Mice Lacking NMDA Receptors in Parvalbumin Neurons Display Normal Depression-Related Behavior and Response to Antidepressant Action of NMDAR Antagonists
The underlying circuit imbalance in major depression remains unknown and current therapies remain inadequate for a large group of patients. Discovery of the rapid antidepressant effects of ketamine - an NMDA receptor (NMDAR) antagonist – has linked the glutamatergic system to depression. Interestingly, dysfunction in the inhibitory GABAergic system has also been proposed to underlie depression and deficits linked to GABAergic neurons have been found with human imaging and in post-mortem material from depressed patients. Parvalbumin-expressing (PV) GABAergic interneurons regulate local circuit function through perisomatic inhibition and their activity is NMDAR-dependent, providing a possible link between NMDAR and the inhibitory system in the antidepressant effect of ketamine. We have therefore investigated the role of the NMDAR-dependent activity of PV interneurons for the development of depression-like behavior as well as for the response to rapid antidepressant effects of NMDAR antagonists. We used mutant mice lacking NMDA neurotransmission specifically in PV neurons (PV-Cre+/NR1f/f) and analyzed depression-like behavior and anhedonia. To study the acute and sustained effects of a single NMDAR antagonist administration, we established a behavioral paradigm of repeated exposure to forced swimming test (FST). We did not observe altered behavioral responses in the repeated FST or in a sucrose preference test in mutant mice. In addition, the behavioral response to administration of NMDAR antagonists was not significantly altered in mutant PV-Cre+/NR1f/f mice. Our results show that NMDA-dependent neurotransmission in PV neurons is not necessary to regulate depression-like behaviors, and in addition that NMDARs on PV neurons are not a direct target for the NMDAR-induced antidepressant effects of ketamine and MK801.
References
[1]
Trivedi MH, Rush AJ, Wisniewski SR, Nierenberg AA, Warden D, et al. (2006) Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. The American J Psychiatry 163: 28–40.
[2]
Sanacora G, Zarate CA, Krystal JH, Manji HK (2008) Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders. Nat Rev Drug Discov 7: 426–437.
[3]
Autry AE, Adachi M, Nosyreva E, Na ES, Los MF, et al. (2011) NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature 475: 91–95.
[4]
Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, et al. (2000) Antidepressant effects of ketamine in depressed patients. Biological Psychiatry 47: 351–354.
[5]
Murrough JW, Perez AM, Pillemer S, Stern J, Parides MK, et al. (2013) Rapid and Longer-Term Antidepressant Effects of Repeated Ketamine Infusions in Treatment-Resistant Major Depression. Biological Psychiatry 74(4): 250–256.
[6]
Ma XC, Dang YH, Jia M, Ma R, Wang F, et al. (2013) Long-lasting antidepressant action of ketamine, but not glycogen synthase kinase-3 inhibitor SB216763, in the chronic mild stress model of mice. PLoS One 8: 2,
[7]
Layer RT, Popik P, Olds T, Skolnick P (1995) Antidepressant-like actions of the polyamine site NMDA antagonist, eliprodil (SL-82.0715). Pharmacol Biochem Behav 52: 621–627.
[8]
Papp M, Moryl E (1994) Antidepressant activity of non-competitive and competitive NMDA receptor antagonists in a chronic mild stress model of depression. Eur J Pharmacol 263: 1–7.
[9]
Trullas R, Skolnick P (1990) Functional Antagonists at the NMDA Receptor Complex Exhibit Antidepressant Actions. European Journal of Pharmacology 185: 1–10.
[10]
Machado-Vieira R, Salvadore G, Ibrahim LA, Diaz-Granados N, Zarate CA Jr (2009) Targeting glutamatergic signaling for the development of novel therapeutics for mood disorders. Curr Pharm Des 15: 1595–1611.
[11]
Mathews DC, Henter ID, Zarate CA (2012) Targeting the glutamatergic system to treat major depressive disorder: rationale and progress to date. Drugs 72: 1313–1333.
[12]
Goforth HW, Holsinger T (2007) Rapid relief of severe major depressive disorder by use of preoperative ketamine and electroconvulsive therapy. J ECT 23: 23–25.
[13]
Zarate CA Jr, Singh JB, Carlson PJ, Brutsche NE, Ameli R, et al. (2006) A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 63: 856–864.
[14]
Kugaya A, Sanacora G (2005) Beyond monoamines: glutamatergic function in mood disorders. CNS spectrums 10: 808–819.
[15]
Mohler H (2012) The GABA system in anxiety and depression and its therapeutic potential. Neuropharmacology 62: 42–53.
[16]
Sibille E, Morris HM, Kota RS, Lewis DA (2011) GABA-related transcripts in the dorsolateral prefrontal cortex in mood disorders. Int J Neuropsychopharmacol 14: 721–734.
[17]
Gabbay V, Mao X, Klein RG, Ely BA, Babb JS, et al. (2012) Anterior cingulate cortex gamma-aminobutyric acid in depressed adolescents: relationship to anhedonia. Arch Gen Psychiatry 69: 139–149.
[18]
Rajkowska G, O'Dwyer G, Teleki Z, Stockmeier CA, Miguel-Hidalgo JJ (2007) GABAergic neurons immunoreactive for calcium binding proteins are reduced in the prefrontal cortex in major depression. Neuropsychopharmacology 32: 471–482.
[19]
Sanacora G, Mason GF, Rothman DL, Krystal JH (2002) Increased occipital cortex GABA concentrations in depressed patients after therapy with selective serotonin reuptake inhibitors. The American Journal of Psychiatry 159: 663–665.
[20]
Sanacora G, Gueorguieva R, Epperson CN, Wu YT, Appel M, et al. (2004) Subtype-specific alterations of gamma-aminobutyric acid and glutamate in patients with major depression. Arch Gen Psychiatry 61: 705–713.
[21]
Mohler H (2011) The rise of a new GABA pharmacology. Neuropharmacology 60: 1042–1049.
[22]
Levinson AJ, Fitzgerald PB, Favalli G, Blumberger DM, Daigle M, et al. (2010) Evidence of cortical inhibitory deficits in major depressive disorder. Biological psychiatry 67: 458–464.
[23]
Sanacora G, Treccani G, Popoli M (2012) Towards a glutamate hypothesis of depression: an emerging frontier of neuropsychopharmacology for mood disorders. Neuropharmacology 62: 63–77.
[24]
Cardin JA, Carlén M, Meletis K, Knoblich U, Zhang F, et al. (2009) Driving fast-spiking cells induces gamma rhythm and controls sensory responses. Nature 459: 663–667.
[25]
Carlén M, Meletis K, Siegle JH, Cardin JA, Futai K, et al. (2012) A critical role for NMDA receptors in parvalbumin interneurons for gamma rhythm induction and behavior. Molecular psychiatry 17: 537–548.
[26]
Sohal VS, Zhang F, Yizhar O, Deisseroth K (2009) Parvalbumin neurons and gamma rhythms enhance cortical circuit performance. Nature 459: 698–702.
[27]
Yizhar O, Fenno LE, Prigge M, Schneider F, Davidson TJ, et al. (2011) Neocortical excitation/inhibition balance in information processing and social dysfunction. Nature 477: 171–178.
[28]
Gonzalez-Burgos G, Lewis DA (2008) GABA neurons and the mechanisms of network oscillations: implications for understanding cortical dysfunction in schizophrenia. Schizophr Bull 34: 944–961.
[29]
Nakazawa K, Quirk MC, Chitwood RA, Watanabe M, Yeckel MF, et al. (2002) Requirement for hippocampal CA3 NMDA receptors in associative memory recall. Science 297: 211–218.
[30]
Korotkova T, Fuchs EC, Ponomarenko A, von Engelhardt J, Monyer H (2010) NMDA receptor ablation on parvalbumin-positive interneurons impairs hippocampal synchrony, spatial representations, and working memory. Neuron 68: 557–569.
[31]
Moghaddam B, Krystal JH (2012) Capturing the angel in “angel dust”: twenty years of translational neuroscience studies of NMDA receptor antagonists in animals and humans. Schizophr Bull 38: 942–949.
[32]
Homayoun H, Moghaddam B (2007) NMDA receptor hypofunction produces opposite effects on prefrontal cortex interneurons and pyramidal neurons. J Neurosci 27: 11496–11500.
[33]
Lewis DA, Moghaddam B (2006) Cognitive dysfunction in schizophrenia: convergence of gamma-aminobutyric acid and glutamate alterations. Archives of Neurology 63: 1372–1376.
[34]
Quirk MC, Sosulski DL, Feierstein CE, Uchida N, Mainen ZF (2009) A defined network of fast-spiking interneurons in orbitofrontal cortex: responses to behavioral contingencies and ketamine administration. Front Syst Neurosci 3: 13.
[35]
Zhou ZQ, Zhang GF, Li XM, Yang C, Yang JJ (2012) Fast-spiking interneurons and gamma oscillations may be involved in the antidepressant effects of ketamine. Med Hypotheses 79: 85–86.
[36]
Jones RS, Buhl EH (1993) Basket-like interneurones in layer II of the entorhinal cortex exhibit a powerful NMDA-mediated synaptic excitation. Neurosci Lett 149: 35–39.
[37]
Porsolt RD, Le Pichon M, Jalfre M (1977) Depression: a new animal model sensitive to antidepressant treatments. Nature 266: 730–732.
[38]
Hippenmeyer S, Vrieseling E, Sigrist M, Portmann T, Laengle C, et al. (2005) A developmental switch in the response of DRG neurons to ETS transcription factor signaling. PLoS Biol 3: e159.
[39]
Tsien JZ, Huerta PT, Tonegawa S (1996) The essential role of hippocampal CA1 NMDA receptor-dependent synaptic plasticity in spatial memory. Cell 87: 1327–1338.
[40]
Moghaddam B, Adams B, Verma A, Daly D (1997) Activation of glutamatergic neurotransmission by ketamine: a novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with the prefrontal cortex. J Neurosci 17: 2921–2927.
[41]
Jackson ME, Homayoun H, Moghaddam B (2004) NMDA receptor hypofunction produces concomitant firing rate potentiation and burst activity reduction in the prefrontal cortex. Proc Natl Acad Sci U S A 101: 8467–8472.
[42]
Nowak K, Meyza K, Nikolaev E, Hunt MJ, Kasicki S (2012) Local blockade of NMDA receptors in the rat prefrontal cortex increases c-Fos expression in multiple subcortical regions. Acta Neurobiol Exp (Wars) 72: 207–218.
[43]
Burgdorf J, Zhang XL, Nicholson KL, Balster RL, Leander JD, et al. (2013) GLYX-13, a NMDA receptor glycine-site functional partial agonist, induces antidepressant-like effects without ketamine-like side effects. Neuropsychopharmacol 38(5): 729–742.
[44]
Vardigan JD, Huszar SL, McNaughton CH, Hutson PH, Uslaner JM (2010) MK-801 produces a deficit in sucrose preference that is reversed by clozapine, D-serine, and the metabotropic glutamate 5 receptor positive allosteric modulator CDPPB: relevance to negative symptoms associated with schizophrenia? Pharmacol Biochem and Beh 95(2): 223–229.
[45]
Marona-Lewicka D, Nichols DE (1997) The effect of selective serotonin releasing agents in the chronic mild stress model of depression in rats. Stress 2(2): 91–100.
[46]
Willner P (1997) Validity, reliability and utility of the chronic mild stress model of depression: a 10-year review and evaluation. Psychopharmacology (Berl) 134(4): 319–329.
[47]
Muscat R, Papp M, Willner P (1992) Antidepressant-like effects of dopamine agonists in an animal model of depression. Biol Psychiatry 1; 31(9): 937–946.
[48]
Wang DD, Kriegstein AR (2008) GABA regulates excitatory synapse formation in the neocortex via NMDA receptor activation. J Neurosci 28: 5547–5558.
