Development of the mammalian neocortex

Question 1

What does the mammalian neocortex contain

Answer 1

pyramidal cells: excitatory (glutamatergic), connections with other cortical/subcortical areas (80% R/60% H)
interneurons: inhibitory (GABAergic), local, 20% R/40% H

Question 2

stages of cortical circuit emergence

Answer 2

progenitors
neuronal birth post-mitotic
neuronal migration
axons find their target
dendrites merge
synapse formation
modification of synaptic connections (throughout life)

Question 3

where are pyramidal cells and interneurons born

Answer 3

PC - Ventricular zone VZ (radial migration)
interneurons - LGE/MGE (tangenital migration)

both have a large diversity

Question 4

neuronal motility during development

Answer 4

migration
neuritogenesis
axon growth and guidance
large-scale pruning (refinement)

small scale pruning
synapse formation and refinement

Question 5

specificity of cortical circuits

Answer 5

cellular synaptic specificity (which cell to target)
subcellular synaptic specificity (within the cell)
synaptic specificity

Question 6

chemoaffinity based recognition strategies

Answer 6

contact dependent recognition
contact dependent repulsion
secreted attractive cues
secreted repulsive cues

Question 7

how do 20000 genes specific 10^14 connections

Answer 7

many proteins from a single gene
many levels from a single gene
multiple functions from a single protein
same protein used in multiple times and places
combinatorial use of a protein
use of experience and spontaneous neuronal activity

Question 8

neuronal processes before and after birth

Answer 8

before birth: neurogenesis/migration
after birth: synaptic pruning/myelination

Question 9

what is the mutant associated with lissencephaly

Answer 9

Lis1 (deletion/missense mutation)
affects neuronal proliferation and migration
Lis1 RNAi (mRNA deletion): no RG movement, prevents asymmetrical/symmetrical division/no attachment

Question 10

Zika Virus (Microcephaly)

Answer 10

RG express AXL receptor which allow the entry of ZIKA virus causes RG depletion
experience: positive symptoms of psychosis/cognitive defects/connected syndrome (errors in memory and communication and myelin defects)

Question 11

what is epilepsy

Answer 11

chronic condition characterised by recurrent seizures
affects ~1% of the population

Question 12

ion channel mutant which causes epilepsy

Answer 12

NaV1.1 - severe myoclonic epilepsy/Dravet’s syndrome
DI-IV subunit. S1328P mutant in DIII subunit
use iPSCs - voltage dependent Na+ current reduced in inhibitory neurons not excitatory (reduced AP firing)

Question 13

Rett’s syndrome

Answer 13

defects in MeCP2 (regulates global gene expression and chromatin binding protein) on the X chromosome
affects 1 in 10000/15000 girls

Question 14

cre+flox of MeCP2 in rats

Answer 14

increased time spent grooming
decreased GABA in interneurons/Gad1/Gad2 expression (enzymes which synthesise GABA)

Question 15

Fragile X syndrome

Answer 15

defects in FMRP (RNA BP) regulates local translation
affects 1 in 5000 boys (X chromosome)

gap near the tip of the long arm of the chromsome

Question 16

FMRP mutant

Answer 16

S6 kinase adds phosphate to FMRP - blocks translation
Fmr1-/- - increased synaptic spines
mGluR5+/- Fmr1-/- decreased mGluR5 rescues spines

Question 17

imbalance of e/i in ASD

Answer 17

reduction of PV cells

Question 18

schizophrenia

Answer 18

affects 1% of the population
triad of symptoms: positive/negative/cognitive
48% (high heritability from monozygotic twin because 100% shared genes
108 common gene variants and de novo mutations

Question 19

what is affected in schizophrenia

Answer 19

altered distribution in cortical interneurons and abnormal expression of GABAergic transmission markers (PV/GAD67)
decreased: GAD67 mRNA/GABAAa1 mRNA/GAT-1 candleticks (antibody GABA transporter)

increased gamma oscillations (how PCs synchronise) via interneurons
causes cognitive defects - working memory

Question 20

ErbB4 receptor gene

Answer 20

expressed in PV+ basket/chandelier cells
disruption of ErbB4 decreases synapses and GAT-1 synapses
increases excitability and gamma oscillations

Question 21

overlapping gene in ASD/epilepsy/schizophrenia

Answer 21

SCN2A

Question 22

prevention

Answer 22

22q11.2 deletion syndrome - 25% develop schizophrenia (strongest molecular risk factor)
rescue using D2 antagonist/enhance pV interneuron activity only during a specific developmental time

Question 23

imaging

Answer 23

advantage: human/in vivo/whole brain
disadvantage: resolution, mechanisms (correlation)

Question 24

iPSCs 2D culture

Answer 24

adv: human mechanisms/good for fast screening
dis: loss of neuronal diversity/in vitro/no function/behaviour /does not capture later stages of development like cortical layer development

Question 25

3D organoids

Answer 25

adv: human mechanisms/good for fast screening/converse diversity
dis: in vitro/no function/behaviour/only early development

Question 26

non-human primates (monkeys)

Answer 26

adv: primate mechanisms, diversity, in vivo, function/behaviour
dis: ethical concerns, low sample, manipulations are difficult

Question 27

animal models

Answer 27

adv: diversity, in vivo, easy to manipulate, big samples, cognition/motor function
dis: less close to humans, some processes unique to humans (like language)