L5 MIA & Offspring Neurodevelopment

Question 1

Pregnancy involves complex changes to the maternal immune system that can be categorised into 3 stages:

Answer 1

1. Implantation
2. The duration of pregnancy
3. Late pregnancy and labour

Question 2

The first few weeks of pregnancy are characterised by…

Answer 2

an increased pro-inflammatory response

Question 3

On day 6, the blastocyst attaches to the endometrium. The endometrium transforms into the __ , which is then infiltrated by __

Answer 3

decidua
maternal innate immune cells

Question 4

Syncytiotrophoblast expresses no __

Answer 4

HLA

Question 5

What is placenta-decidua crosstalk via immune molecules, such as cytokines, crucial for?

Answer 5

implantation, uterine remodelling and placentation

Question 6

For the longest part of gestation (late 1st to early 3rd trimester), the immune response is generally __

Answer 6

anti-inflammatory

Question 7

A heightened immune response for the duration of pregnancy is associated with…

Answer 7

placental disorders and miscarriage

Question 8

Changes to cells of the immune system for the duration of pregnancy

Answer 8

• increased activity of complement system & monocytes
• reduction in T & B cells

Question 9

What type of immune response is seen towards the end of a healthy pregnancy?

Answer 9

pro-inflammatory (important for labour & childbirth)

Question 10

Which cytokine in particular is crucial for initiating childbirth?

Answer 10

IL-6

Question 11

Schizophrenia risk factors

Answer 11

• seasonality effect: Spring baby
• birth in a city
• maternal 2nd trimester Influenza infection
• genetics

Question 12

The most common vertically transmitted pathogens

Answer 12

TORCH pathogens: Toxoplasma gondii, other (HepB, HepE, HIV, Zika, syphilis), rubella, CMV, HSV

Question 13

2 examples of vertically transmitted viruses that can directly affect fetal neurodevelopment

Answer 13

HSV and Zika (high degree of neurotropism)

Question 14

Maternal infection increases the risk of…

Answer 14

Schizophrenia and ASD development

Question 15

What is the term given to stimulation of a pro-inflammatory state by the mother’s immune system during pregnancy?

Answer 15

Maternal immune activation (MIA)

Question 16

When does MIA occur?

Answer 16

in response to infection and other stimuli, and certain maternal or gestational disorders

Question 17

4 ways to induce MIA in animals

Answer 17

Poly I:C (dsRNA)
LPS
Enterotoxins
Transgenic animals with human receptors

Question 18

What causes Influenza-induced behavioural deficits in mice?

Answer 18

viral-induced MIA, rather than the virus itself

Question 19

Early prenatal LPS exposure in rats alters __ , whereas late exposure causes __

Answer 19

reward-seeking behaviour
motor deficits

Question 20

Prenatal Poly I:C exposure in mice causes…

Answer 20

DA and 5-HT imbalances, mimicking the neurochemical alterations of schizophrenia

Question 21

How does MIA affect microglial activity?

Answer 21

It increases microglial activity, thereby affecting cortical cytoarchitecture and neural activity in brains of exposed offspring

Question 22

What is the Cytokine Hypothesis of neurodevelopmental disorders?

Answer 22

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.

Question 23

Neuroinflammation can be seen in patients with…

Answer 23

ASD and schizophrenia

Question 24

Roles of IL-6 in the brain

Answer 24

• promotes neuronal differentiation, growth & survival
• induces death in 5-HT neurons
• activates microglia

Question 25

Elevated maternal IL-6 is associated with…

Answer 25

altered structural and functional connectivity in offspring

Question 26

How does IL-6 elicit its effects?

Answer 26

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.

Question 27

Blocking/knocking out maternal or placental IL-6 results in…

Answer 27

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)

Question 28

True or False: IL-17 is downstream of IL-6

Answer 28

True

Question 29

IL-17 injection promotes __ in mice

Answer 29

sociability

Question 30

Circulating IL-17 is elevated in certain people with __

Answer 30

ASD

Question 31

How does IL-17 elicit its effects?

Answer 31

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

Question 32

In the paper by Su et al. (2020), how did conditional knockout of STAT3 in NPCs affect neurogenesis?

Answer 32

it suppressed neurogenesis

Question 33

In the paper by Su et al. (2020), STAT3 promoted expression of __ genes and reduced __ in NPCs.

Answer 33

OXPHOS genes
reduced ROS

Question 34

Conclusion of paper by Su et al. (2020)

Answer 34

STAT3 loss-of-function promotes proliferation via regulation of mitochondrial metabolism and downstream signalling pathways