Transactional Model of Development

What % variability in IQ is explained by genes and which % by environment and does it change over time?

The environment plays much stronger role early in life, with genetics only explaining 26% variability in IQ, but this rises to about 85% by age 50

What is the difference between the Grey Matter and White Matter in the human brain? 

Grey Matter = cell bodies, axonal arbors, dendrites and synapses

White Matter = myelinated axon tracts (wiring)

• all mental activity is mediated by brain and therefor dependent on biological mechanisms
• all human genes are known
• we can understand how genes contribute to psy. functioning -> neurobiological mechanisms
• we can understand environmental factors effecting brain development, plasticity and function
• knowing biomechanisms underlying pathology may allow effect pharmacotherapy and behavioral interventions

At the level of cellular mechanisms:

genes-> proteins-> cellular mechanisms-> neural structure-> function-> neuronal networks

->information processing-> cognition

Transcription Factor (TF)

TF is a protein that binds to specific DNA sequence thereby controlling the movement (transcription) of genetic information from DNA to mRNA

CODON

• A sequence of 3 bases which encodes for one specific amino acid

• 1 meter of DNA strand is folded into a nucleus of 0.01mm
• This is achieved by folding DNA onto nuclear scaffold proteins = nucleosomes

In what 2 ways can DNA be folded onto nucleosomes?

• condensed form (packed)
• open configuration (beads on a string)
• the condensed form can be opened - allowing gene experssion

• DNA accessibility
• Activation, suppression by specific TF's
• Gene transcription Machinery (RNA Poly II)

• Normal sequence
• slower
• lower ceiling
• Abilities develop similar rate

• Qualitatively altered development
• Some abilities affected more or less
• Varying cognitive profiles

• Mild = IQ 55 - 70
• Moderate = IQ 25 - 55
• Severe = IQ < 25

• Austism
• ADHD
• Schizophrenia

Genetic form of MR related to FMR gene

• 1:4000 in MALE
• 1:8000 in FEMALE

• # chromosomes
• chromosomal deletion
• chromosomal inversion
• chromosomal duplication
• point mutations
• polygenic inheritance

• prenatal infection HIV / STORCH
• pre/perinatal oxygen deficiency
• prenatal toxicity (FAS)
• nutritional insufficiency 

• verbal intelligence
• visual intelligence (gestalt closure)
• relevant real life content (visual test)

• short term working memory (digispan)
• abstract content (visual tests)

What are the main structural brain abnormalities in MR

• fewer neurons
• neuronal migration disorders
• reduced dendritic complexity
• reduced density of spines
• immature spine morphology
• common theme: altered structural neuronal network connectivity

Neuronal Network Hypothesis MR

• MR is caused by abnormal development of structural neuronal network connectivity
• this results in deficient information processing
• it is the structure, not just the function, i.e. altered synapses, dendrites, axoms, NOT problem neurotransmission, or myelination etc..

Increase mushroom spines

More dendrites

both in mice

Could this be related to pruning phase?

Hippocampus

Oligphrene 1

alpha pix

fdg1

• no change in dendrites
• reducted spine density on apical dedrites
• more shaft synapses
• increased hydrocephaly in older mice
• immature spine morphology in cultured neurons

• ARHGEF6 gene encodes alpha pix
• deletion in CLT domain causes MR

• increased dedrite length in C1 hippocampus
• increased dendrite branching in C1 hippocampus
• similar changes seen in visual system

• increase mushroom spines CA1
• decrease thins spines on distal apical dendrite CA1
• increase filapodia CA1
• no change spines on basal dendrites CA1
• similar changes V1

1. overproduction
2. deficient pruning

A computational analyses concludes that assuming an equal number of spines:

1. lower ampliture depolarization soma
2. slower propogation depolarization soma

1. altered spatial memory (morris maze)
2. impaired reversal learning (morris maze)

• water maze
• mice placed in maze look for platform
• mice build mental map
• mouse placed different parts of bath
• learning curve over trials

What happens to ARHGEF6 KO mice in the morris maze when compared to wild type?

1. no difference in the probe trial
2. reversal trial - KO mice take longer to find the platform ..... could this be caused by stabalization spines?

What effect does Enriched Environment have in fear response experiment on alpha pix KO mice versus wild type?

• all mice show more freezing after EE, all conditions
• KO mice from EE perform better
• all EE mice show more freezing (higher anxiety)
• could this be environmental compensation for a genetic caused behavioral deficiency?

a protein which modulates RhoGTP

• improved memory effect
• can CNF-1 solve memory problems in MR??

1. classical autistm (1-2 / 1000)
2. asperger syndrome ( 0.6 / 1000)
3. pervasive development disorder (3.7 / 1000)
4. ASD combined (6/1000)

• Early preschool years, since then they interact first time and it becomes clear to care takers
• Parents commonly seen help at 3 -4 years of age because at that point they notice the inability to interact with others normally

Deviations in at least 6 items from:

• social interaction (at least 2)
• communication (at least 1)
• repetitive sterotyped behavior (at least 1)

• impaired non verbal communication / eye contact
• facial expression, body posture, social gestures
• failure to develop peer relations for age
• lack of enjoyment in sharing emotional states
• lack of social / emotional reciprocity

• delay or lack dev. spoken language with absence of non verbal compensation
• marked impairment ability to sustain conversation
• stereotyped repetitive use of language or idiosyncratic langauge
• lack of varied, spontaneous make believe play of social imitative play appropriate to dev. level
• take everything at face value - TOM

• pre-occupation with stereotyped restricted patternss of interest, with abnormal focus or intensity
• inflexible adherence to specific apparently non-functional routines or rituals
• stereotyped repetitive motor mannerisms such as hand of finger flapping, twisting etc
• persistant pre-occupation with parts of objects

• ability to understand what another person thinks of beleives in a given situation
• normally emerges age 4
• sally-anne task

Sally Anne Task

The experimenter uses two dolls, "Sally" and "Anne". Sally has a basket; Anne has a box. Experimenters show their subjects (usually children) a simple skit, in which Sally puts a marble in her basket and then leaves the scene. While Sally is away and cannot watch, Anne takes the marble out of Sally's basket and puts it into her box. Sally then returns and the children are asked where they think she will look for her marble. Children are said to "pass" the test if they understand that Sally will most likely look inside her basket before realizing that her marble isn't there

80% failure

• Presents two boxes, one of which has smarties and the child has to point to the box without the smarties in order to get them
• if points at box with smarties, someone else eats them
• 3 year old children and children with Autism cannot learn to inhibit the the dominant response which is pointing at what they want

• Problems percieving things in terms of overall meaning or coherence
• e.g. remembering words rather than meaning
• may explain exceptional ability in autism
• predicts good performance when attention to local details is advantageous
• predicts problems when stimuli have to be interpreted in context or more globally

• such developmental brain disorders have their origin in early life
• interventions such as pharmacotherpy would have maximum effect early in life
• basic building blocks of cognition, language
• difficiencies get bigger with age

What can go wrong in parental - child interaction in early childhood when a child has ID or ASD? 

• parents expect certain behavior based on age
• child is cognitively unable to behave this way
• parents frustrated 
• child frustrated
• unfortunate interaction
• can be helped through early intervention 

AbeCederian Project

1. broad early preschool intervention USA
2. non retarded otherwise at risk children
3. longitudinal
4. improved IQ scores
5. improved school performance
6. improved social and economic status
7. suggests that early intervention can help normal children at least

Perry Pre-School Study

shows the cost benefit of EI (in USA)

costs of not doing it are welfare, schooling, justice, crime victims etc

• parent mediated intervention -> cost effective
• uses Vygotsky zone of proximal development
• regular assessments on 7 domains
• tailored advice to parents on activities to stimulate development to next level, in small steps

What is the ideal goal of Early Intervention?

Enabling a child to participate in normal schooling by age 4

What percentage of children with autism are also mentally retarded?

70% or more

• Together with Sonic Hedgehog, is responsible for dorsal ventral patterning neural tube. 
• Secreted from roof-plate forming gradient inducing formation dorsal commissural interneurons
• BMP I&II receptors free floating in plasma until BMP attaches

Sonic Hedgehog (SHH)

• Secreted from floor-plate
• SHH gradient determines ventral spinal chord neural identity

Neuronal Progenitor Cells

1. symmetrical division
2. asymmetrical division
3. symmetrical termination

• Early type astrocytes which span neural tube ventral to pial
• mediate radial neuronal migration by acting as a scaffold that neurons migrate along 
• destined to become excitatory neurons

• Gives rise to pool of neurons and glia cells for brain

• Gives rise to post-mitotic cells and depletion progenitor pool
• Once cells are post-mitotic, they will begin to migrate and differentiate

• post-mitotic cells move up alone radial glia to their location
• inside is formed first and outside last
• newest cells must move past the older ones
• disruption would mean cells placed in wrong layer -> MR

• Inhibitory neurons (GABAergic) migrate tangentially from pallium (ventral) to cortex - and then radially to final layer
• Disruption results in fewer GABAergic neurons cerebral cortex -> severe epilepsy 

• Rostro-caudal (longitudinal) differentiation is largely dependent on segmental expression HOX genes
• HOX genes are transcription factors are the major regulators of longitudinal differentiation

• Reelin is excreted from Cajal-Retzius in layer 1 of cortex
• Acts as extracellular messenger protein in radial migration 
• mutation reelin leads to inversion layers 2 and 6 cortex

• Neuronal survival is dependent on a limited supply of a trophic factor by the target tissue, which is taken up by nerve terminals
• Different neural populations depend on different trophic factors

• NGF = nerve growth factor
• NT 3, 4, 5 = neurotrophin
• Trk = tyrosine kinase receptor
• GDNF = glia derived neurotrophic factor
• CNTF = ciliary neurotrophic factor

• NGF binds to Trk A
• NT3 binds to Trk C
• BDNF binds to Trk B
• NT 4/5 binds to Trk B

Patterning genes lead to gradients in expressioon of various types of genes (transcription factors, nuclear receptors, cell adhesion molecules, axon guidance molecules etc) before thalamacortical axon (TCA) innervation. Over time these gradients transform into areas of differential gene expression.

What happens if you knock out patterning genes Pax6 or Emx2? 

KO Pax6 = motor cortex shrinks

KO Emx2 = visual cortex shrinks

The other areas grow to compensate - probably progenitor cells are effected by the gene that is not knocked out

What happens in the sensory cortex if you cote one of a mouse's whiskers with iron and place the mouse in a magnetic field for some time?

The barrel in S1 representing that whisker will expand. Experience modulates the development of the structure. 

• Neuroligins (post-synaptic) bind with Neurexins (presynaptic) 
• Neuroligin 1,3,4 induce glutamatergic presynapses
• Neuroligin 2 induces GABAergic presynapses
• Affect balance excitatory and inhibitory synapses
• Mutation Neuroligin 4 in Autism

Beta-Neurexin

• Induce glutamatergic synaptic properties through neuroligins

• Scaffolding protein on post-synaptic side of excitatory neurons
• Facilitate clustering of receptors (NMDA-R)

• Because they stimulate the matching of presynaptic output with post-synaptic receptors
• This can happen both directions, (post to pre) or (pre to post).