title: Combination of prenatal immune challenge and restraint stress affects prepulse inhibition and dopaminergic/GABAergic markers.
abstract: Gestational immune challenge with the viral-like antigen poly I:C is a well-established neurodevelopmental model of schizophrenia. However, exposure to inflammation during early life may sensitize the developing brain to secondary insults and enhance the central nervous system vulnerability. To gain a better understanding of the pathophysiology of schizophrenia, we thus developed a two-hit animal model based on prenatal poly I:C immune challenge followed by restraint stress in juvenile mice. C57BL/6 gestational mice were intraperitoneally injected with poly I:C or saline at gestational day 12. Pups were then submitted or not, to restraint stress for 2h, for three consecutive days, from postnatal days 33 to 35. Prepulse inhibition (PPI) of acoustic startle response is commonly used to assess sensorimotor gating, a neural process severely disrupted in patients with schizophrenia. Our results revealed that the combination of prenatal immune challenge with poly I:C followed by a restraint stress period was able to induce a PPI disruption in 36-day-old pups, as opposed to each insult applied separately. PPI deficits were accompanied by dopaminergic and GABAergic abnormalities in the prefrontal cortex and striatum. Indeed, measurements of cortical and striatal dopamine D2 receptor (D2R) mRNA and protein levels revealed that the combination of gestational exposure to poly I:C and postnatal restraint stress induced an increase in D2R protein and mRNA levels. Likewise, the combination of both insults reduced the mRNA and protein expression levels of the 67 kDa form of glutamic acid decarboxylase (GAD67), in those two brain regions. To our knowledge, this two-hit animal model is the first in vivo model reporting PPI deficits at pubertal age. This two-hit animal model may also help in studying innovative therapies dedicated to the treatment of schizophrenia, especially in its early phase.
authors.affiliation: Department of Physiology and Biophysics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 12e avenue Nord, Sherbrooke, QC J1H 5N4, Canada.
authors.forename: Jessica
authors.initials: J
authors.lastname: Deslauriers
authors.forename: Annie
authors.initials: A
authors.lastname: Larouche
authors.forename: Philippe
authors.initials: P
authors.lastname: Sarret
authors.forename: Sylvain
authors.initials: S
authors.lastname: Grignon
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005968:Glutamate Decarboxylase / Q000378:metabolism*; D008297:Male; D051379:Mice; D011070:Poly I-C / Q000276:immunology; D017397:Prefrontal Cortex / Q000378:metabolism; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000276:immunology*; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D012149:Restraint, Physical; D012559:Schizophrenia / Q000378:metabolism / Q000503:physiopathology; D055139:Sensory Gating / Q000502:physiology*; D013312:Stress, Physiological
chemical_list: D017448:Receptors, Dopamine D2; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; D011070:Poly I-C
keywords: CNS; D2R; DAT; Dopamine D2 receptor; GAD67; IL-1β; IL-6; N-methyl D-aspartate; NMDA; PFC; PIC; PPI; Poly I:C; Poly I:C (poly-inosinic/cytidylic acid); Prepulse inhibition; RS; Restraint stress; TH; TLR3; TNF-α; central nervous system; dopamine D2 receptor; dopamine transporter; interleukin-1β; interleukin-6; prefrontal cortex; prepulse inhibition of acoustic startle; restraint stress; the 67 kDa form of glutamic acid decarboxylase; toll-like receptor 3; tumor necrosis factor-α; tyrosine hydroxylase