L5 MIA & Offspring Neurodevelopment Flashcards
Pregnancy involves complex changes to the maternal immune system that can be categorised into 3 stages:
- Implantation
- The duration of pregnancy
- Late pregnancy and labour
The first few weeks of pregnancy are characterised by…
an increased pro-inflammatory response
On day 6, the blastocyst attaches to the endometrium. The endometrium transforms into the __ , which is then infiltrated by __
decidua
maternal innate immune cells
Syncytiotrophoblast expresses no __
HLA
What is placenta-decidua crosstalk via immune molecules, such as cytokines, crucial for?
implantation, uterine remodelling and placentation
For the longest part of gestation (late 1st to early 3rd trimester), the immune response is generally __
anti-inflammatory
A heightened immune response for the duration of pregnancy is associated with…
placental disorders and miscarriage
Changes to cells of the immune system for the duration of pregnancy
- increased activity of complement system & monocytes
- reduction in T & B cells
What type of immune response is seen towards the end of a healthy pregnancy?
pro-inflammatory (important for labour & childbirth)
Which cytokine in particular is crucial for initiating childbirth?
IL-6
Schizophrenia risk factors
- seasonality effect: Spring baby
- birth in a city
- maternal 2nd trimester Influenza infection
- genetics
The most common vertically transmitted pathogens
TORCH pathogens: Toxoplasma gondii, other (HepB, HepE, HIV, Zika, syphilis), rubella, CMV, HSV
2 examples of vertically transmitted viruses that can directly affect fetal neurodevelopment
HSV and Zika (high degree of neurotropism)
Maternal infection increases the risk of…
Schizophrenia and ASD development
What is the term given to stimulation of a pro-inflammatory state by the mother’s immune system during pregnancy?
Maternal immune activation (MIA)
When does MIA occur?
in response to infection and other stimuli, and certain maternal or gestational disorders
4 ways to induce MIA in animals
Poly I:C (dsRNA)
LPS
Enterotoxins
Transgenic animals with human receptors
What causes Influenza-induced behavioural deficits in mice?
viral-induced MIA, rather than the virus itself
Early prenatal LPS exposure in rats alters __ , whereas late exposure causes __
reward-seeking behaviour
motor deficits
Prenatal Poly I:C exposure in mice causes…
DA and 5-HT imbalances, mimicking the neurochemical alterations of schizophrenia
How does MIA affect microglial activity?
It increases microglial activity, thereby affecting cortical cytoarchitecture and neural activity in brains of exposed offspring
What is the Cytokine Hypothesis of neurodevelopmental disorders?
The increased risk for neurodevelopmental disorders caused by maternal infection is due not to the specific pathogen itself, but the MIA it induces, and as a result, high levels of cytokines reaching the fetal brain.
Neuroinflammation can be seen in patients with…
ASD and schizophrenia
Roles of IL-6 in the brain
- promotes neuronal differentiation, growth & survival
- induces death in 5-HT neurons
- activates microglia
Elevated maternal IL-6 is associated with…
altered structural and functional connectivity in offspring
How does IL-6 elicit its effects?
IL-6 binds a kinase-linked receptor, IL-6Rα, which activates JAK. This leads to a phosphorylation cascade and subsequent activation of STAT3. STAT3 is phosphorylated, dissociates from its receptor complex, dimerises and translocates to nucleus, where it directly binds promoter regions of genes involved in cell survival etc.
Blocking/knocking out maternal or placental IL-6 results in…
the effects of MIA on offspring brain and behaviour being blocked (means that IL-6 is necessary for the effects of MIA on fetal brain development)
True or False: IL-17 is downstream of IL-6
True
IL-17 injection promotes __ in mice
sociability
Circulating IL-17 is elevated in certain people with __
ASD
How does IL-17 elicit its effects?
IL-17 binds to specific receptors to cause ubiquitination of Traf6, which then activates a number of different signalling pathways such as NF-κβ → translocate to nucleus to stimulate target gene expression
In the paper by Su et al. (2020), how did conditional knockout of STAT3 in NPCs affect neurogenesis?
it suppressed neurogenesis
In the paper by Su et al. (2020), STAT3 promoted expression of __ genes and reduced __ in NPCs.
OXPHOS genes
reduced ROS
Conclusion of paper by Su et al. (2020)
STAT3 loss-of-function promotes proliferation via regulation of mitochondrial metabolism and downstream signalling pathways
