Selective changes in vasopressin neurons and astrocytes in the suprachiasmatic nucleus of Prader-Willi syndrome subjects

TY - JOUR

T1 - Selective changes in vasopressin neurons and astrocytes in the suprachiasmatic nucleus of Prader-Willi syndrome subjects

AU - Correa-da-Silva, Felipe

AU - Berkhout, Jari B

AU - Schouten, Pim

AU - Sinnema, Margje

AU - Stumpel, Constance T R M

AU - Curfs, Leopold M G

AU - Höybye, Charlotte

AU - Mahfouz, Ahmed

AU - Meijer, Onno C

AU - Pereira, Alberto M

AU - Fliers, Eric

AU - Swaab, Dick F

AU - Kalsbeek, Andries

AU - Yi, Chun-Xia

N1 - © 2025 The Author(s). Journal of Neuroendocrinology published by John Wiley & Sons Ltd on behalf of British Society for Neuroendocrinology.

PY - 2025/3/8

Y1 - 2025/3/8

N2 - The hypothalamic suprachiasmatic nucleus (SCN) hosts the central circadian pacemaker and regulates daily rhythms in physiology and behavior. The SCN is composed of peptidergic neuron populations expressing arginine vasopressin (AVP) and vasoactive intestinal polypeptide (VIP), as well as glial cells. Patients with Prader-Willi Syndrome (PWS) commonly experience circadian disturbances, which are particularly evident in their sleep/wake patterns. Using publicly available single-cell RNA sequencing data, we assessed the cell-type specificity of PWS-causative genes in murine SCN, which revealed the differential presence of PWS-related genes in glial and neural subpopulations. We then investigated neurons and glial cells in the SCN using immunohistochemistry in the postmortem hypothalami of PWS subjects and matched controls. We profiled neural populations characterized by AVP and VIP, astroglia characterized by glial fibrillary acid protein (GFAP), and microglia marked by ionized calcium-binding adapter molecule 1 (Iba1) and NADPH oxidase 2 (NOX2). Our analysis revealed an increased total number, neuronal density, and relative staining intensity of AVP-containing neurons in the PWS compared to controls while VIP-containing cells were unaltered. In contrast, GFAP-expressing astroglial cells were significantly lower in PWS subjects. Moreover, we did not detect any differences in microglia between PWS subjects and controls. Collectively, our findings show that PWS selectively affects AVP-containing neurons and GFAP-expressing astrocytes in the SCN. As each of these cell populations can affect the daily rhythmicity of the SCN biological clock machinery, the disruption of these cells may contribute to the circadian disturbances in patients with PWS.

AB - The hypothalamic suprachiasmatic nucleus (SCN) hosts the central circadian pacemaker and regulates daily rhythms in physiology and behavior. The SCN is composed of peptidergic neuron populations expressing arginine vasopressin (AVP) and vasoactive intestinal polypeptide (VIP), as well as glial cells. Patients with Prader-Willi Syndrome (PWS) commonly experience circadian disturbances, which are particularly evident in their sleep/wake patterns. Using publicly available single-cell RNA sequencing data, we assessed the cell-type specificity of PWS-causative genes in murine SCN, which revealed the differential presence of PWS-related genes in glial and neural subpopulations. We then investigated neurons and glial cells in the SCN using immunohistochemistry in the postmortem hypothalami of PWS subjects and matched controls. We profiled neural populations characterized by AVP and VIP, astroglia characterized by glial fibrillary acid protein (GFAP), and microglia marked by ionized calcium-binding adapter molecule 1 (Iba1) and NADPH oxidase 2 (NOX2). Our analysis revealed an increased total number, neuronal density, and relative staining intensity of AVP-containing neurons in the PWS compared to controls while VIP-containing cells were unaltered. In contrast, GFAP-expressing astroglial cells were significantly lower in PWS subjects. Moreover, we did not detect any differences in microglia between PWS subjects and controls. Collectively, our findings show that PWS selectively affects AVP-containing neurons and GFAP-expressing astrocytes in the SCN. As each of these cell populations can affect the daily rhythmicity of the SCN biological clock machinery, the disruption of these cells may contribute to the circadian disturbances in patients with PWS.

U2 - 10.1111/jne.70015

DO - 10.1111/jne.70015

M3 - Article

C2 - 40055943

SN - 0953-8194

VL - 37

SP - e70015

JO - Journal of Neuroendocrinology

JF - Journal of Neuroendocrinology

ER -