Prenatal poly I:C age-dependently alters cannabinoid type 1 receptors in offspring: a longitudinal small animal PET study using [(18)F]MK-9470.
Evidence suggests that there is a link between the endocannabinoid system (ECS) and neuropsychiatric illnesses, including schizophrenia. Whilst the ECS has been shown to be involved in immune system regulation in various ways, it is known that infections during pregnancy can modulate the immune system of the mother and increase the risk for schizophrenia in offspring. In animal studies, maternal immune activation following administration of viral or bacterial mimics has been shown to reproduce many key structural, behavioural, and pharmacological abnormalities in offspring that resemble schizophrenia. In the present study, we used Positron Emission Tomography (PET) and [(18)F]MK-9470, a selective high-affinity inverse agonist radioligand for cannabinoid type 1 receptors (CB1R), to longitudinally assess CB1R expression in the progeny of female rats exposed to the viral mimic polyriboinosinic-polyribocytidilic acid (poly I:C) (4mg/kg i.v.) or vehicle at gestational day 15 (GD 15). PET scans were performed in offspring at postnatal days (PND) 32-42 (adolescence) and in the same animals again at PNDs 75-79 (adulthood). Sixteen regions of interest were assessed, encompassing the whole rat brain. At adolescence, offspring exposed prenatally to poly I:C had significantly lower CB1R relative Standard Uptake Values (rSUV) compared to controls in the globus pallidus (p=0.046). In adulthood, however, poly I:C exposed offspring had higher levels of CB1R rSUV in sensory cortex (p=0.034) and hypothalamus (p=0.032) compared to controls. Our results suggest that prenatal poly I:C leads to long term alterations in the integrity of the ECS that are age and region-specific. The increased CB1R expression in adulthood following poly I:C mirrors the increased CB1R observed in patients with schizophrenia in post-mortem and in vivo PET studies.
Schizophrenia Research Institute, Sydney, Australia; ANSTO LifeSciences, ANSTO, PMB 1 Menai, NSW 2234, Australia; Neuroscience Research Center Lyon (CRNL, CNRS UMR5292, INSERM U1028), BioRaN Team, Lyon, France. Electronic address: verdurand@cermep.fr.
Mathieu
M
Verdurand
Schizophrenia Research Institute, Sydney, Australia; ANSTO LifeSciences, ANSTO, PMB 1 Menai, NSW 2234, Australia; Department of Psychiatry and Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin 2, Ireland. Electronic address: daltonv@tcd.ie.
Victoria S
VS
Dalton
ANSTO LifeSciences, ANSTO, PMB 1 Menai, NSW 2234, Australia. Electronic address: vhn@ansto.gov.au.
Vu
V
Nguyen
ANSTO LifeSciences, ANSTO, PMB 1 Menai, NSW 2234, Australia. Electronic address: mcg@ansto.gov.au.
Marie-Claude
MC
Grégoire
ANSTO LifeSciences, ANSTO, PMB 1 Menai, NSW 2234, Australia. Electronic address: dzx@ansto.gov.au.
David
D
Zahra
ANSTO LifeSciences, ANSTO, PMB 1 Menai, NSW 2234, Australia. Electronic address: naomi.wyatt@ansto.gov.au.
Naomi
N
Wyatt
ANSTO LifeSciences, ANSTO, PMB 1 Menai, NSW 2234, Australia. Electronic address: lbs@ansto.gov.au.
Leena
L
Burgess
ANSTO LifeSciences, ANSTO, PMB 1 Menai, NSW 2234, Australia. Electronic address: ivg@ansto.gov.au.
Ivan
I
Greguric
Schizophrenia Research Institute, Sydney, Australia; ANSTO LifeSciences, ANSTO, PMB 1 Menai, NSW 2234, Australia; Neuroscience Research Australia, Randwick, NSW 2031, Australia; School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia. Electronic address: k.zavitsanou@neura.edu.au.
Katerina
K
Zavitsanou
D000367:Age Factors; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects / Q000254:growth & development; D001931:Brain Mapping; D004195:Disease Models, Animal; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology*; D008279:Magnetic Resonance Imaging; D008297:Male; D011070:Poly I-C / Q000494:pharmacology*; D049268:Positron-Emission Tomography; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000503:physiopathology*; D011485:Protein Binding / Q000187:drug effects; D011725:Pyridines / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000187:drug effects* / Q000378:metabolism
C528731:MK-9470; D011725:Pyridines; D043884:Receptor, Cannabinoid, CB1; D011070:Poly I-C
CB(1) receptors; Maternal immune activation; Neurodevelopment; PET imaging; Poly I:C; Schizophrenia; [(18)F]MK-9470