Bruce Tomblin University of Iowa Genetics and Developmental Language Disorders

Parents often ask “why is my child having this problem?”

Honest response: I (we) don’t know, but we will focus on things that we know can help the child develop. This means:

We have to do our best given what we know. As we understand the problem better, our interventions should improve.

Effective treatments do not require understanding the basic nature of the problem.

This talk rejects the later. The more we understand the system we are working with, the more effective our treatment should be.

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Language emerges from complex interactions within and between levels of brain and cognitive systems and environment.

Individual differences at higher levels are reflective of variations in function at lower levels.

Ultimately the story that to be told will require a coherent theory across levels.

Our focus today will be on genetics.

Learning about genetics is just one way we can gain insight into the more complex pathways.

Envir

onm

enta

l

Individual

Differences

Language

Cognitive

Neural

Genetic

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• Composition

• Strings of amino acids (20 in the body)

• Nature of amino acids determines shape

• Protein function is driven by it’s shap

• Functions

• Provide structure (make tissue)

• Catalyze (enhance) chemical reactions (enzymes)

• Serve as information (chemical messengers)

• Respond to messages (act as receptors)

Protein-protein interaction

Genes made of DNA that

encodes amino acid

sequences.

Transcription: DNA

copied into mRNA

Translation: information

transferred to protein

Mutations: changes in

DNA

Changes in DNA can

produce changes in

proteins

mRNA

Nucleus Cytoplasm

Protein√ DNA

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promoter

Exons Intron

Regulatory Region

Gene expression is specific to cell line (neurons, liver)

Only 5–10% genes active at any time in any cell.

Gene regulation turns genes on and off

Promoters controls expression (on/off)

Enhancers/Silencers increase/decrease protein

production under the control of regulatory proteins

(transcription factors)

Coding Region Enhancer/silencer

Protein product of gene can vary and lead to individual differences Flavor of the protein

Due to variation in coding region Protein function may vary.

Amount of the protein Turned on or off (influence by the biochemical environment) Turned up or down. (regulatory proteins)

The regulation of expression is controlled by the cellular environment and other gene activity. Biochemical pathways.

This regulation can lead to developmental timing or miss-timing. Recent studies of complex neuropsychiatric disorders (Cox lab) has

shown that much of the genetic influence comes from variations in the regulatory region.

Laying the foundation Early production of neurons and glia

Building a cortex: migration

Forming a Neural Network Productive events

Regressive events

Changing the Neural Network Changing connectivity strength between neurons

(learning)

Synaptogenesis: Networks and Learning

8 mo. (35 weeks)

5 mo. (20 weeks)

Neurons don’t work in isolation. All behavior and cognition requires that neurons connect and compute.

Computation is performed by activation or inhibition of partner neurons.

During the last trimester of development, neural networks are formed. Axonal Path finding

Formation of synapse

Pruning of synapse Activity Dependent

After migration, neurons extend axons seeking to make contact with another neuron.

At the end of the axon are growth cones that have “feelers”

Growth is “guided” by the biochemical signals that either attract or detract growth.

This growth is exuberant in that temporary contacts are made when ever possible.

By week 34, 40,000 new synapses are formed every second and this continues into early postnatal life.

Synapse formation begins with a transient contact that is aided by cell adhesion molecule.

The Synapse is stabilized by activity-dependent processes, including the action of neurexins/neuroligins.

Axonal guidance signaling ADAM10, BMP15, CRKL, EPHA7, FZD6, MAPK12,

MLC1, OPN1SW, PDGFA, PIK3C3, PLXNB2, PRKAR1B, RAC3, SEMA3A; SEMA3D, SEMA5A, SEMA7A, SMO, WASL, WNT16, WNT2

Cell Adhesion NRXN1 CNTNAP2, NLGN3 , NLGN4X, NLGN1 and

ASTN2. CNTN4, ASTN2

Brain Imaging Evidence Under connectivity for circuits

involving social function.

The “leading current hypothesis is that autism is a disease of abnormal connectivity and synapse formation in the brain” (Tyszka,Kennedy, Paul & Ralph Adolphs ,2013).

Activity at Synapse

Triggering 2nd Messenger Cascade

Up regulating translation of neural growth hormone

Protein or RNA Travels to Active Site

BDNF

We are beginning to understand how genes contribute to individual differences in language.

Genes for brain development do not contain a blue print for brain architecture, but rather influence protein production at local levels along the developmental process.

Alterations in the kind, amount or timing of the gene product can alter the brain formation.

Ongoing refinement and modification of brain connectivity that results in learning and memory

Brains do not develop normally in the absence of critical genetic signaling and they do not develop normally in the absence of essential and contingent environmental input (Stiles, 2009).

Speech and language intervention is essentially the use of the environment of the child to trigger neural changes including gene activity.

Eric Kandel, 2000 Nobel Prize winner in physiology or medicine