasticity.
        Biochem Biophys Res Commun. 2003; 311: 1195-1208
        • Mineur Y.S.
        • Abizaid A.
        • Rao Y.
        • Salas R.
        • DiLeone R.J.
        • Gundisch D.
        • et al.
        Nicotine decreases food intake through activation of POMC neurons.
        Science. 2011; 332: 1330-1332
        • Hommel J.D.
        • Sears R.M.
        • Georgescu D.
        • Simmons D.L.
        • DiLeone R.J.
        Local gene knockdown in the brain using viral-mediated RNA interference.
        Nat Med. 2003; 9: 1539-1544
        • Lin C.H.
        • Lee C.C.
        • Gean P.W.
        Involvement of a calcineurin cascade in amygdala depotentiation and quenching of fear memory.
        Mol Pharmacol. 2003; 63: 44-52
        • Paxinos G.
        • Franklin K.B.J.
        The Mouse Brain in Stereotaxic Coordinates.
        Elsevier Academic Press, Waltham2008
        • Crawley J.N.
        Behavioral phenotyping strategies for mutant mice.
        Neuron. 2008; 57: 809-818
        • Caldarone B.J.
        • King S.L.
        • Picciotto M.R.
        Sex differences in anxiety-like behavior and locomotor activity following chronic nicotine exposure in mice.
        Neurosci Lett. 2008; 439: 187-191
        • Crawley J.N.
        Exploratory behavior models of anxiety in mice.
        Neurosci Biobehav Rev. 1985; 9: 37-44
        • Crawley J.
        • Goodwin F.K.
        Preliminary report of a simple animal behavior model for the anxiolytic effects of benzodiazepines.
        Pharmacol Biochem Behav. 1980; 13: 167-170
        • Mineur Y.S.
        • Somenzi O.
        • Picciotto M.R.
        Cytisine, a partial agonist of high-affinity nicotinic acetylcholine receptors, has antidepressant-like properties in male C57BL/6J mice.
        Neuropharmacology. 2007; 52: 1256-1262
        • Prut L.
        • Belzung C.
        The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: A review.
        Eur J Pharmacol. 2003; 463: 3-33
        • Jindal R.M.
        • Joseph J.T.
        • Morris M.C.
        • Santella R.N.
        • Baines L.S.
        Noncompliance after kidney transplantation: A systematic review.
        Transplant Proc. 2003; 35: 2868-2872
        • Sato Y.
        • Onaka T.
        • Kobayashi E.
        • Seo N.
        The differential effect of cyclosporine on hypnotic response and pain reaction in mice.
        Anesth Analg. 2007; 105: 1489-1493
        • Telarovic S.
        • Telarovic S.
        • Mihanovic M.
        [Cyclosporine-induced depressive psychosis in a liver transplant patient: A case report].
        Lijec Vjesn. 2007; 129: 74-76
        • Crozatier C.
        • Farley S.
        • Mansuy I.M.
        • Dumas S.
        • Giros B.
        • Tzavara E.T.
        Calcineurin (protein phosphatase 2B) is involved in the mechanisms of action of antidepressants.
        Neuroscience. 2007; 144: 1470-1476
        • Mathieu F.
        • Miot S.
        • Etain B.
        • El Khoury M.A.
        • Chevalier F.
        • Bellivier F.
        • et al.
        Association between the PPP3CC gene, coding for the calcineurin gamma catalytic subunit, and bipolar disorder.
        Behav Brain Funct. 2008; 4: 2