Skip to main content Accessibility help

We use cookies to distinguish you from other users and to provide you with a better experience on our websites. Close this message to accept cookies or find out how to manage your cookie settings.

Close cookie message
×
Hostname: page-component-cd9895bd7-jkksz Total loading time: 0 Render date: 2024-12-28T13:28:00.151Z Has data issue: false hasContentIssue false

Chapter 14 - The Neurobiology of Prader-Willi Syndrome

Published online by Cambridge University Press:  26 May 2022

By
Deepan Singh
Edited by
Deepan Singh
Deepan Singh
Affiliation:
Maimonides Medical Center in Brooklyn
Get access

Summary

This chapter is intended to provide a neurobiologically based framework to understand the behavioral problems seen in PWS. These abnormalities are as a direct result of the loss of function of chromosome 15q11-13. The main brain abnormalities in PWS arise from a dysfunction of areas of higher functioning such as the hypothalamus, insula, orbitofrontal, and anterior cingulate cortices. Additionally, there is abnormal functioning of the serotonin, dopamine, and norepinephrine systems. These dysfunctions collectively lead to the failure of the response monitoring or model-based learning function of the brain. Inadequate or impaired functioning of the response monitoring system in patients with PWS leads to multiple issues including impulsivity and response perseveration. Finally, in place of utilizing the response monitoring system, patients with PWS resort to habit-based learning, which leads to inflexibility. Reminding ourselves of the complex neurobiology that drives our patients and loved ones with PWS might lead to better tolerance for their maladaptive behaviors and more useful management strategies.

Keywords

neurobiologyhypothalamusresponse monitoringMagel2SNORDnecdinimprinting centerimpulsivityserotonin receptorresponse perseveration
Type
Chapter
Information
Neuro-behavioral Manifestations of Prader-Willi Syndrome
A Guide for Clinicians and Caregivers
 , pp. 154 - 170
Publisher: Cambridge University Press
Print publication year: 2022

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Hall, JEH. Guyton and Hall Textbook of Medical Physiology (Guyton Physiology). Philadelphia: Elsevier, 2016.Google Scholar
Bortolozzi, A, Díaz-Mataix, L, Scorza, MC, Celada, P, Artigas, F. The activation of 5-HT receptors in prefrontal cortex enhances dopaminergic activity. J Neurochem 2005;95(6):1597–607.CrossRefGoogle ScholarPubMed
Kummerfeld, D-M, Raabe, CA, Brosius, J, Mo, D, Skryabin, BV, Rozhdestvensky, TS. A comprehensive review of genetically engineered mouse models for Prader-Willi syndrome research. Int J Mol Sci 2021;22(7):3613. doi: 10.3390/ijms22073613. PMID: 33807162. PMCID: PMC8037846.Google Scholar
Pena-Leon, V, Perez-Lois, R, Seoane, LM. mTOR pathway is involved in energy homeostasis regulation as a part of the gut–brain axis. Int J Mol Sci 2020;21(16):5715. doi: 10.3390/ijms21165715. PMID: 32784967. PMCID: PMC7460813CrossRefGoogle ScholarPubMed
McCarthy, J, Lupo, PJ, Kovar, E, Rech, M, Bostwick, B, Scott, D, et al. Schaaf-Yang syndrome overview: Report of 78 individuals. Am J Med Genet A 2018;176(12):2564–74.Google Scholar
Zanella, S, Watrin, F, Mebarek, S, Marly, F, Roussel, M, Gire, C, et al. Necdin plays a role in the serotonergic modulation of the mouse respiratory network: Implication for Prader-Willi syndrome. J Neurosci 2008;28(7):1745–55.CrossRefGoogle Scholar
Muscatelli, F, Abrous, DN, Massacrier, A, Boccaccio, I, Le Moal, M, Cau, P, et al. Disruption of the mouse Necdin gene results in hypothalamic and behavioral alterations reminiscent of the human Prader-Willi syndrome. Hum Mol Genet 2000;9(20):3101–10.CrossRefGoogle ScholarPubMed
Wu, R-N, Hung, W-C, Chen, C-T, Tsai, L-P, Lai, W-S, Min, M-Y, et al. Firing activity of locus coeruleus noradrenergic neurons decreases in necdin-deficient mice, an animal model of Prader-Willi syndrome. J Neurodev Disord 2020;12(1):21.CrossRefGoogle ScholarPubMed
Adhikari, A, Copping, NA, Onaga, B, Pride, MC, Coulson, RL, Yang, M, et al. Cognitive deficits in the Snord116 deletion mouse model for Prader-Willi syndrome. Neurobiol Learn Mem 2019;165:106874.CrossRefGoogle ScholarPubMed
Pace, M, Falappa, M, Freschi, A, Balzani, E, Berteotti, C, Lo Martire, V, et al. Loss of Snord116 impacts lateral hypothalamus, sleep, and food-related behaviors. JCI Insight 2020;5(12):e137495. doi: 10.1172/jci.insight.137495. PMID: 32365348. PMCID: PMC7406246CrossRefGoogle ScholarPubMed
Raabe, CA, Voss, R, Kummerfeld, D-M, Brosius, J, Galiveti, CR, Wolters, A, et al. Ectopic expression of Snord115 in choroid plexus interferes with editing but not splicing of 5-Ht2c receptor pre-mRNA in mice. Sci Rep 2019;9(1):4300.CrossRefGoogle Scholar
Swaab, DF. Prader-Willi syndrome and the hypothalamus. Acta Paediatr Suppl 1997;423:50–4.Google ScholarPubMed
Berteotti, C, Liguori, C, Pace, M. Dysregulation of the orexin/hypocretin system is not limited to narcolepsy but has far-reaching implications for neurological disorders. Eur J Neurosci 2021;53(4):1136–54.CrossRefGoogle Scholar
Kuhlmann, L, Joensson, IM, Froekjaer, JB, Krogh, K, Farholt, S. A descriptive study of colorectal function in adults with Prader-Willi syndrome: High prevalence of constipation. BMC Gastroenterol 2014;14:63.Google Scholar
Bertone, G, Bilo, G. Cardiovascular features of Prader-Willi syndrome. J Hypertens 2021;39(Supplement 1):e335.CrossRefGoogle Scholar
Diene, G, Mimoun, E, Feigerlova, E, Caula, S, Molinas, C, Grandjean, H, et al. Endocrine disorders in children with Prader-Willi syndrome: Data from 142 children of the French database. Horm Res Paediatr 2010;74(2):121–8.Google Scholar
Blanco-Hinojo, L, Pujol, J, Esteba-Castillo, S, Martínez-Vilavella, G, Giménez-Palop, O, Gabau, E, et al. Lack of response to disgusting food in the hypothalamus and related structures in Prader Willi syndrome. Neuroimage Clin 2019;21:101662.CrossRefGoogle ScholarPubMed
Mu, M-D, Geng, H-Y, Rong, K-L, Peng, R-C, Wang, S-T, Geng, L-T, et al. A limbic circuitry involved in emotional stress-induced grooming. Nat Commun 2020;11(1):2261.Google Scholar
Manning, KE, Tait, R, Suckling, J, Holland, AJ. Grey matter volume and cortical structure in Prader-Willi syndrome compared to typically developing young adults. Neuroimage Clin 2018;17:899–909.Google Scholar
Lee, SA, Tucci, V, Vallortigara, G. Spatial impairment and memory in genetic disorders: Insights from mouse models. Brain Sci 2017;7(2):17 doi: 10.3390/brainsci7020017. PMID: 28208764; PMCID: PMC5332960CrossRefGoogle ScholarPubMed
Pujol, J, Blanco-Hinojo, L, Esteba-Castillo, S, Caixàs, A, Harrison, BJ, Bueno, M, et al. Anomalous basal ganglia connectivity and obsessive-compulsive behaviour in patients with Prader Willi syndrome. J Psychiatry Neurosci 2016;41(4):261–71.Google Scholar
Xu, M, Zhang, Y, Von Deneen, KM, Zhu, H, Gao, J-H. Brain structural alterations in obese children with and without Prader-Willi syndrome. Hum Brain Mapp 2017;38(8):4228–38.CrossRefGoogle ScholarPubMed
Akam, T, Rodrigues-Vaz, I, Marcelo, I, Zhang, X, Pereira, M, Oliveira, RF, et al. The anterior cingulate cortex predicts future states to mediate model-based action selection. Neuron 2021;109(1):149–63.e7.CrossRefGoogle ScholarPubMed
Gogolla, N. The insular cortex. Curr Biol 2017;27(12):R580–6.CrossRefGoogle ScholarPubMed
De Ruiter, MB, Veltman, DJ, Goudriaan, AE, Oosterlaan, J, Sjoerds, Z, Van den Brink, W. Response perseveration and ventral prefrontal sensitivity to reward and punishment in male problem gamblers and smokers. Neuropsychopharmacology 2009;34(4):1027–38.Google Scholar
Klabunde, M, Saggar, M, Hustyi, KM, Hammond, JL, Reiss, AL, Hall, SS. Neural correlates of self-injurious behavior in Prader-Willi syndrome. Hum Brain Mapp 2015;36(10):4135–43.Google Scholar
Freitas, LGA, Liverani, MC, Siffredi, V, Schnider, A, Borradori Tolsa, C, Ha-Vinh Leuchter, R, et al. Altered orbitofrontal activation in preterm-born young adolescents during performance of a reality filtering task. Neuroimage Clin 2021;30:102668.CrossRefGoogle ScholarPubMed
Schnider, A, Ptak, R. Spontaneous confabulators fail to suppress currently irrelevant memory traces. Nat Neurosci 1999;2(7):677–81.Google Scholar
Waszczuk, K, Rek-Owodziń, K, Tyburski, E, Mak, M, Misiak, B, Samochowiec, J. Disturbances in white matter integrity in the ultra-high-risk psychosis state: A systematic review. J Clin Med 2021;10(11):2515. doi: 10.3390/jcm10112515. PMID: 34204171. PMCID: PMC8201371Google Scholar
Niida, R, Yamagata, B, Niida, A, Uechi, A, Matsuda, H, Mimura, M. Aberrant anterior thalamic radiation structure in bipolar disorder: A diffusion tensor tractography study. Front Psychiatry 2018;9:522.CrossRefGoogle ScholarPubMed
Loe, IM, Adams, JN, Feldman, HM. Executive function in relation to white matter in preterm and full term children. Front Pediatr 2018;6:418.CrossRefGoogle ScholarPubMed
Singh, D, Sasson, A, Rusciano, V, Wakimoto, Y, Pinkhasov, A, Angulo, M. Cycloid psychosis comorbid with Prader-Willi syndrome: A case series. Am J Med Genet A 2019;179(7):1241–5.CrossRefGoogle ScholarPubMed
Mamiya, PC, Richards, TL, Kuhl, PK. Right forceps minor and anterior thalamic radiation predict executive function skills in young bilingual adults. Front Psychol 2018;9:118.Google Scholar
Roux, A, Lemaitre, A-L, Deverdun, J, Ng, S, Duffau, H, Herbet, G. Combining electrostimulation with fiber tracking to stratify the inferior fronto-occipital fasciculus. Front Neurosci 2021;15:683348.Google Scholar
Bateman, A, Fonagy, P. Mentalization based treatment for borderline personality disorder. World Psychiatry 2010;9(1):11–15.Google Scholar
Hoffman, P. An individual differences approach to semantic cognition: Divergent effects of age on representation, retrieval and selection. Sci Rep 2018;8(1):8145.CrossRefGoogle ScholarPubMed
Felsing, DE, Anastasio, NC, Miszkiel, JM, Gilbertson, SR, Allen, JA, Cunningham, KA. Biophysical validation of serotonin 5-HT2A and 5-HT2C receptor interaction. PLoS ONE 2018;13(8):e0203137.CrossRefGoogle ScholarPubMed
Peters, KZ, Cheer, JF, Tonini, R. Modulating the neuromodulators: Dopamine, serotonin, and the endocannabinoid system. Trends Neurosci 2021;44(6):464–77.CrossRefGoogle ScholarPubMed
Forster, J, Duis, J, Butler, MG. Pharmacogenetic testing of cytochrome P450 drug metabolizing enzymes in a case series of patients with Prader-Willi syndrome. Genes (Basel) 2021;12(2):152. doi: 10.3390/genes12020152. PMID: 33498922. PMCID: PMC7912498Google Scholar
Davies, JR, Wilkinson, LS, Isles, AR, Humby, T. Prader-Willi syndrome imprinting centre deletion mice have impaired baseline and 5-HT2CR-mediated response inhibition. Hum Mol Genet 2019;28(18):3013–23.CrossRefGoogle ScholarPubMed
Alex, KD, Yavanian, GJ, McFarlane, HG, Pluto, CP, Pehek, EA. Modulation of dopamine release by striatal 5-HT2C receptors. Synapse 2005;55(4):242–51.CrossRefGoogle ScholarPubMed
Price, AE, Sholler, DJ, Stutz, SJ, Anastasio, NC, Cunningham, KA. Endogenous serotonin 5-HT2A and 5-HT2C receptors associate in the medial prefrontal cortex. ACS Chem Neurosci 2019;10(7):3241–8.CrossRefGoogle ScholarPubMed
Anastasio, NC, Stutz, SJ, Fink, LHL, Swinford-Jackson, SE, Sears, RM, DiLeone, RJ, et al. Serotonin (5-HT) 5-HT2A receptor (5-HT2AR):5-HT2CR imbalance in medial prefrontal cortex associates with motor impulsivity. ACS Chem Neurosci 2015;6(7):1248–58.Google Scholar
Yu, C, Garcia-Olivares, J, Candler, S, Schwabe, S, Maletic, V. New insights into the mechanism of action of viloxazine: Serotonin and norepinephrine modulating properties. J Exp Pharmacol 2020;12:285–300.Google Scholar
Sarva, H, Henchcliffe, C. Evidence for the use of pimavanserin in the treatment of Parkinson’s disease psychosis. Ther Adv Neurol Disord 2016;9(6):462–73.CrossRefGoogle ScholarPubMed
Lambe, EK, Fillman, SG, Webster, MJ, Shannon Weickert, C. Serotonin receptor expression in human prefrontal cortex: Balancing excitation and inhibition across postnatal development. PLoS ONE 2011;6(7):e22799.Google Scholar
Van Galen, KA, Ter Horst, KW, Serlie, MJ. Serotonin, food intake, and obesity. Obes Rev 2021;22(7):e13210.Google Scholar
Gadde, KM, Martin, CK, Berthoud, H-R, Heymsfield, SB. Obesity: Pathophysiology and management. J Am Coll Cardiol 2018;71(1):69–84.CrossRefGoogle ScholarPubMed
Nilsson, SRO, Somerville, EM, Clifton, PG. Dissociable effects of 5-HT2C receptor antagonism and genetic inactivation on perseverance and learned non-reward in an egocentric spatial reversal task. PLoS ONE 2013;8(10):e77762.Google Scholar
Kwan Cheung, KA, Mitchell, MD, Heussler, HS. Cannabidiol and neurodevelopmental disorders in children. Front Psychiatry 2021;12:643442.Google Scholar
Knani, I, Earley, BJ, Udi, S, Nemirovski, A, Hadar, R, Gammal, A, et al. Targeting the endocannabinoid/CB1 receptor system for treating obesity in Prader-Willi syndrome. Mol Metab 2016;5(12):1187–99.CrossRefGoogle ScholarPubMed
Posner, MI, Petersen, SE. The attention system of the human brain. Annu Rev Neurosci 1990;13:25–42.Google Scholar
Deason, RG, Tat, MJ, Flannery, S, Mithal, PS, Hussey, EP, Crehan, ET, et al. Response bias and response monitoring: Evidence from healthy older adults and patients with mild Alzheimer’s disease. Brain Cogn 2017;119:17–24.Google Scholar
Kahneman, D. Thinking, Fast and Slow. New York: Farrar, Straus and Giroux, 2011.Google Scholar
Sutton, RS, Barto, AG. Reinforcement Learning: An Introduction. Cambridge, MA: MIT Press.Google Scholar

Save book to Kindle

To save this book to your Kindle, first ensure no-reply@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Available formats
×

Save book to Dropbox

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Dropbox.

Available formats
×

Save book to Google Drive

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Google Drive.

Available formats
×