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01-07-2019 | Original Article

Deficiency of the palmitoyl acyltransferase ZDHHC7 impacts brain and behavior of mice in a sex-specific manner

Authors: Christa Hohoff, Mingyue Zhang, Oliver Ambrée, Mykola Kravchenko, Jens Buschert, Nicole Kerkenberg, Nataliya Gorinski, Dalia Abdel Galil, Christiane Schettler, Kari Lavinia vom Werth, Maximilian F.-J. Wewer, Ilona Schneider, Dominik Grotegerd, Lydia Wachsmuth, Cornelius Faber, Boris V. Skryabin, Juergen Brosius, Evgeni Ponimaskin, Weiqi Zhang

Published in: Brain Structure and Function | Issue 6/2019

Abstract

The palmitoyl acyltransferase ZDHHC7 belongs to the DHHC family responsible for the covalent attachment of palmitic acid (palmitoylation) to target proteins. Among synaptic proteins, its main targets are sex steroid receptors such as the estrogen receptors. When palmitoylated, these couple to membrane microdomains and elicit non-genomic rapid responses. Such coupling is found particularly in cortico-limbic brain areas which impact structure, function, and behavioral outcomes. Thus far, the functional role of ZDHHC7 has not been investigated in this context. To directly analyze an impact of ZDHHC7 on brain anatomy, microstructure, connectivity, function, and behavior, we generated a mutant mouse in which the Zdhhc7 gene is constitutively inactivated. Male and female Zdhhc7^−/− mice were phenotypically compared with wild-type mice using behavioral tests, electrophysiology, protein analyses, and neuroimaging with diffusion tensor-based fiber tractography. Zdhhc7-deficiency impaired excitatory transmission, synaptic plasticity at hippocampal Schaffer collateral CA1 synapses, and hippocampal structural connectivity in both sexes in similar manners. Effects on both sexes but in different manners appeared in medial prefrontal cortical synaptic transmission and in hippocampal microstructures. Finally, Zdhhc7-deficiency affected anxiety-related behaviors exclusively in females. Our data demonstrated the importance of Zdhhc7 for assembling proper brain structure, function, and behavior on a system level in mice in a sex-related manner. Given the prominent role of sex-specificity also in humans and associated mental disorders, Zdhhc7^−/− mice might provide a promising model for in-depth investigation of potentially underlying sex-specifically altered mechanisms.

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Agarwal A, Zhang M, Trembak-Duff I, Unterbarnscheidt T, Radyushkin K, Dibaj P et al (2014) Dysregulated expression of neuregulin-1 by cortical pyramidal neurons disrupts synaptic plasticity. Cell Rep 8:1130–1145CrossRefPubMed

Ambrée O, Klassen I, Forster I, Arolt V, Scheu S, Alferink J (2016) Reduced locomotor activity and exploratory behavior in CC chemokine receptor 4 deficient mice. Behav Brain Res 314:87–95CrossRefPubMed

Anacker C, Scholz J, O’Donnell KJ, Allemang-Grand R, Diorio J, Bagot RC et al (2016) Neuroanatomic differences associated with stress susceptibility and resilience. Biol Psychiatry 79:840–849CrossRefPubMed

Antinone SE, Ghadge GD, Lam TT, Wang L, Roos RP, Green WN (2013) Palmitoylation of superoxide dismutase 1 (SOD1) is increased for familial amyotrophic lateral sclerosis-linked SOD1 mutants. J Biol Chem 288:21606–21617CrossRefPubMedPubMedCentral

Baker KE, Parker R (2004) Nonsense-mediated mRNA decay: terminating erroneous gene expression. Curr Opin Cell Biol 16:293–299CrossRefPubMed

Balthazart J, Ball GF (2006) Is brain estradiol a hormone or a neurotransmitter? Trends Neurosci 29:241–249CrossRefPubMed

Bandler R, Keay KA, Floyd N, Price J (2000) Central circuits mediating patterned autonomic activity during active vs. passive emotional coping. Brain Res Bull 53:95–104CrossRefPubMed

Baudry M, Bi X, Aguirre C (2013) Progesterone-estrogen interactions in synaptic plasticity and neuroprotection. Neuroscience 239:280–294CrossRefPubMed

Boulware MI, Mermelstein PG (2009) Membrane estrogen receptors activate metabotropic glutamate receptors to influence nervous system physiology. Steroids 74:608–613CrossRefPubMed

Boulware MI, Weick JP, Becklund BR, Kuo SP, Groth RD, Mermelstein PG (2005) Estradiol activates group I and II metabotropic glutamate receptor signaling, leading to opposing influences on cAMP response element-binding protein. J Neurosci 25:5066–5078CrossRefPubMed

Brinton RD, Thompson RF, Foy MR, Baudry M, Wang J, Finch CE et al (2008) Progesterone receptors: form and function in brain. Front Neuroendocrinol 29:313–339CrossRefPubMedPubMedCentral

Butland SL, Sanders SS, Schmidt ME, Riechers SP, Lin DT, Martin DD et al (2014) The palmitoyl acyltransferase HIP14 shares a high proportion of interactors with huntingtin: implications for a role in the pathogenesis of Huntington’s disease. Hum Mol Genet 23:4142–4160CrossRefPubMedPubMedCentral

Crawley JN (2007) What’s wrong with my mouse? Behavioral phenotyping of transgenic and knockout mice, 2nd edn. Wiley, New YorkCrossRef

Cryan JF, Kaupmann K (2005) Don’t worry ‘B’happy!: a role for GABAB receptors in anxiety and depression. Trends Pharmacol Sci 26:36–43CrossRefPubMed

Damasio AR, Grabowski TJ, Bechara A, Damasio H, Ponto LL, Parvizi J et al (2000) Subcortical and cortical brain activity during the feeling of self-generated emotions. Nat Neurosci 3:1049–1056CrossRefPubMed

Doyère V, Burette F, Negro CR, Laroche S (1993) Long-term potentiation of hippocampal afferents and efferents to prefrontal cortex: implications for associative learning. Neuropsychol 31:1031–1053CrossRef

El-Husseini Ael-D, Bredt DS (2002) Protein palmitoylation: a regulator of neuronal development and function. Nat Rev Neurosci 3:791–802CrossRef

Fernandez Marron, de Velasco E, Hearing M, Xia Z, Victoria NC, Luján R, Wickman K (2015) Sex differences in GABA(B)R-GIRK signaling in layer 5/6 pyramidal neurons of the mouse prelimbic cortex. Neuropharmacology 95:353–360CrossRef

Fish EW, Wieczorek LA, Rumple A, Suttie M, Moy SS, Hammond P et al (2018) The enduring impact of neurulation stage alcohol exposure: a combined behavioral and structural neuroimaging study in adult male and female C57BL/6 J mice. Behav Brain Res 338:173–184CrossRefPubMed

Franklin KBJ, Chudasama Y (2012) Chapter 30 - Prefrontal Cortex. In: Watson C, Paxinos G, Puelles L (eds) The Mouse Nervous System. Academic Press, San Diego, pp 727–735CrossRef

Fukata Y, Fukata M (2010) Protein palmitoylation in neuronal development and synaptic plasticity. Nat Rev Neurosci 11:161–175CrossRefPubMed

Galvin C, Ninan I (2014) Regulation of the mouse medial prefrontal cortical synapses by endogenous estradiol. Neuropsychopharmacology 39:2086–2094CrossRefPubMedPubMedCentral

Hammelrath L, Škokić S, Khmelinskii A, Hess A, van der Knaap N, Staring M et al (2016) Morphological maturation of the mouse brain: an in vivo MRI and histology investigation. Neuroimage 125:144–152CrossRefPubMed

Hart SA, Snyder MA, Smejkalova T, Woolley CS (2007) Estrogen mobilizes a subset of estrogen receptor-alpha-immunoreactive vesicles in inhibitory presynaptic boutons in hippocampal CA1. J Neurosci 27:2102–2111CrossRefPubMed

Hughes RN (2004) The value of spontaneous alternation behavior (SAB) as a test of retention in pharmacological investigations of memory. Neurosci Biobehav Rev 28:497–505CrossRefPubMed

Jay TM, Burette F, Laroche S (1996) Plasticity of the hippocampal-prefrontal cortex synapses. J Physiol Paris 90:361–366CrossRefPubMed

Jonas P, Bischofberger J, Sandkühler J (1998) Corelease of two fast neurotransmistters at a central synapse. Science 281:419–424CrossRefPubMed

Kilpatrick CL, Murakami S, Feng M, Wu X, Lal R, Chen G et al (2016) Dissociation of Golgi-associated DHHC-type Zinc Finger Protein (GODZ)- and Sertoli Cell Gene with a Zinc Finger Domain-β (SERZ-β)-mediated Palmitoylation by Loss of Function Analyses in Knock-out Mice. J Biol Chem 291:27371–27386CrossRefPubMedPubMedCentral

Korycka J, Łach A, Heger E, Bogusławska DM, Wolny M, Toporkiewicz M et al (2012) Human DHHC proteins: a spotlight on the hidden player of palmitoylation. Eur J Cell Biol 91:107–117CrossRefPubMed

Kreher BW, Hennig J, Il’yasov KA (2006) DTI&FiberTools: a complete toolbox for dti calculation, fiber tracking and combined evaluation. In: proceeding of ISMRM 14th international scientific meeting seattle, USA

Lemonidis K, Werno MW, Greaves J, Diez-Ardanuy C, Sanchez-Perez MC, Salaun C et al (2015) The zDHHC family of S-acyltransferases. Biochem Soc Trans 43:217–221CrossRefPubMed

Linder ME, Deschenes RJ (2007) Palmitoylation: policing protein stability and traffic. Nat Rev Mol Cell Biol 8:74–84CrossRefPubMed

Lynch MA (2004) Long-term potentiation and memory. Physiol Rev 84:87–136CrossRefPubMed

Mateo Z, Porter JT (2007) Group II metabotropic glutamate receptors inhibit glutamate release at thalamocortical synapses in the developing somatosensory cortex. Neuroscience 146:1062–1072CrossRefPubMedPubMedCentral

Medrihan L, Tantalaki E, Aramuni G, Sargsyan V, Dudanova I, Missler M et al (2008) Early defects of GABAergic synapses in the brain stem of a MeCP2 mouse model of Rett syndrome. J Neurophysiol 99:112–121CrossRefPubMed

Meitzen J, Mermelstein PG (2011) Estrogen receptors stimulate brain region specific metabotropic glutamate receptors to rapidly initiate signal transduction pathways. J Chem Neuroanat 42:236–241CrossRefPubMedPubMedCentral

Meitzen J, Grove DD, Mermelstein PG (2012) The organizational and aromatization hypotheses apply to rapid, nonclassical hormone action: neonatal masculinization eliminates rapid estradiol action in female hippocampal neurons. Endocrinology 153:4616–4621CrossRefPubMedPubMedCentral

Meitzen J, Luoma JI, Boulware MI, Hedges VL, Peterson BM, Tuomela K et al (2013) Palmitoylation of estrogen receptors is essential for neuronal membrane signaling. Endocrinology 154:4293–4304CrossRefPubMedPubMedCentral

Meitzen J, Britson KA, Tuomela K, Mermelstein PG (2017) The expression of select genes necessary for membrane-associated estrogen receptor signaling differ by sex in adult rat hippocampus. Steroids 142:21–27CrossRefPubMed

Mitchell DA, Hamel LD, Reddy KD, Farh L, Rettew LM, Sanchez PR et al (2014) Mutations in the X-linked intellectual disability gene, zDHHC9, alter autopalmitoylation activity by distinct mechanisms. J Biol Chem 289:18582–18592CrossRefPubMedPubMedCentral

Mori S, Crain BJ, Chacko VP, van Zijl PC (1999) Three-dimensional tracking of axonal projections in the brain by magnetic resonance imaging. Ann Neurol 45:265–269CrossRefPubMed

Nabekura J, Katsurabayashi S, Kakazu Y, Shibata S, Matsubara A, Jinno S et al (2004) Developmental switch from GABA to Glycine release in single central synaptic terminals. Nat Neurosci 7:17–23CrossRefPubMed

Naumenko VS, Ponimaskin E (2018) Palmitoylation as a Functional Regulator of Neurotransmitter Receptors. Neur Plast 2018:5701348

Oberlander JG, Woolley CS (2016) 17β-Estradiol acutely potentiates glutamatergic synaptic transmission in the hippocampus through distinct mechanisms in males and females. J Neurosci 36:2677–2690CrossRefPubMedPubMedCentral

Oh SW, Harris JA, Ng L, Winslow B, Cain N, Mihalas S et al (2014) A mesoscale connectome of the mouse brain. Nature 508:207–214CrossRefPubMedPubMedCentral

Ohno Y, Kihara A, Sano T, Igarashi Y (2006) Intracellular localization and tissue-specific distribution of human and yeast DHHC cysteine-rich domain-containing proteins. Biochim Biophys Acta 1761:474–483CrossRefPubMed

Ooishi Y, Kawato S, Hojo Y, Hatanaka Y, Higo S, Murakami G et al (2012) Modulation of synaptic plasticity in the hippocampus by hippocampus-derived estrogen and androgen. J Steroid Biochem Mol Biol 131:37–51CrossRefPubMed

Palanza P, Parmigiani S (2017) How does sex matter? Behavior, stress and animal models of neurobehavioral disorders. Neurosci Biobehav Rev 76:134–143CrossRefPubMed

Paxinos G, Franklin KBJ (2013) Paxinos and Franklin’s the mouse brain in stereotaxic coordinates, 4th edn. Academic Press, San Diego

Pedram A, Razandi M, Deschenes RJ, Levin ER (2012) DHHC-7 and -21 are palmitoylacyltransferases for sex steroid receptors. Mol Biol Cell 23:188–199CrossRefPubMedPubMedCentral

Pilc A, Chaki S, Nowak G, Witkin JM (2008) Mood disorders: regulation by metabotropic glutamate receptors. Biochem Pharmacol 75:997–1006CrossRefPubMed

Ponimaskin E, Dityateva G, Ruonala MO, Fukata M, Fukata Y, Kobe F et al (2008) Fibroblast growth factor-regulated palmitoylation of the neural cell adhesion molecule determines neuronal morphogenesis. J Neurosci 28:8897–8907CrossRefPubMedPubMedCentral

Saffari R, Teng Z, Zhang M, Kravchenko M, Hohoff C, Ambrée O et al (2016) NPY⁺-, but not PV⁺-GABAergic neurons mediated long-range inhibition from infra- to prelimbic cortex. Transl Psychiatry 6:e736CrossRefPubMedPubMedCentral

Sakalem ME, Seidenbecher T, Zhang M, Saffari R, Kravchenko M, Wördemann S et al (2017) Environmental enrichment and physical exercise revert behavioral and electrophysiological impairments caused by reduced adult neurogenesis. Hippocampus 27:36–51CrossRefPubMed

Scholz J, Niibori Y, Frankland PW, Lerch JP (2015) Rotarod training in mice is associated with changes in brain structure observable with multimodal MRI. Neuroimage 107:182–189CrossRefPubMed

Seney ML, Sibille E (2014) Sex differences in mood disorders: perspectives from humans and rodent models. Biology Sex Differ 5:17CrossRef

Shipston MJ (2011) Ion channel regulation by protein palmitoylation. J Biol Chem 286:8709–8716CrossRefPubMedPubMedCentral

Spampinato SF, Molinaro G, Merlo S, Iacovelli L, Caraci F, Battaglia G et al (2012) Estrogen receptors and type 1 metabotropic glutamate receptors are interdependent in protecting cortical neurons against β-amyloid toxicity. Mol Pharmacol 81:12–20CrossRefPubMed

Steinke KV, Gorinski N, Wojciechowski D, Todorov V, Guseva D, Ponimaskin E et al (2015) Human CLC–K channels require palmitoylation of their accessory subunit barttin to be functional. J Biol Chem 290:17390–17400CrossRefPubMedPubMedCentral

Suzuki H, Barros RP, Sugiyama N, Krishnan V, Yaden BC, Kim HJ et al (2013) Involvement of estrogen receptor β in maintenance of serotonergic neurons of the dorsal raphe. Mol Psychiatry 18:674–680CrossRefPubMed

Tonn Eisinger KR, Woolfrey KM, Swanson SP, Schnell SA, Meitzen J, Dell’Acqua M et al (2018) Palmitoylation of caveolin-1 is regulated by the same DHHC acyltransferases that modify steroid hormone receptors. J Biol Chem 293:15901–15911CrossRefPubMed

Tripathi A, Schenker E, Spedding M, Jay TM (2016) The hippocampal to prefrontal cortex circuit in mice: a promising electrophysiological signature in models for psychiatric disorders. Brain Struct Funct 221:2385–2391CrossRefPubMed

Uylings HB, Groenewegen HJ, Kolb B (2003) Do rats have a prefrontal cortex? Behav Brain Res 146:3–17CrossRefPubMed

Wehr MC, Hinrichs W, Brzózka MM, Unterbarnscheidt T, Herholt A, Wintgens J et al (2017) Spironolactone is an antagonist of NRG1-ERBB4 signaling and schizophrenia-relevant endophenotypes in mice. EMBO Mol Med 9:1448–1462CrossRefPubMedPubMedCentral

Wilcoxon JS, Nadolski GJ, Samarut J, Chassande O, Redei EE (2007) Behavioral inhibition and impaired spatial learning and memory in hypothyroid mice lacking thyroid hormone receptor alpha. Behav Brain Res 177:109–116CrossRefPubMed

Wójtowicz T, Lebida K, Mozrzymas JW (2008) 17beta-estradiol affects GABAergic transmission in developing hippocampus. Brain Res 1241:7–17CrossRefPubMed

Wright RA, Johnson BG, Zhang C, Salhoff C, Kingston AE, Calligaro DO et al (2013) CNS distribution of metabotropic glutamate 2 and 3 receptors: transgenic mice and [3H] LY459477 autoradiography. Neuropharmacology 66:89–98CrossRefPubMed

Wu MV, Tollkuhn J (2017) Estrogen receptor alpha is required in GABAergic, but not glutamatergic, neurons to masculinize behavior. Horm Behav 95:3–12CrossRefPubMed

Zagni E, Simoni L, Colombo D (2016) Sex and gender differences in central nervous system-related disorders. Neurosci J 2016:2827090CrossRefPubMedPubMedCentral

Title: Deficiency of the palmitoyl acyltransferase ZDHHC7 impacts brain and behavior of mice in a sex-specific manner
Authors: Christa Hohoff
Mingyue Zhang
Oliver Ambrée
Mykola Kravchenko
Jens Buschert
Nicole Kerkenberg
Nataliya Gorinski
Dalia Abdel Galil
Christiane Schettler
Kari Lavinia vom Werth
Maximilian F.-J. Wewer
Ilona Schneider
Dominik Grotegerd
Lydia Wachsmuth
Cornelius Faber
Boris V. Skryabin
Juergen Brosius
Evgeni Ponimaskin
Weiqi Zhang
Publication date: 01-07-2019
Publisher: Springer Berlin Heidelberg
Published in: Brain Structure and Function / Issue 6/2019
Print ISSN: 1863-2653
Electronic ISSN: 1863-2661
DOI: https://doi.org/10.1007/s00429-019-01898-6

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Deficiency of the palmitoyl acyltransferase ZDHHC7 impacts brain and behavior of mice in a sex-specific manner

Abstract

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Abstract

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