TY - JOUR
T1 - Maternal P7C3-A20 treatment protects offspring from neuropsychiatric sequelae of prenatal stress
AU - Schroeder, Rachel
AU - Sridharan, Preethy
AU - Nguyen, Lynn
AU - Loren, Alexandra
AU - Williams, Noelle S.
AU - Kettimuthu, Kavitha P.
AU - Cintrón-Pérez, Coral J.
AU - Vázquez-Rosa, Edwin
AU - Pieper, Andrew A.
AU - Stevens, Hanna E.
N1 - Funding Information:
H.E.S. and R.S. were supported by a Junior Research Program of Excellence awarded to H.E.S. from the Roy J. Carver Charitable Trust and research grants from the Nellie Ball Trust to H.E.S. H.E.S. was also supported by NIH grant R01 MH122485-01 and by a Career Development Award from the University of Iowa Environmental Health Science Research Center (P30 ES005605). R.S. was supported by the University of Iowa Graduate Post-Comprehensive Research Fellowship and the Ballard-Seashore Dissertation Fellowship.
Funding Information:
A.A.P. was supported by a grant from the Brockman Foundation. A.A.P. was also supported by the Elizabeth Ring Mather & William Gwinn Mather Fund, S. Livingston Samuel Mather Trust, G.R. Lincoln Family Foundation, Wick Foundation, Gordon & Evie Safran, the Leonard Krieger Fund of the Cleveland Foundation, the Maxine and Lester Stoller Parkinson’s Research Fund, the Louis Stokes VA Medical Center resources and facilities, and Project 19PABH134580006-AHA/Allen Initiative in Brain Health and Cognitive Impairment.
Publisher Copyright:
© Mary Ann Liebert, Inc.
PY - 2021/9/1
Y1 - 2021/9/1
N2 - Aims: Impaired embryonic cortical interneuron development from prenatal stress is linked to adult neuropsychiatric impairment, stemming in part from excessive generation of reactive oxygen species in the developing embryo. Unfortunately, there are no preventive medicines that mitigate the risk of prenatal stress to the embryo, as the underlying pathophysiologic mechanisms are poorly understood. Our goal was to interrogate the molecular basis of prenatal stress-mediated damage to the embryonic brain to identify a neuroprotective strategy. Results: Chronic prenatal stress in mice dysregulated nicotinamide adenine dinucleotide (NAD+) synthesis enzymes and cortical interneuron development in the embryonic brain, leading to axonal degeneration in the hippocampus, cognitive deficits, and depression-like behavior in adulthood. Offspring were protected from these deleterious effects by concurrent maternal administration of the NAD+-modulating agent P7C3-A20, which crossed the placenta to access the embryonic brain. Prenatal stress also produced axonal degeneration in the adult corpus callosum, which was not prevented by maternal P7C3-A20. Innovation: Prenatal stress dysregulates gene expression of NAD+-synthesis machinery and GABAergic interneuron development in the embryonic brain, which is associated with adult cognitive impairment and depression-like behavior. We establish a maternally directed treatment that protects offspring from these effects of prenatal stress. Conclusion: NAD+-synthesis machinery and GABAergic interneuron development are critical to proper embryonic brain development underlying postnatal neuropsychiatric functioning, and these systems are highly susceptible to prenatal stress. Pharmacologic stabilization of NAD+ in the stressed embryonic brain may provide a neuroprotective strategy that preserves normal embryonic development and protects offspring from neuropsychiatric impairment. Antioxid. Redox Signal. 35, 511–530.
AB - Aims: Impaired embryonic cortical interneuron development from prenatal stress is linked to adult neuropsychiatric impairment, stemming in part from excessive generation of reactive oxygen species in the developing embryo. Unfortunately, there are no preventive medicines that mitigate the risk of prenatal stress to the embryo, as the underlying pathophysiologic mechanisms are poorly understood. Our goal was to interrogate the molecular basis of prenatal stress-mediated damage to the embryonic brain to identify a neuroprotective strategy. Results: Chronic prenatal stress in mice dysregulated nicotinamide adenine dinucleotide (NAD+) synthesis enzymes and cortical interneuron development in the embryonic brain, leading to axonal degeneration in the hippocampus, cognitive deficits, and depression-like behavior in adulthood. Offspring were protected from these deleterious effects by concurrent maternal administration of the NAD+-modulating agent P7C3-A20, which crossed the placenta to access the embryonic brain. Prenatal stress also produced axonal degeneration in the adult corpus callosum, which was not prevented by maternal P7C3-A20. Innovation: Prenatal stress dysregulates gene expression of NAD+-synthesis machinery and GABAergic interneuron development in the embryonic brain, which is associated with adult cognitive impairment and depression-like behavior. We establish a maternally directed treatment that protects offspring from these effects of prenatal stress. Conclusion: NAD+-synthesis machinery and GABAergic interneuron development are critical to proper embryonic brain development underlying postnatal neuropsychiatric functioning, and these systems are highly susceptible to prenatal stress. Pharmacologic stabilization of NAD+ in the stressed embryonic brain may provide a neuroprotective strategy that preserves normal embryonic development and protects offspring from neuropsychiatric impairment. Antioxid. Redox Signal. 35, 511–530.
KW - Axon degeneration
KW - Cortical interneurons
KW - Learning and memory
KW - Neuroprotection
KW - P7C3
KW - Prenatal stress
UR - http://www.scopus.com/inward/record.url?scp=85112738170&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85112738170&partnerID=8YFLogxK
U2 - 10.1089/ars.2020.8227
DO - 10.1089/ars.2020.8227
M3 - Review article
C2 - 33501899
AN - SCOPUS:85112738170
SN - 1523-0864
VL - 35
SP - 511
EP - 530
JO - Antioxidants and Redox Signaling
JF - Antioxidants and Redox Signaling
IS - 7
ER -