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Changes in the Prefrontal Glutamatergic and Parvalbumin Systems of Mice Exposed to Unpredictable Chronic Stress

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Abstract

The prefrontal cortex (PFC) is highly sensitive to the effects of stress, a known risk factor of mood disorders including anxiety and depression. Abnormalities in PFC functioning have been well described in humans displaying stress-induced depressive symptoms, and hypoactivity of the PFC is now recognized to be a key feature of the depressed brain. However, little is known about the causes and mechanisms leading to this altered prefrontal functional activity in the context of stress-related mood disorders. We previously showed that unpredictable chronic mild stress (UCMS) in mice increases prefrontal expression of parvalbumin (PV), an activity-dependent calcium-binding albumin protein expressed in a specific subtype of GABAergic neurons, highlighting a potential mechanism through which chronic stress leads to hypofunction of the PFC. In this study, we aimed to investigate the mechanisms by which chronic stress alters the prefrontal GABA system. We hypothesized that chronic stress-induced enhancement of glutamatergic transmission in the PFC is a crucial contributing factor to changes within the prefrontal GABAergic and, specifically, PV system. BALB/c male and female mice were exposed to daily handling (control) or 2 or 4 weeks of UCMS. Female mice displayed a more severe altered phenotype than males, as shown by increased anxiety- and depressive-like behaviors and deficits in PFC-dependent cognitive abilities, particularly after exposure to 2 weeks of UCMS. This behavioral phenotype was paralleled by a large increase in prefrontal PV messenger RNA (mRNA) and number of PV-expressing neurons, supporting our previous findings. We further showed that the expression of pre- and postsynaptic markers of glutamatergic transmission (VGlut1 presynaptic terminals and pERK1/2, respectively) onto PV neurons was increased by 2 weeks of UCMS in a sex-specific manner; this was associated with sex-specific changes in the mRNA expression of the NR2B subunit of the NMDA receptor. These findings provide evidence of increased glutamatergic transmission onto prefrontal PV neurons, particularly in female mice, which could potentially contribute to their increased PV expression and the extent of their behavioral impairment following UCMS. Finally, our analysis of activity of subcortical regions sending glutamatergic afferents to the PFC reveals that glutamatergic neurons from the basolateral amygdala might be specifically involved in UCMS-induced changes in prefrontal glutamatergic transmission.

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References

  1. Kessler RC, Berglund PA, Demler O, Jin R, Walters EE (2005) Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry 62(6):593–602

    Article  PubMed  Google Scholar 

  2. Covington HE 3rd, Kikusui T, Goodhue J, Nikulina EM, Hammer RP Jr, Miczek KA (2005) Brief social defeat stress: long lasting effects on cocaine taking during a binge and zif268 mRNA expression in the amygdala and prefrontal cortex. Neuropsychopharmacology 30(2):310–321

    Article  CAS  PubMed  Google Scholar 

  3. Duman CH, Duman RS (2015) Spine synapse remodeling in the pathophysiology and treatment of depression. Neurosci Lett 601:20–29

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Baxter LR Jr, Schwartz JM, Phelps ME, Mazziotta JC, Guze BH, Selin C et al (1989) Reduction of prefrontal cortex glucose metabolism common to three types of depression. Arch Gen Psychiatry 46(3):243–250

    Article  CAS  PubMed  Google Scholar 

  5. Rogers MA, Kasai K, Koji M, Fukuda R, Iwanami A, Nakagome K, Fukuda M, Kato N (2004) Executive and prefrontal dysfunction in unipolar depression: a review of neuropsychological and imaging evidence. Neurosci Res 50(1):1–11

    Article  PubMed  Google Scholar 

  6. Hashimoto K, Sawa A, Iyo M (2007) Increased levels of glutamate in brains from patients with mood disorders. Biol Psychiatry 62(11):1310–1316

    Article  CAS  PubMed  Google Scholar 

  7. Musazzi L, Treccani G, Popoli M (2015) Functional and structural remodeling of glutamate synapses in prefrontal and frontal cortex induced by behavioral stress. Front Psychiatry 6:60

    Article  PubMed  PubMed Central  Google Scholar 

  8. Duman RS (2014) Pathophysiology of depression and innovative treatments: remodeling glutamatergic synaptic connections. Dialogues Clin Neurosci 16(1):11–27

    PubMed  PubMed Central  Google Scholar 

  9. Veeraiah P, Noronha JM, Maitra S, Bagga P, Khandelwal N, Chakravarty S et al (2014) Dysfunctional glutamatergic and γ-aminobutyric acidergic activities in prefrontal cortex of mice in social defeat model of depression. Biol Psychiatry 76(3):231–238

    Article  CAS  PubMed  Google Scholar 

  10. McKlveen JM, Morano RL, Fitzgerald M, Zoubovsky S, Cassella SN, Scheimann JR et al (2016) Chronic stress increases prefrontal inhibition: a mechanism for stress-induced prefrontal dysfunction. Biol Psychiatry 80(10):754–764

    Article  PubMed  PubMed Central  Google Scholar 

  11. Shepard R, Page CE, Coutellier L (2016) Sensitivity of the prefrontal GABAergic system to chronic stress in male and female mice: relevance for sex differences in stress-related disorders. Neuroscience 332:1–12

    Article  CAS  PubMed  Google Scholar 

  12. Gilabert-Juan J, Castillo-Gomez E, Guirado R, Moltó MD, Nacher J (2013) Chronic stress alters inhibitory networks in the medial prefrontal cortex of adult mice. Brain Struct Funct 218(6):1591–1605

    Article  CAS  PubMed  Google Scholar 

  13. Maguire J (2014) Stress-induced plasticity of GABAergic inhibition. Front Cell Neurosci 8:157

    Article  PubMed  PubMed Central  Google Scholar 

  14. Battaglioli G, Liu H, Martin DL (2003) Kinetic differences between the isoforms of glutamate decarboxylase: implications for the regulation of GABA synthesis. J Neurochem 86(4):879–887

    Article  CAS  PubMed  Google Scholar 

  15. Tropea D, Kreiman G, Lyckman A, Mukherjee S, Yu H, Horng S, Sur M (2006) Gene expression changes and molecular pathways mediating activity-dependent plasticity in visual cortex. Nat Neurosci 9(5):660–668

    Article  CAS  PubMed  Google Scholar 

  16. Behrens MM, Ali SS, Dao DN, Lucero J, Shekhtman G, Quick KL, Dugan LL (2007) Ketamine-induced loss of phenotype of fast-spiking interneurons is mediated by NADPH-oxidase. Science 318:1645–1647

    Article  CAS  PubMed  Google Scholar 

  17. McGarry LM, Carter AG (2016) Inhibitory gating of basolateral amygdala inputs to the prefrontal cortex. J Neurosci 36(36):9391–9406

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Joëls M, Karst H, Krugers HJ, Lucassen PJ (2007) Chronic stress: implications for neuronal morphology, function and neurogenesis. Front Neuroendocrinol 28:72–96

    Article  PubMed  Google Scholar 

  19. Joëls M (2008) Functional actions of corticosteroids in the hippocampus. Eur J Pharmacol 583:312–321

    Article  PubMed  Google Scholar 

  20. Lee YA, Goto Y (2011) Chronic stress modulation of prefrontal cortical NMDA receptor expression disrupts limbic structure-prefrontal cortex interaction. Eur J Neurosci 34(3):426–436

    Article  PubMed  Google Scholar 

  21. Wei J, Yuen EY, Liu W, Li X, Zhong P, Karatsoreos IN, McEwen BS, Yan Z (2014) Estrogen protects against the detrimental effects of repeated stress on glutamatergic transmission and cognition. Mol Psychiatry 19(5):588–598

    Article  CAS  PubMed  Google Scholar 

  22. Farooq RK, Isingrini E, Tanti A, Le Guisquet AM, Arlicot N, Minier F et al (2012) Is unpredictable chronic mild stress (UCMS) a reliable model to study depression-induced neuroinflammation? Behav Brain Res 231:130–137

    Article  PubMed  Google Scholar 

  23. Nollet M, Le Guisquet AM, Belzung C (2013) Models of depression: unpredictable chronic mild stress in mice. Curr Protoc Pharmacol 5(5):65

    PubMed  Google Scholar 

  24. Gabbott P, Headlam A, Busby S (2002) Morphological evidence that CA1 hippocampal afferents monosynaptically innervate PV-containing neurons and NADPH-diaphorase reactive cells in the medial prefrontal cortex (areas 25/32) of the rat. Brain Res 946(2):314–322

    Article  CAS  PubMed  Google Scholar 

  25. Esmaeili B, Grace AA (2013) Afferent drive of medial prefrontal cortex by hippocampus and amygdala is altered in MAM-treated rats: evidence for interneuron dysfunction. Neuropsychopharmacology 38(10):1871–1880

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Felix-Ortiz AC, Burgos-Robles A, Bhagat ND, Leppla CA, Tye KM (2016) Bidirectional modulation of anxiety-related and social behaviors by amygdala projections to the medial prefrontal cortex. Neuroscience 321:197–209

    Article  CAS  PubMed  Google Scholar 

  27. Razzoli M, Carboni L, Andreoli M, Ballottari A, Arban R (2011) Different susceptibility to social defeat stress of BalbC and C57BL6/J mice. Behav Brain Res 216:100–108

    Article  PubMed  Google Scholar 

  28. Spanswick SC, Dyck RH (2012) Object/context specific memory deficits following medial frontal cortex damage in mice. PLoS One 7(8):e43698

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Coutellier L, Gilbert V, Shepard R (2015) Npas4 deficiency increases vulnerability to juvenile stress in mice. Behav Brain Res 295:17–25

    Article  CAS  PubMed  Google Scholar 

  30. Lalonde R (2002) The neurobiological basis of spontaneous alternation. Neurosci Biobehav Rev 26(1):91–104

    Article  CAS  PubMed  Google Scholar 

  31. Franklin KBJ, Paxinos G (2008) The mouse brain in stereotaxic coordinates. Academic, San Diego

    Google Scholar 

  32. Yang JM, Zhang J, Chen XJ, Geng HY, Ye M, Spitzer NC, Luo JH, Duan SM et al (2013) Development of GABA circuitry of fast-spiking basket interneurons in the medial prefrontal cortex of erbb4-mutant mice. J Neurosci 33(50):19724–19733

    Article  CAS  PubMed  Google Scholar 

  33. Kinney JW, Davis CN, Tabarean I, Conti B, Bartfai T, Behrens MM (2006) A specific role for NR2A-containing NMDA receptors in the maintenance of parvalbumin and GAD67 immunoreactivity in cultured interneurons. J Neurosci 26(5):1604–1615

    Article  CAS  PubMed  Google Scholar 

  34. McDonald AJ, Muller JF, Mascagni F (2002) GABAergic innervation of alpha type II calcium/calmodulin-dependent protein kinase immunoreactive pyramidal neurons in the rat basolateral amygdala. J Comp Neurol 446(3):199–218

    Article  CAS  PubMed  Google Scholar 

  35. Sík A, Hájos N, Gulácsi A, Mody I, Freund TF (1998) The absence of a major Ca2+ signaling pathway in GABAergic neurons of the hippocampus. Proc Natl Acad Sci U S A 95(6):3245–3250

    Article  PubMed  PubMed Central  Google Scholar 

  36. Mineur YS, Belzung C, Crusio WE (2006) Effects of unpredictable chronic mild stress on anxiety and depression-like behavior in mice. Behav Brain Res 175(1):43–50

    Article  PubMed  Google Scholar 

  37. Farley S, Dumas S, El Mestikawy S, Giros B (2012) Increased expression of the vesicular glutamate transporter-1 (VGLUT1) in the prefrontal cortex correlates with differential vulnerability to chronic stress in various mouse strains: effects of fluoxetine and MK-801. Neuropharmacology 62(1):503–517

    Article  CAS  PubMed  Google Scholar 

  38. Belzung C, Griebel G (2001) Measuring normal and pathological anxiety-like behaviour in mice: a review. Behav Brain Res 125(1–2):141–149

    Article  CAS  PubMed  Google Scholar 

  39. Kim S, Lee S, Ryu S, Suk J, Park C (2002) Comparative analysis of the anxiety-related behaviors in four inbred mice. Behav Process 60(2):181–190

    Article  Google Scholar 

  40. Sugimoto Y, Kajiwara Y, Hirano K, Yamada S, Tagawa N, Kobayashi Y, Hotta Y, Yamada J (2008) Mouse strain differences in immobility and sensitivity to fluvoxamine and desipramine in the forced swimming test: analysis of serotonin and noradrenaline transporter binding. Eur J Pharmacol 592(1–3):116–122

    Article  CAS  PubMed  Google Scholar 

  41. Sadler AM, Bailey SJ (2016) Repeated daily restraint stress induces adaptive behavioural changes in both adult and juvenile mice. Physiol Behav 167:313–323

    Article  CAS  PubMed  Google Scholar 

  42. Markham JA, Mullins SE, Koenig JI (2013) Periadolescent maturation of the prefrontal cortex is sex-specific and is disrupted by prenatal stress. J Comp Neurol 521(8):1828–1843

    Article  PubMed  PubMed Central  Google Scholar 

  43. Bale TL, Epperson CN (2015) Sex differences and stress across the lifespan. Nat Neurosci 18(10):1413–1420

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Hu W, Zhang M, Czéh B, Flügge G, Zhang W (2010) Stress impairs GABAergic network function in the hippocampus by activating nongenomic glucocorticoid receptors and affecting the integrity of the parvalbumin-expressing neuronal network. Neuropsychopharmacology 35(8):1693–1707

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Winkelmann A, Maggio N, Eller J, Caliskan G, Semtner M, Häussler U, Jüttner R, Dugladze T et al (2014) Changes in neural network homeostasis trigger neuropsychiatric symptoms. J Clin Invest 124(2):696–711

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Çalışkan G, Müller I, Semtner M, Winkelmann A, Raza AS, Hollnagel JO, Rösler A, Heinemann U et al (2016) Identification of parvalbumin interneurons as cellular substrate of fear memory persistence. Cereb Cortex 26(5):2325–2340

    Article  PubMed  PubMed Central  Google Scholar 

  47. Lucas EK, Jegarl A, Clem RL (2014) Mice lacking TrkB in parvalbumin-positive cells exhibit sexually dimorphic behavioral phenotypes. Behav Brain Res 274:219–225

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Mark KA, Quinton MS, Russek SJ, Yamamoto BK (2007) Dynamic changes in vesicular glutamate transporter 1 function and expression related to methamphetamine-induced glutamate release. J Neurosci 27(25):6823–6831

    Article  CAS  PubMed  Google Scholar 

  49. Tang J, Xue W, Xia B, Ren L, Tao W, Chen C, Zhang H, Wu R et al (2015) Involvement of normalized NMDA receptor and mTOR-related signaling in rapid antidepressant effects of Yueju and ketamine on chronically stressed mice. Sci Rep 5:13573

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Krapivinsky G, Krapivinsky L, Manasian Y, Ivanov A, Tyzio R, Pellegrino C, Ben-Ari Y, Clapham DE et al (2003) The NMDA receptor is coupled to the ERK pathway by a direct interaction between NR2B and RasGRF1. Neuron 40(4):775–784

    Article  CAS  PubMed  Google Scholar 

  51. Reznikov LR, Reagan LP, Fadel JR (2008) Activation of phenotypically distinct neuronal subpopulations in the anterior subdivision of the rat basolateral amygdala following acute and repeated stress. J Comp Neurol 508(3):458–472

    Article  PubMed  Google Scholar 

  52. Rostkowski AB, Leitermann RJ, Urban JH (2013) Differential activation of neuronal cell types in the basolateral amygdala by corticotropin releasing factor. Neuropeptides 47(4):273–280

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Rei D, Mason X, Seo J, Gräff J, Rudenko A, Wang J, Rueda R, Siegert S et al (2015) Basolateral amygdala bidirectionally modulates stress-induced hippocampal learning and memory deficits through a p25/Cdk5-dependent pathway. Proc Natl Acad Sci U S A 112(23):7291–7296

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We would like to thank Elizabeth Stone for her technical assistance in the animal behavioral testing and video scoring. We are also grateful to the laboratory animal technician team for animal husbandry.

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Correspondence to Laurence Coutellier.

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All procedures described here were approved by The Ohio State University Office of Responsible Research Practices and conformed to the US National Institutes of Health Guide for the Care and Use of Laboratory Animals.

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The authors declare that they have no conflict of interest.

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Shepard, R., Coutellier, L. Changes in the Prefrontal Glutamatergic and Parvalbumin Systems of Mice Exposed to Unpredictable Chronic Stress. Mol Neurobiol 55, 2591–2602 (2018). https://doi.org/10.1007/s12035-017-0528-0

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