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Early Neurobehavioral Development of Mice Lacking Endogenous PACAP

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Abstract

Pituitary adenylate cyclase activating polypeptide (PACAP) is a multifunctional neuropeptide. In addition to its diverse physiological roles, PACAP has important functions in the embryonic development of various tissues, and it is also considered as a trophic factor during development and in the case of neuronal injuries. Data suggest that the development of the nervous system is severely affected by the lack of endogenous PACAP. Short-term neurofunctional outcome correlates with long-term functional deficits; however, the early neurobehavioral development of PACAP-deficient mice has not yet been evaluated. Therefore, the aim of the present study was to describe the postnatal development of physical signs and neurological reflexes in mice partially or completely lacking PACAP. We examined developmental hallmarks during the first 3 weeks of the postnatal period, during which period most neurological reflexes and motor coordination show most intensive development, and we describe the neurobehavioral development using a complex battery of tests. In the present study, we found that PACAP-deficient mice had slower weight gain throughout the observation period. Interestingly, mice partially lacking PACAP weighed significantly less than homozygous mice. There was no difference between male and female mice during the first 3 weeks. Some other signs were also more severely affected in the heterozygous mice than in the homozygous mice, such as air righting, grasp, and gait initiation reflexes. Interestingly, incisor teeth erupted earlier in mice lacking PACAP. Motor coordination, shown by the number of foot-faults on an elevated grid, was also less developed in PACAP-deficient mice. In summary, our results show that mice lacking endogenous PACAP have slower weight gain during the first weeks of development and slower neurobehavioral development regarding a few developmental hallmarks.

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References

  • Adams BA, Gray SL, Isaac ER et al (2008) Feeding and metabolism in mice lacking pituitary adenylate cyclase-activating polypeptide. Endocrinology 149:1571–1580

    Article  CAS  PubMed  Google Scholar 

  • Adnani L, Langevin LM, Gautier E et al (2015) Zac1 regulates the differentiation and migration of neocortical neurons via PAC1. J Neurosci 35:13430–13447

    Article  CAS  PubMed  Google Scholar 

  • Allais A, Burel D, Isaac ER et al (2007) Altered cerebellar development in mice lacking pituitary adenylate cyclase-activating polypeptide. Eur J Neurosci 25:2604–2618

    Article  PubMed  Google Scholar 

  • Allais A, Burel D, Roy V et al (2010) Balanced effect of PACAP and FasL on granule cell death during cerebellar development: a morphological, functional and behavioural characterization. J Neurochem 113:329–340

    Article  CAS  PubMed  Google Scholar 

  • Atlasz T, Vaczy A, Werling D et al (2016) Neuroprotective effects of PACAP in the retina. In: Reglodi D, Tamas A (eds) Pituitary adenylate cyclase activating polypeptide—PACAP. Springer Nature, New York, pp 501–527

    Chapter  Google Scholar 

  • Banki E, Pakai E, Gaszner B et al (2014) Characterization of the thermoregulatory response to pituitary adenylate cyclase-activating polypeptide in rodents. J Mol Neurosci 54:543–554

    Article  CAS  PubMed  Google Scholar 

  • Bardosi S, Bardosi A, Nagy Z, Reglodi D (2016) Expression of PACAP and PAC1 receptor in normal human thyroid gland and in thyroid papillary carcinoma. J Mol Neurosci 60:171–178

  • Botz B, Bolcskei K, Kereskai L et al (2014) Differential regulatory role of pituitary adenylate-cyclase activating polypeptide in the serum-transfer-induced arthritis model. Arthritis Rheumatism 66:2739–2750

    Article  CAS  Google Scholar 

  • Clason TA, Girard BM, May V, Parsons RL (2016) Activation of MEK/ERK signaling by PACAP in guinea pig cardiac neurons. J Mol Neurosci 59:309–316

  • Egri P, Fekete C, Dénes Á, Reglődi D, Hashimoto H, Fülöp BD, Balázs Gereben (2016) Pituitary adenylate cyclase-activating polypeptide (PACAP) regulates the hypothalamo-pituitary-thyroid (HPT) axis via type 2 deiodinase in male mice. Endocrinology 157:2356–2366

  • Endo K, Nakamachi T, Seki T et al (2011) Neuroprotective effect of PACAP against NMDA-induced retinal damage in the mouse. J Mol Neurosci 43:22–29

    Article  CAS  PubMed  Google Scholar 

  • Falluel-Morel A, Aubert N, Vaudry D et al (2008) Interactions of PACAP and ceramides in the control of granule cell apoptosis during cerebellar development. J Mol Neurosci 36:8–15

    Article  CAS  PubMed  Google Scholar 

  • Farkas J, Reglodi D, Gaszner B et al (2009) Effects of maternal separation on the neurobehavioral development of newborn Wistar rats. Brain Res Bull 79:208–214

    Article  PubMed  Google Scholar 

  • Gaszner B, Kormos V, Kozicz T, Hashimoto H, Reglodi D, Helyes Z (2012) The behavioral phenotype of pituitary adenylate-cyclase activating polypeptide-deficient mice in anxiety and depression tests is accompanied by blunted c-Fos expression in the bed nucleus of the stria terminalis, central projecting Edinger-Westphal nucleus, ventral lateral septum, and dorsal raphe nucleus. Neuroscience 202:283–299

    Article  CAS  PubMed  Google Scholar 

  • Girard BA, Lelievre V, Braas KM et al (2006) Noncompensation in peptide/receptor gene expression and distinct behavioral phenotypes in VIP- and PACAP-deficient mice. J Neurochem 99:499–513

    Article  CAS  PubMed  Google Scholar 

  • Girard BM, Malley SE, Mathews MM, May V, Vizzard MA (2016) Intravesical PAC1 receptor antagonist, PACAP(6-38), reduces urinary bladder frequency and pelvic sensitivity in NGF-OE mice. J Mol Neurosci 59:290–299

    Article  CAS  PubMed  Google Scholar 

  • Gray SL, Cummings KJ, Jirik FR, Sherwood NM (2001) Targeted disruption of the pituitary adenylate cyclase-activating polypeptide gene results in early postnatal death associated with dysfunction of lipid and carbohydrate metabolism. Mol Endocrinol 15:1739–1747

    Article  CAS  PubMed  Google Scholar 

  • Hashimoto H, Shintani N, Tanaka K et al (2001) Altered psychomotor behaviors in mice lacking pituitary adenylate cyclase-activating polypeptide (PACAP). Proc Natl Acad Sci U S A 98:13355–13360

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Horvath G, Kiss P, Nemeth J, Lelesz B, Tamas A, Reglodi D (2015a) Environmental enrichment increases PACAP levels in the CNS of adult rats. Neuroendocrinol Lett 36:143–147

    CAS  PubMed  Google Scholar 

  • Horvath G, Reglodi D, Farkas J et al (2015b) Perinatal positive and negative influences on the early neurobehavioral reflex and motor development. Adv Neurobiol 10:149–167

    Article  PubMed  Google Scholar 

  • Irwin M, Greig A, Tvrdik P, Lucero MT (2015) PACAP modulation of calcium ion activity in developing granule cells of the neonatal mouse olfactory bulb. J Neurophysiol 113:1234–1248

    Article  CAS  PubMed  Google Scholar 

  • Isaac ER, Sherwood NM (2008) Pituitary adenylate cyclase-activating polypeptide (PACAP) is important for embryo implantation in mice. Mol Cell Endocrinol 280:13–19

    Article  CAS  PubMed  Google Scholar 

  • Ishihama T, Ago Y, Shintani N et al (2010) Environmental factors during early developmental period influence psychobehavioral abnormalities in adult PACAP-deficient mice. Behav Brain Res 209:274–280

    Article  CAS  PubMed  Google Scholar 

  • Juhasz T, Helgadottir SL, Reglodi D, Tamas A, Zakany R (2015) Signalisation of VIP and PACAP in chondrogenesis and osteogenesis. Peptides 66:51–57

    Article  CAS  PubMed  Google Scholar 

  • Kiss P, Szogyi D, Reglodi D et al (2009) Effects of perinatal asphyxia on the neurobehavioral and retinal development of newborn rats. Brain Res 1255:42–50

    Article  CAS  PubMed  Google Scholar 

  • Kiss P, Vadasz G, Kiss-Illes B et al (2013) Environmental enrichment decreases asphyxia-induced neurobehavioral developmental delay in neonatal rats. Int J Mol Sci 14:22258–22273

    Article  PubMed  PubMed Central  Google Scholar 

  • Kormos V, Gaspar L, Kovacs LA et al (2016) Reduced response to chronic mild stress in PACAP mutant mice is associated with blunted FosB expression in limbic forebrain and brainstem centers. Neuroscience 330:335–358

    Article  CAS  PubMed  Google Scholar 

  • Kvarik T, Mammel B, Reglodi D et al (2016a) Effects of maternal stress during different periods of pregnancy on the early neurobehavioral response of rats. J Neurol Neurosci 7(2):80

    Article  Google Scholar 

  • Kvarik T, Mammel B, Reglodi D et al (2016b) PACAP is protective in a rat model of retinopathy of prematurity. J Mol Neurosci 60:179–185

    Article  CAS  PubMed  Google Scholar 

  • Laszlo E, Varga A, Kovacs K et al (2015) Ischemia/reperfusion-induced kidney injury in heterozygous PACAP deficient mice. Transplant Proc 47:2210–2215

    Article  CAS  PubMed  Google Scholar 

  • Lehmann ML, Mustafa T, Eiden AM, Herkenham M, Eiden LE (2013) PACAP-deficient mice show attenuated corticosterone secretion and fail to develop depressive behavior during chronic social defeat stress. Psychoneuroendocrinology 38:702–715

    Article  CAS  PubMed  Google Scholar 

  • Lindholm D, Makela J, Korhonen L (2016) PACAP and neural progenitor cells. In: Pituitary adenylate cyclase activating polypeptide—PACAP, edited by Dora Reglodi and Andrea Tamas. Springer Nature, New York, pp 53–63

  • Lubics A, Reglodi D, Tamas A et al (2005) Neurological reflexes and early motor behavior in rats subjected to neonatal hypoxic/ischemic injury. Behav Brain Res 157:157–165

    Article  PubMed  Google Scholar 

  • Maduna T, Lelievre V (2016) Neuropeptides shaping the central nervous system development: spatiotemporal actions of VIP and PACAP through complementary signaling pathways. J Neurosci Res 94:1472–1487

    Article  CAS  PubMed  Google Scholar 

  • Marquez P, Bebawy D, Lelievre V et al (2009) The role of endogenous PACAP in motor stimulation and conditioned place preference induced by morphine in mice. Psychopharmacology 204:457–463

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Matsumoto M, Nakamachi T, Watanabe J et al (2016) Pituitary adenylate cyclase-activating polypeptide (PACAP) is involved in adult mouse hippocampal neurogenesis after stroke. J Mol Neurosci 59:270–279

    Article  CAS  PubMed  Google Scholar 

  • Miyata A, Jiang L, Dahl RD et al (1989) Isolation of a neuropeptide corresponding to the N-terminal 27 residues of the pituitary adenylate cyclase activating polypeptide with 38 residues (PACAP38). Biochem Biophys Res Commun 170:643–648

    Article  Google Scholar 

  • Mori H, Nakamachi T, Ohtaki H et al (2010) Cardioprotective effect of endogenous pituitary adenylate cyclase-activating polypeptide on doxorubicin-induced cardiomyopathy in mice. Circ J 74:1183–1190

    Article  CAS  PubMed  Google Scholar 

  • Nakamachi T, Ohtaki H, Yofu S et al (2010) Endogenous pituitary adenylate cyclase activating polypeptide is involved in suppression of edema in the ischemic brain. Acta Neurochir Suppl 106:43–46

    Article  PubMed  Google Scholar 

  • Nakamachi T, Ohtaki H, Seki T et al (2016) PACAP suppresses dry eye signs by stimulating tear secretion. Nat Commun 7:12034

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nemeth A, Szabadfi K, Fulop B et al (2014) Examination of calcium-binding protein expression in the inner ear of wild type, heterozygous and homozygous pituitary adenylate cyclase activating polypeptide (PACAP)-knockout mice in kanamycin-induced ototoxicity. Neurotox Res 25:57–67

    Article  CAS  PubMed  Google Scholar 

  • Njaine B, Rocha-Martins M, Vieira-Vieira CH et al (2014) Pleiotropic functions of pituitary adenylyl cyclase-activating polypeptide on retinal ontogenesis: involvement of KLF4 in the control of progenitor cell proliferation. J Mol Neurosci 54:430–442

    Article  CAS  PubMed  Google Scholar 

  • Ogawa T, Nakamachi T, Ohtaki H et al (2005) Monoaminergic neuronal development is not affected in PACAP-gene-deficient mice. Regul Pept 126:103–108

    Article  CAS  PubMed  Google Scholar 

  • Ohtaki H, Nakamachi T, Dohi K et al (2006) Pituitary adenylate cyclase-activating polypeptide (PACAP) decreases ischemic neuronal cell death in association with IL-6. Proc Natl Acad Sci U S A 103:7488–7493

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Olsen D, Kaas M, Schwartz O, Nykjaer A, Glerup S (2013) Loss of BDNF or its receptors in three mouse models has unpredictable consequences for anxiety and fear acquisition. Learn Mem 20:499–504

    Article  CAS  PubMed  Google Scholar 

  • Padua D, Vu JP, Germano PM, Pisegna JR (2016) The role of neuropeptides in mouse models of colitis. J Mol Neurosci 59:203–210

    Article  CAS  PubMed  Google Scholar 

  • Reglodi D, Kiss P, Szabadfi K et al (2012) PACAP is an endogenous protective factor—insights from PACAP deficient mice. J Mol Neurosci 48:482–492

    Article  CAS  PubMed  Google Scholar 

  • Sandor B, Fintor K, Felszeghy S et al (2014) Structural and morphometric comparison of the molar teeth in pre-eruptive developmental stage of PACAP-deficient and wild-type mice. J Mol Neurosci 54:331–341

    Article  CAS  PubMed  Google Scholar 

  • Sandor B, Fintor K, Reglodi D et al (2016) Structural and morphometric comparison of lower incisors in PACAP-deficient and wild-type mice. J Mol Neurosci 59:300–308

    Article  CAS  PubMed  Google Scholar 

  • Sehic A, Peterkova R, Lesot H, Risnes S (2009) Distribution and structure of the initial dental enamel formed in incisors of young wild-type and Tabby mice. Eur J Oral Sci 117:644–654

    Article  PubMed  Google Scholar 

  • Shibasaki Y, Hayata-Takano A, Hazama K et al (2015) Atomoxetine reverses locomotor hyperactivity, impaired novel object recognition, and prepulse inhibition impairment in mice lacking pituitary adenylate cyclase-activating polypeptide. Neuroscience 297:95–104

    Article  CAS  PubMed  Google Scholar 

  • Shintani N, Mori W, Hashimoto H et al (2002) Defects in reproductive functions in PACAP-deficient female mice. Regul Pept 109:45–48

    Article  CAS  PubMed  Google Scholar 

  • Shioda S, Nakamachi T (2015) PACAP as a neuroprotective factor in ischemic neuronal injuries. Peptides 72:202–207

    Article  CAS  PubMed  Google Scholar 

  • Suh J, Lu N, Nicot A, Tatsuno I, DiCicco-Bloom E (2001) PACAP is an anti-mitogenic signal in developing cerebral cortex. Nat Neurosci 4:123–124

    Article  CAS  PubMed  Google Scholar 

  • Szabadfi K, Atlasz T, Kiss P et al (2012) Mice deficient in pituitary adenylate cyclase activating polypeptide (PACAP) are more susceptible to retinal ischemic injury in vivo. Neurotox Res 21:41–48

    Article  CAS  PubMed  Google Scholar 

  • Szakaly P, Laszlo E, Kovacs K et al (2011) Mice deficient in pituitary adenylate cyclase activating polypeptide (PACAP) show increased susceptibility to in vivo renal ischemia/reperfusion injury. Neuropeptides 45:113–121

    Article  CAS  PubMed  Google Scholar 

  • Takuma K, Maeda Y, Ago Y et al (2014) An enriched environment ameliorates memory impairments in PACAP-deficient mice. Behav Brain Res 272:269–278

    Article  CAS  PubMed  Google Scholar 

  • Tamas A, Szabadfi K, Nemeth A et al (2012) Comparative examination of inner ear in wild type and pituitary adenylate cyclase activating polypeptide (PACAP) deficient mice. Neurotox Res 21:435–444

    Article  CAS  PubMed  Google Scholar 

  • Ten VS, Bradley-Moore M, Gingrich JA, Stark RI, Pinsky DJ (2003) Brain injury and neurofunctional deficit in neonatal mice with hypoxic-ischemic encephalopathy. Behav Brain Res 145:209–219

    Article  PubMed  Google Scholar 

  • Tsuchikawa D, Nakamachi T, Tsuchida M et al (2012) Neuroprotective effect of endogenous pituitary adenylate cyclase-activating polypeptide on spinal cord injury. J Mol Neurosci 48:508–517

    Article  CAS  PubMed  Google Scholar 

  • Tuka B, Szabo N, Toth E et al (2016) Release of PACAP-38 in episodic cluster headache patients—an exploratory study. J Headache Pain 17:69

    Article  PubMed  PubMed Central  Google Scholar 

  • Uyttebroek L, Shepherd IT, Hubens G, Timmermans JP, Van Nassauw L (2013) Expression of neuropeptides and anoctamin 1 in the embryonic and adult zebrafish intestine, revealing neuronal subpopulations and ICC-like cells. Cell Tissue Res 354:355–370

    Article  CAS  PubMed  Google Scholar 

  • Vaczy A, Reglodi D, Somoskeoy T et al (2016) The protective role of PAC1-receptor agonist maxadilan in BCCAO-induced retinal degeneration. J Mol Neurosci 60:186–194

    Article  CAS  PubMed  Google Scholar 

  • Vamos Z, Ivic I, Cseplo P et al (2014) Pituitary adenylate cyclase activating polypeptide (PACAP) induces relaxations of peripheral and cerebral arteries, which are impaired differently by aging. J Mol Neurosci 54:535–542

    Article  CAS  PubMed  Google Scholar 

  • Vaudry D, Falluel-Morel A, Bourgault S et al (2009) Pituitary adenylate cyclase-activating polypeptide and its receptors: 20 years after the discovery. Pharmacol Rev 61:283–357

    Article  CAS  PubMed  Google Scholar 

  • Vincze A, Reglodi D, Helyes Z, Hashimoto H, Shintani H, Abraham H (2011) Role of pituitary adenylate cyclase activating polypeptide (PACAP) in myelination of the rodent brain: lessons from PACAP-deficient mice. Int J Dev Neurosci 29:923–935

    Article  CAS  PubMed  Google Scholar 

  • Watanabe J, Nakamachi T, Matsuno R et al (2007) Localization, characterization and function of pituitary adenylate cyclase-activating polypeptide during brain development. Peptides 28:1713–1719

    Article  CAS  PubMed  Google Scholar 

  • Watanabe J, Seki T, Shioda S (2016) PACAP and neural development. In: Pituitary adenylate cyclase activating polypeptide – PACAP, edited by Dora Reglodi and Andrea Tamas. Springer Nature pp, New York, pp 65–82

    Chapter  Google Scholar 

  • Wilhelm I, Fazakas C, Tamas A, Reglodi D, Krizbai IA (2014) PACAP enhances barrier properties of cerebral microvessels. J Mol Neurosci 54:469–476

    Article  CAS  PubMed  Google Scholar 

  • Wilson RJ, Cumming KJ (2008) Pituitary adenylate cyclase-activating polypeptide is vital for neonatal survival and the neuronal control of breathing. Respir Physiol Neurobiol 164:168–178

    Article  CAS  PubMed  Google Scholar 

  • Yamada K, Matsuzaki S, Hattori T et al (2010) Increased stathmin1 expression in the dentate gyrus of mice causes abnormal axonal arborizations. PLoS One 5:e8596

    Article  PubMed  PubMed Central  Google Scholar 

  • Yan Y, Zhou X, Pan Z, Ma J, Waschek JA, DiCicco-Bloom E (2013) Pro- and anti-mitogenic actions of pituitary adenylate cyclase-activating polypeptide in developing cerebral cortex: potential mediation by developmental switch of PAC1 receptor mRNA isoforms. J Neurosci 33:3865–3878

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

OTKA K104984, PD109644, National Research, Development and Innovation Fund K119759, GINOP-2.3.2-15-2016-00050 “PEPSYS”, PTE AOK Research Grant, Hungarian Brain Research Program—KTIA_13_NAP-A-III/5, Centre for Neuroscience of the University of Pecs. The UNKP-16-4-IV New National Excellence Program of the Ministry of Human Capacities, and Centre for Neuroscience, University of Pecs, TAMOP 4.2.4.A/2-11-1-2012-0001 “National Excellence Program. Bolyai János Scholarship , Szodoray Lajos and Magyary Zoltán Funds by the European Union and the State of Hungary, University of Debrecen (RH/751/2015). The present scientific contribution is dedicated to the 650th anniversary of the foundation of the University of Pecs, Hungary.

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Authors and Affiliations

  1. Department of Anatomy, Medical School, University of Pecs, Szigeti u 12, 7624, Pecs, Hungary

    Jozsef Farkas, Balazs Sandor, Andrea Tamas, Peter Kiss, Andras D. Nagy, Balazs D. Fulop, Sridharan Manavalan & Dora Reglodi

  2. Department of Dentistry, Oral and Maxillofacial Surgery, University of Pecs, Pecs, Hungary

    Balazs Sandor

  3. Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences and Molecular Research Center for Children’s Mental Development, United Graduate School of Child Development, Osaka University, Osaka, Japan

    Hitoshi Hashimoto

  4. Department of Anatomy, Histology and Embryology, University of Debrecen, Debrecen, Hungary

    Tamas Juhasz

  5. Department of Basic Sciences, National University of Health Sciences, Florida, USA

    Sridharan Manavalan

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  1. Jozsef Farkas
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  2. Balazs Sandor
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  3. Andrea Tamas
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  4. Peter Kiss
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  5. Hitoshi Hashimoto
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  6. Andras D. Nagy
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  8. Tamas Juhasz
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  9. Sridharan Manavalan
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  10. Dora Reglodi
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Correspondence to Dora Reglodi.

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The study was carried out in accordance with ethical guidelines of the University of Pecs, Hungary (BA02/2000-15024/2011).

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Farkas, J., Sandor, B., Tamas, A. et al. Early Neurobehavioral Development of Mice Lacking Endogenous PACAP. J Mol Neurosci 61, 468–478 (2017). https://doi.org/10.1007/s12031-017-0887-z

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