Molecular Neurobiology

, Volume 56, Issue 12, pp 8435–8450 | Cite as

Early Sociability and Social Memory Impairment in the A53T Mouse Model of Parkinson’s Disease Are Ameliorated by Chemogenetic Modulation of Orexin Neuron Activity

  • Milos StanojlovicEmail author
  • Jean Pierre Pallais YllescasJr
  • Aarthi Vijayakumar
  • Catherine Kotz


Parkinson’s disease (PD) is a multi-layered progressive neurodegenerative disease. Signature motor system impairments are accompanied by a variety of other symptoms such as mood, sleep, metabolic, and cognitive disorders. Interestingly, social cognition impairments can be observed from the earliest stages of the disease, prior to the onset of the motor symptoms. In this study, we investigated age-related reductions in sociability and social memory in the A53T mouse model of PD. Since inflammation and astrogliosis are an integral part of PD pathology and impair proper neuronal function, we examined astrogliosis and inflammation markers and parvalbumin expression in medial pre-frontal cortex (mPFC), part of the brain responsible for social cognition regulation. Finally, we used DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) for the stimulation and inhibition of orexin neuronal activity to modulate sociability and social memory in A53T mice. We observed that social cognition impairment in A53T mice is accompanied by an increase in astrogliosis and inflammation markers, in addition to loss of parvalbumin neurons and inhibitory pre-synaptic terminals in the mPFC. Moreover, DREADD-induced activation of orexin neurons restores social cognition in the A53T mouse model of PD.

Significance Statement

Social cognition is severely affected in the early stages of Parkinson’s disease. In this study, we identified the A53T mouse as a model of social cognitive impairment in PD. Observed alterations in sociability and social memory are accompanied by loss of parvalbumin positive neurons and loss of inhibitory input to mPFC. Stimulating orexin neurons using a chemogenetic approach (DREADDs) ameliorated social cognitive impairment. This study identifies a role for orexin neurons in social cognition in PD and suggests potential therapeutic targets for PD-related social cognition impairments.


Parkinson’s disease Orexin Social cognition Neuromodulation mPFC 



We would like to thank the Department of Neuroscience Mouse Behavior Core at the University of Minnesota for their support of the behavioral studies; the University of Minnesota Imaging Centers for their support of the confocal imaging; Dr. Chuanfeng Wang, MD, PhD from the Minneapolis VA Health Care System for providing the Stereo Investigator software and Axio Imager M2 fluorescence microscope; and Cagla Eroglu, PhD, Duke university for providing the Puncta Analyzer plugin for ImageJ software.

Authors’ Contribution

MS: conceived and designed research, performed experiments, analyzed data, interpreted results of experiments, prepared figures, drafted manuscript.

JPP: performed experiments, prepared figures.

AV: performed experiments, prepared figures.

CK: conceived and designed research, interpreted results of experiments, edited and revised manuscript, approved final version of manuscript.


This work was supported by Department of Veterans Affairs (5I01RX000441-04 to CMK), the National Institute of Health (5R01DK100281-03).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.


  1. 1.
    Poewe W, Seppi K, Tanner CM, Halliday GM, Brundin P, Volkmann J, Schrag AE, Lang AE (2017) Parkinson disease. Nat Rev Dis Primer 3(17013).
  2. 2.
    Kalia LV, Lang AE (2015) Parkinson’s disease. Lancet 386:896–912. CrossRefPubMedGoogle Scholar
  3. 3.
    Anandhan A, Jacome MS, Lei S, Hernandez-Franco P, Pappa A, Panayiotidis MI, Powers R, Franco R (2017) Metabolic dysfunction in Parkinson’s disease: Bioenergetics, redox homeostasis and central carbon metabolism. Brain Res Bull 133:12–30. CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Tan LCS (2012) Mood disorders in Parkinson’s disease. Parkinsonism Relat Disord 18:S74–S76. CrossRefPubMedGoogle Scholar
  5. 5.
    Davis AA, Racette B (2016) Parkinson disease and cognitive impairment. Neurol Clin Pract 6:452–458. CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Goldman JG, Litvan I (2011) Mild cognitive impairment in Parkinson’s disease. Minerva Med 102:441–459PubMedPubMedCentralGoogle Scholar
  7. 7.
    Sakurai T, Nagata R, Yamanaka A, Kawamura H, Tsujino N, Muraki Y, Kageyama H, Kunita S et al (2005) Input of orexin/hypocretin neurons revealed by a genetically encoded tracer in mice. Neuron 46:297–308. CrossRefPubMedGoogle Scholar
  8. 8.
    Yoshida K, McCormack S, España RA, Crocker A, Scammell TE (2006) Afferents to the orexin neurons of the rat brain. J Comp Neurol 494:845–861. CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Girault EM, Yi C-X, Fliers E, Kalsbeek A (2012) Orexins, feeding, and energy balance. Prog Brain Res 198:47–64. CrossRefPubMedGoogle Scholar
  10. 10.
    Tsujino N, Sakurai T (2009) Orexin/Hypocretin: A neuropeptide at the Interface of sleep, energy homeostasis, and reward system. Pharmacol Rev 61:162–176. CrossRefPubMedGoogle Scholar
  11. 11.
    Inutsuka A, Yamanaka A (2013) The physiological role of orexin/hypocretin neurons in the regulation of sleep/wakefulness and neuroendocrine functions. Front Endocrinol 4.
  12. 12.
    De Lecea L, Huerta R (2014) Hypocretin (orexin) regulation of sleep-to-wake transitions. Front Pharmacol 5.
  13. 13.
    Kotz CM (2006) Integration of feeding and spontaneous physical activity: Role for orexin. Physiol Behav 88:294–301. CrossRefPubMedGoogle Scholar
  14. 14.
    Perez-Leighton CE, Little MR, Grace MK, Billington C, Kotz CM (2016) Orexin signaling in rostral lateral hypothalamus and nucleus accumbens shell in the control of spontaneous physical activity in high and low activity rats. Am J Physiol - Regul Integr Comp Physiol ajpregu 312:R338–R346. CrossRefGoogle Scholar
  15. 15.
    Johnson PL, Molosh A, Fitz SD et al (2012) Orexin, stress, and anxiety/panic states. Prog Brain Res 198:133–161. CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Yeoh JW, Campbell EJ, James MH, Graham BA, Dayas CV (2014) Orexin antagonists for neuropsychiatric disease: Progress and potential pitfalls. Front Neurosci 8.
  17. 17.
    Muschamp JW, Hollander JA, Thompson JL, Voren G, Hassinger LC, Onvani S, Kamenecka TM, Borgland SL et al (2014) Hypocretin (orexin) facilitates reward by attenuating the antireward effects of its cotransmitter dynorphin in ventral tegmental area. Proc Natl Acad Sci 111:E1648–E1655. CrossRefPubMedGoogle Scholar
  18. 18.
    Mavanji V, Butterick TA, Duffy CM, Nixon JP, Billington CJ, Kotz CM (2017) Orexin/hypocretin treatment restores hippocampal-dependent memory in orexin-deficient mice. Neurobiol Learn Mem 146:21–30. CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Flores Á, Valls-Comamala V, Costa G, Saravia R, Maldonado R, Berrendero F (2014) The Hypocretin/orexin system mediates the extinction of fear memories. Neuropsychopharmacology 39:2732–2741. CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    James MH, Campbell EJ, Dayas CV (2017) Role of the orexin/Hypocretin system in stress-related psychiatric disorders. Curr Top Behav Neurosci 33:197–219. CrossRefPubMedGoogle Scholar
  21. 21.
    Razavi BM, Hosseinzadeh H (2017) A review of the role of orexin system in pain modulation. Biomed Pharmacother Biomedecine Pharmacother 90:187–193. CrossRefGoogle Scholar
  22. 22.
    Bridoux A, Moutereau S, Covali-Noroc A et al (2013) Ventricular orexin-a (hypocretin-1) levels correlate with rapid-eye-movement sleep without atonia in Parkinson’s disease. Nat Sci Sleep 5:87–91. CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Baumann CR, Scammell TE, Bassetti CL (2008) Parkinson’s disease, sleepiness and hypocretin/orexin. Brain J Neurol 131:e91. CrossRefGoogle Scholar
  24. 24.
    Thannickal TC, Lai Y-Y, Siegel JM (2007) Hypocretin (orexin) cell loss in Parkinson’s disease. Brain J Neurol 130:1586–1595. CrossRefGoogle Scholar
  25. 25.
    Fronczek R, van Geest S, Frölich M, Overeem S, Roelandse FWC, Lammers GJ, Swaab DF (2012) Hypocretin (orexin) loss in Alzheimer’s disease. Neurobiol Aging 33:1642–1650. CrossRefPubMedGoogle Scholar
  26. 26.
    Wood JN (2003) Social cognition and the prefrontal cortex. Behav Cogn Neurosci Rev 2:97–114. CrossRefPubMedGoogle Scholar
  27. 27.
    Amodio DM, Frith CD (2006) Meeting of minds: The medial frontal cortex and social cognition. Nat Rev Neurosci 7:268–277. CrossRefPubMedGoogle Scholar
  28. 28.
    Zaki J, Hennigan K, Weber J, Ochsner KN (2010) Social cognitive conflict resolution: Contributions of domain general and domain specific neural systems. J Neurosci 30:8481–8488. CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Bicks LK, Koike H, Akbarian S, Morishita H (2015) Prefrontal cortex and social cognition in mouse and man. Front Psychol 6.
  30. 30.
    Lieberman MD (2007) Social cognitive neuroscience: A review of core processes. Annu Rev Psychol 58:259–289. CrossRefPubMedGoogle Scholar
  31. 31.
    Jin J, Chen Q, Qiao Q, Yang L, Xiong J, Xia J, Hu Z, Chen F (2016) Orexin neurons in the lateral hypothalamus project to the medial prefrontal cortex with a rostro-caudal gradient. Neurosci Lett 621:9–14. CrossRefPubMedGoogle Scholar
  32. 32.
    Lambe EK, Aghajanian GK (2003) Hypocretin (orexin) induces calcium transients in single spines postsynaptic to identified thalamocortical boutons in prefrontal slice. Neuron 40:139–150CrossRefGoogle Scholar
  33. 33.
    Lee MG, Hassani OK, Jones BE (2005) Discharge of identified orexin/hypocretin neurons across the sleep-waking cycle. J Neurosci 25:6716–6720. CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Xia J, Chen X, Song C, Ye J, Yu Z, Hu Z (2005) Postsynaptic excitation of prefrontal cortical pyramidal neurons by hypocretin-1/orexin a through the inhibition of potassium currents. J Neurosci Res 82:729–736. CrossRefPubMedGoogle Scholar
  35. 35.
    Aitta-aho T, Pappa E, Burdakov D, Apergis-Schoute J (2016) Cellular activation of hypothalamic hypocretin/orexin neurons facilitates short-term spatial memory in mice. Neurobiol Learn Mem 136:183–188. CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Calva CB, Fayyaz H, Fadel JR (2018) Increased acetylcholine and glutamate efflux in the prefrontal cortex following intranasal orexin-a (hypocretin-1). J Neurochem 145:232–244. CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Prakash KG, Bannur BM, Chavan MD, Saniya K, Sailesh KS, Rajagopalan A (2016) Neuroanatomical changes in Parkinson’s disease in relation to cognition: An update. J Adv Pharm Technol Res 7:123–126. CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Kendi ATK, Lehericy S, Luciana M et al (2008) Altered diffusion in the frontal lobe in Parkinson disease. Am J Neuroradiol 29:501–505. CrossRefGoogle Scholar
  39. 39.
    Palmeri R, Lo Buono V, Corallo F, Foti M, di Lorenzo G, Bramanti P, Marino S (2017) Nonmotor symptoms in Parkinson disease: A descriptive review on social cognition ability. J Geriatr Psychiatry Neurol 30:109–121. CrossRefPubMedGoogle Scholar
  40. 40.
    Yoshimura N, Kawamura M (2005) Impairment of social cognition in Parkinson’s disease. No To Shinkei 57:107–113PubMedGoogle Scholar
  41. 41.
    Dawson TM, Ko HS, Dawson VL (2010) Genetic animal models of Parkinson’s disease. Neuron 66:646–661. CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Paumier KL, Rizzo SJS, Berger Z et al (2013) Behavioral characterization of A53T mice reveals early and late stage deficits related to Parkinson’s disease. PLoS One 8:e70274. CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Lee MK, Stirling W, Xu Y, Xu X, Qui D, Mandir AS, Dawson TM, Copeland NG et al (2002) Human α-synuclein-harboring familial Parkinson’s disease-linked ala-53 → Thr mutation causes neurodegenerative disease with α-synuclein aggregation in transgenic mice. Proc Natl Acad Sci U S A 99:8968–8973. CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Farrell KF, Krishnamachari S, Villanueva E, Lou H, Alerte TNM, Peet E, Drolet RE, Perez RG (2014) Non-motor parkinsonian pathology in aging A53T α-Synuclein mice is associated with progressive synucleinopathy and altered enzymatic function. J Neurochem 128:536–546. CrossRefPubMedGoogle Scholar
  45. 45.
    Graham DR, Sidhu A (2010) Mice expressing the A53T mutant form of human alpha-Synuclein exhibit hyperactivity and reduced anxiety-like behavior. J Neurosci Res 88:1777–1783. CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Unger EL, Eve DJ, Perez XA, Reichenbach DK, Xu Y, Lee MK, Andrews AM (2006) Locomotor hyperactivity and alterations in dopamine neurotransmission are associated with overexpression of A53T mutant human alpha-synuclein in mice. Neurobiol Dis 21:431–443. CrossRefPubMedGoogle Scholar
  47. 47.
    Matsuki T, Nomiyama M, Takahira H, Hirashima N, Kunita S, Takahashi S, Yagami KI, Kilduff TS et al (2009) Selective loss of GABA(B) receptors in orexin-producing neurons results in disrupted sleep/wakefulness architecture. Proc Natl Acad Sci U S A 106:4459–4464. CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Zink AN, Bunney PE, Holm AA, Billington CJ, Kotz CM (2005) (2018) neuromodulation of orexin neurons reduces diet-induced adiposity. Int J Obes 42:737–745. CrossRefGoogle Scholar
  49. 49.
    Giasson BI, Duda JE, Quinn SM, Zhang B, Trojanowski JQ, Lee VMY (2002) Neuronal α-Synucleinopathy with severe movement disorder in mice expressing A53T human α-Synuclein. Neuron 34:521–533. CrossRefPubMedGoogle Scholar
  50. 50.
    Franklin K (2008) The mouse brain in stereotaxic coordinates. Acad. Press Amsterdam] [u.a. Google Scholar
  51. 51.
    McKinstry SU, Karadeniz YB, Worthington AK et al (2014) Huntingtin is required for Normal excitatory synapse development in cortical and striatal circuits. J Neurosci 34:9455–9472. CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Ippolito DM, Eroglu C (2010) Quantifying synapses: An immunocytochemistry-based assay to quantify synapse number. J Vis Exp JoVE.
  53. 53.
    Franklin KBJ, Paxinos G (2008) The mouse brain in stereotaxic coordinatesGoogle Scholar
  54. 54.
    Lee S, Oh ST, Jeong HJ, Pak SC, Park HJ, Kim J, Cho HS, Jeon S (2017) MPTP-induced vulnerability of dopamine neurons in A53T α-synuclein overexpressed mice with the potential involvement of DJ-1 downregulation. Korean J Physiol Pharmacol Off J Korean Physiol Soc Korean Soc Pharmacol 21:625–632. CrossRefGoogle Scholar
  55. 55.
    Xie Z, Turkson S, Zhuang X (2015) A53T human α-Synuclein overexpression in transgenic mice induces pervasive mitochondria macroautophagy defects preceding dopamine neuron degeneration. J Neurosci 35:890–905. CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Phani S, Loike JD, Przedborski S (2012) Neurodegeneration and inflammation in Parkinson’s disease. Parkinsonism Relat Disord 18:S207–S209. CrossRefPubMedGoogle Scholar
  57. 57.
    Booth HDE, Hirst WD, Wade-Martins R (2017) The role of astrocyte dysfunction in Parkinson’s disease pathogenesis. Trends Neurosci 40:358–370. CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Fellner L, Jellinger KA, Wenning GK, Stefanova N (2011) Glial dysfunction in the pathogenesis of α-synucleinopathies: Emerging concepts. Acta Neuropathol (Berl) 121:675–693. CrossRefGoogle Scholar
  59. 59.
    Gu X-L, Long C-X, Sun L, Xie C, Lin X, Cai H (2010) Astrocytic expression of Parkinson’s disease-related A53T α-synuclein causes neurodegeneration in mice. Mol Brain 3:12. CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Murray AJ, Woloszynowska-Fraser MU, Ansel-Bollepalli L, Cole KLH, Foggetti A, Crouch B, Riedel G, Wulff P (2015) Parvalbumin-positive interneurons of the prefrontal cortex support working memory and cognitive flexibility. Sci Rep 5:16778. CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Chen C-C, Lu J, Yang R, Ding JB, Zuo Y (2018) Selective activation of parvalbumin interneurons prevents stress-induced synapse loss and perceptual defects. Mol Psychiatry 23:1614–1625. CrossRefPubMedGoogle Scholar
  62. 62.
    Wöhr M, Orduz D, Gregory P, Moreno H, Khan U, Vörckel KJ, Wolfer DP, Welzl H et al (2015) Lack of parvalbumin in mice leads to behavioral deficits relevant to all human autism core symptoms and related neural morphofunctional abnormalities. Transl Psychiatry 5:e525. CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Yizhar O, Fenno LE, Prigge M, Schneider F, Davidson TJ, O’Shea DJ, Sohal VS, Goshen I et al (2011) Neocortical excitation/inhibition balance in information processing and social dysfunction. Nature 477:171–178. CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Takahashi Y, Kanbayashi T, Hoshikawa M, Imanishi A, Sagawa Y, Tsutsui K, Takeda Y, Kusanagi H et al (2015) Relationship of orexin (hypocretin) system and astrocyte activation in Parkinson’s disease with hypersomnolence. Sleep Biol Rhythms 13:252–260. CrossRefGoogle Scholar
  65. 65.
    Fronczek R, Overeem S, Lee SYY, Hegeman IM, van Pelt J, van Duinen SG, Lammers GJ, Swaab DF (2007) Hypocretin (orexin) loss in Parkinson’s disease. Brain J Neurol 130:1577–1585. CrossRefGoogle Scholar
  66. 66.
    Delli Pizzi S, Chiacchiaretta P, Mantini D, Bubbico G, Edden RA, Onofrj M, Ferretti A, Bonanni L (2017) GABA content within medial prefrontal cortex predicts the variability of fronto-limbic effective connectivity. Brain Struct Funct 222:3217–3229. CrossRefPubMedGoogle Scholar
  67. 67.
    Bañuelos C, Beas BS, McQuail JA et al (2014) Prefrontal cortical GABAergic dysfunction contributes to age-related working memory impairment. J Neurosci 34:3457–3466. CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Houtepen LC, Schür RR, Wijnen JP, Boer VO, Boks MPM, Kahn RS, Joëls M, Klomp DW et al (2017) Acute stress effects on GABA and glutamate levels in the prefrontal cortex: A 7T 1H magnetic resonance spectroscopy study. NeuroImage Clin 14:195–200. CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Gomez JL, Bonaventura J, Lesniak W, Mathews WB, Sysa-Shah P, Rodriguez LA, Ellis RJ, Richie CT et al (2017) Chemogenetics revealed: DREADD occupancy and activation via converted clozapine. Science 357:503–507. CrossRefPubMedGoogle Scholar
  70. 70.
    Aracri P, Banfi D, Pasini ME, Amadeo A, Becchetti A (2015) Hypocretin (orexin) regulates glutamate input to fast-spiking interneurons in layer V of the Fr2 region of the murine prefrontal cortex. Cereb Cortex N Y NY 25:1330–1347. CrossRefGoogle Scholar
  71. 71.
    Xia JX, Fan SY, Yan J, Chen F, Li Y, Yu ZP, Hu ZA (2009) Orexin A-induced extracellular calcium influx in prefrontal cortex neurons involves L-type calcium channels. J Physiol Biochem 65:125–136. CrossRefPubMedGoogle Scholar
  72. 72.
    Bonito-Oliva A, Masini D, Fisone G (2014) A mouse model of non-motor symptoms in Parkinson’s disease: Focus on pharmacological interventions targeting affective dysfunctions. Front Behav Neurosci 8.
  73. 73.
    Vucković MG, Wood RI, Holschneider DP et al (2008) Memory, mood, dopamine, and serotonin in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mouse model of basal ganglia injury. Neurobiol Dis 32:319–327. CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Doty RL, Singh A, Tetrud J, Langston JW (1992) Lack of major olfactory dysfunction in MPTP-induced parkinsonism. Ann Neurol 32:97–100. CrossRefPubMedGoogle Scholar
  75. 75.
    Magen I, Torres ER, Dinh D, Chung A, Masliah E, Chesselet MF (2015) Social cognition impairments in mice overexpressing alpha-Synuclein under the Thy1 promoter, a model of pre-manifest Parkinson’s disease. J Park Dis 5:669–680. CrossRefGoogle Scholar
  76. 76.
    Kurz A, Double KL, Lastres-Becker I, Tozzi A, Tantucci M, Bockhart V, Bonin M, García-Arencibia M et al (2010) A53T-alpha-Synuclein overexpression impairs dopamine signaling and striatal synaptic plasticity in old mice. PLoS One 5:e11464. CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Homberg JR, Olivier JDA, VandenBroeke M, Youn J, Ellenbroek AK, Karel P, Shan L, van Boxtel R et al (2016) The role of the dopamine D1 receptor in social cognition: Studies using a novel genetic rat model­. Dis Model Mech 9:1147–1158. CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Gunaydin LA, Deisseroth K (2014) Dopaminergic dynamics contributing to social behavior. Cold Spring Harb Symp Quant Biol 79:221–227. CrossRefPubMedGoogle Scholar
  79. 79.
    Báez-Mendoza R, Schultz W (2013) The role of the striatum in social behavior. Front Neurosci 7.
  80. 80.
    Narme P, Mouras H, Roussel M, Duru C, Krystkowiak P, Godefroy O (2013) Emotional and cognitive social processes are impaired in Parkinson’s disease and are related to behavioral disorders. Neuropsychology 27:182–192. CrossRefPubMedGoogle Scholar
  81. 81.
    Hoenen C, Gustin A, Birck C, Kirchmeyer M, Beaume N, Felten P, Grandbarbe L, Heuschling P et al (2016) Alpha-Synuclein proteins promote pro-inflammatory cascades in microglia: Stronger effects of the A53T mutant. PLoS One 11:e0162717. CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Martin LJ, Pan Y, Price AC, Sterling W, Copeland NG, Jenkins NA, Price DL, Lee MK (2006) Parkinson’s disease α-Synuclein transgenic mice develop neuronal mitochondrial degeneration and cell death. J Neurosci 26:41–50. CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Rockenstein E, Schwach G, Ingolic E, Adame A, Crews L, Mante M, Pfragner R, Schreiner E et al (2005) Lysosomal pathology associated with alpha-synuclein accumulation in transgenic models using an eGFP fusion protein. J Neurosci Res 80:247–259. CrossRefPubMedGoogle Scholar
  84. 84.
    Paine TA, Swedlow N, Swetschinski L (2017) Decreasing GABA function within the medial prefrontal cortex or basolateral amygdala decreases sociability. Behav Brain Res 317:542–552. CrossRefPubMedGoogle Scholar
  85. 85.
    Kolata SM, Nakao K, Jeevakumar V, Farmer-Alroth EL, Fujita Y, Bartley AF, Jiang SZ, Rompala GR et al (2018) Neuropsychiatric phenotypes produced by GABA reduction in mouse cortex and hippocampus. Neuropsychopharmacol Off Publ Am Coll Neuropsychopharmacol 43:1445–1456. CrossRefGoogle Scholar
  86. 86.
    Hashemi E, Ariza J, Rogers H, Noctor SC, Martínez-Cerdeño V (1991) (2017) the number of Parvalbumin-expressing interneurons is decreased in the prefrontal cortex in autism. Cereb Cortex N Y N 27:1931–1943. CrossRefGoogle Scholar
  87. 87.
    Villalobos CA, Wu Q, Lee PH, May PJ, Basso MA (2018) Parvalbumin and GABA microcircuits in the mouse superior colliculus. Front Neural Circuits 12.
  88. 88.
    Leekam S (2016) Social cognitive impairment and autism: what are we trying to explain? Philos Trans R Soc B Biol Sci 371:20150082. CrossRefGoogle Scholar
  89. 89.
    Dawson TM, Dawson VL (2010) The role of Parkin in familial and sporadic Parkinson’s disease. Mov Disord Off J Mov Disord Soc 25:S32–S39. CrossRefGoogle Scholar
  90. 90.
    Palumbo O, Palumbo P, Leone MP, Stallone R, Palladino T, Vendemiale M, Palladino S, Papadia F et al (2016) PARK2 microduplication: Clinical and molecular characterization of a further case and review of the literature. Mol Syndromol 7:282–286. CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    Compta Y, Santamaria J, Ratti L, Tolosa E, Iranzo A, Munoz E, Valldeoriola F, Casamitjana R et al (2009) Cerebrospinal hypocretin, daytime sleepiness and sleep architecture in Parkinson’s disease dementia. Brain J Neurol 132:3308–3317. CrossRefGoogle Scholar
  92. 92.
    Asai H, Hirano M, Furiya Y, Udaka F, Morikawa M, Kanbayashi T, Shimizu T, Ueno S (2009) Cerebrospinal fluid-orexin levels and sleep attacks in four patients with Parkinson’s disease. Clin Neurol Neurosurg 111:341–344. CrossRefPubMedGoogle Scholar
  93. 93.
    Dhawan V, Healy DG, Pal S, Chaudhuri KR (2006) Sleep-related problems of Parkinson’s disease. Age Ageing 35:220–228. CrossRefPubMedGoogle Scholar
  94. 94.
    Abbott RD, Ross GW, White LR, Tanner CM, Masaki KH, Nelson JS, Curb JD, Petrovitch H (2005) Excessive daytime sleepiness and subsequent development of Parkinson disease. Neurology 65:1442–1446. CrossRefPubMedGoogle Scholar
  95. 95.
    Drouot X, Moutereau S, Nguyen JP, Lefaucheur JP, Creange A, Remy P, Goldenberg F, d'Ortho MP (2003) Low levels of ventricular CSF orexin/hypocretin in advanced PD. Neurology 61:540–543CrossRefGoogle Scholar
  96. 96.
    Yasui K, Inoue Y, Kanbayashi T, Nomura T, Kusumi M, Nakashima K (2006) CSF orexin levels of Parkinson’s disease, dementia with Lewy bodies, progressive supranuclear palsy and corticobasal degeneration. J Neurol Sci 250:120–123. CrossRefPubMedGoogle Scholar
  97. 97.
    Auger ML, Floresco SB (2014) Prefrontal cortical GABA modulation of spatial reference and working memory. Int J Neuropsychopharmacol 18.
  98. 98.
    Ghosal S, Hare B, Duman RS (2017) Prefrontal cortex GABAergic deficits and circuit dysfunction in the pathophysiology and treatment of chronic stress and depression. Curr Opin Behav Sci 14:1–8. CrossRefPubMedPubMedCentralGoogle Scholar
  99. 99.
    Calipari ES, España RA (2012) Hypocretin/orexin regulation of dopamine signaling: Implications for reward and reinforcement mechanisms. Front Behav Neurosci 6.
  100. 100.
    Surmeier DJ (2018) Determinants of dopaminergic neuron loss in Parkinson’s disease. FEBS J 285:3657–3668. CrossRefPubMedPubMedCentralGoogle Scholar
  101. 101.
    Isaias IU, Trujillo P, Summers P, Marotta G, Mainardi L, Pezzoli G, Zecca L, Costa A (2016) Neuromelanin imaging and dopaminergic loss in Parkinson’s disease. Front Aging Neurosci 8.

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Authors and Affiliations

  1. 1.Integrative Biology and PhysiologyUniversity of MinnesotaMinneapolisUSA
  2. 2.GRECCMinneapolis VA Health Care SystemMinneapolisUSA

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