PMID- 34808289
OWN - NLM
STAT- MEDLINE
DCOM- 20220314
LR  - 20220531
IS  - 1090-2139 (Electronic)
IS  - 0889-1591 (Linking)
VI  - 100
DP  - 2022 Feb
TI  - Timing of maternal immune activation and sex influence schizophrenia-relevant 
      cognitive constructs and neuregulin and GABAergic pathways.
PG  - 70-82
LID - S0889-1591(21)00602-4 [pii]
LID - 10.1016/j.bbi.2021.11.006 [doi]
AB  - Maternal immune activation (MIA) during pregnancy is an established environmental 
      risk factor for schizophrenia. Timing of immune activation exposure as well as 
      sex of the exposed offspring are critical factors in defining the effects of MIA. 
      However, the specificity of MIA on the component structure of schizophrenia, 
      especially cognition, has been difficult to assess due to a lack of translational 
      validity of maze-like testing paradigms. We aimed to assess cognitive domains 
      relevant to schizophrenia using highly translational touchscreen-based tasks in 
      male and female mice exposed to the viral mimetic, poly(I:C) (5 mg/k, i.p.), 
      during early (gestational day (GD) 9-11) and late (GD13-15) gestational time 
      points. Gene expression of schizophrenia candidate pathways were assessed in 
      fetal brain immediately following poly(I:C) exposure and in adulthood to identify 
      its influence on neurodevelopmental processes. Sex and window specific 
      alterations in cognitive performance were found with the early window of MIA 
      exposure causing female-specific disruptions to working memory and reduced 
      perseverative behaviour, while late MIA exposure caused male-specific changes to 
      working memory and deficits in reversal learning. GABAergic specification marker, 
      Nkx2.1 gene expression was reduced in fetal brains and reelin expression was 
      reduced in adult hippocampus of both early and late poly(I:C) exposed mice. 
      Neuregulin and EGF signalling were initially upregulated in the fetal brain, but 
      were reduced in the adult hippocampus, with male mice exposed in the late window 
      showing reduced Nrg3 expression. Serine racemase was reduced in both fetal and 
      adult brain, but again, adult reductions were specific to male mice exposed at 
      the late time point. Overall, we show that cognitive constructs relevant to 
      schizophrenia are altered by in utero exposure to maternal immune activation, but 
      are highly dependent on the timing of infection and the sex of the offspring. 
      Glutamatergic and epidermal growth factor pathways were similarly altered by MIA 
      in a timing and sex dependent manner, while MIA-induced GABAergic deficits were 
      independent of timing or sex.
CI  - Copyright (c) 2021 Elsevier Inc. All rights reserved.
FAU - Nakamura, J P
AU  - Nakamura JP
AD  - Department of Psychiatry, School of Clinical Sciences, Monash University, 
      Clayton, VIC 3168, Australia.
FAU - Schroeder, A
AU  - Schroeder A
AD  - Department of Psychiatry, School of Clinical Sciences, Monash University, 
      Clayton, VIC 3168, Australia.
FAU - Gibbons, A
AU  - Gibbons A
AD  - Department of Psychiatry, School of Clinical Sciences, Monash University, 
      Clayton, VIC 3168, Australia.
FAU - Sundram, S
AU  - Sundram S
AD  - Department of Psychiatry, School of Clinical Sciences, Monash University, 
      Clayton, VIC 3168, Australia; Mental Health Program, Monash Health, Clayton, VIC 
      3168, Australia.
FAU - Hill, R A
AU  - Hill RA
AD  - Department of Psychiatry, School of Clinical Sciences, Monash University, 
      Clayton, VIC 3168, Australia. Electronic address: rachel.hill@monash.edu.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20211119
PL  - Netherlands
TA  - Brain Behav Immun
JT  - Brain, behavior, and immunity
JID - 8800478
RN  - 0 (Neuregulins)
RN  - O84C90HH2L (Poly I-C)
SB  - IM
MH  - Animals
MH  - Behavior, Animal/physiology
MH  - Cognition
MH  - Disease Models, Animal
MH  - Female
MH  - Male
MH  - Mice
MH  - Neuregulins
MH  - Poly I-C/pharmacology
MH  - Pregnancy
MH  - *Prenatal Exposure Delayed Effects
MH  - *Schizophrenia
OTO - NOTNLM
OT  - Cognition
OT  - Cognitive flexibility
OT  - GABA
OT  - Maternal immune activation
OT  - Neuregulin
OT  - Poly(I:C)
OT  - Working memory
EDAT- 2021/11/23 06:00
MHDA- 2022/03/15 06:00
CRDT- 2021/11/22 20:16
PHST- 2021/06/15 00:00 [received]
PHST- 2021/10/17 00:00 [revised]
PHST- 2021/11/13 00:00 [accepted]
PHST- 2021/11/23 06:00 [pubmed]
PHST- 2022/03/15 06:00 [medline]
PHST- 2021/11/22 20:16 [entrez]
AID - S0889-1591(21)00602-4 [pii]
AID - 10.1016/j.bbi.2021.11.006 [doi]
PST - ppublish
SO  - Brain Behav Immun. 2022 Feb;100:70-82. doi: 10.1016/j.bbi.2021.11.006. Epub 2021 
      Nov 19.