VC - Autism II & III Flashcards
What are the two views in the Spectrum vs. Overlap debate regarding the triad response?
Fractionable View: Triad components (social, verbal, repetitive) are distinct and independently expressed.
Integral View: Triad components are overlapping and inseparable traits.
What evidence supports the Fractionable View? (5)
Behavioral Studies:
- Social/verbal > verbal/repetitive > social/repetitive linkage observed. However, no significant linkage found among traits
- Normal individuals may show dysfunction in one triad aspect only.
- Autism traits often show partial fractionation e.g. traits like repetitive behavior often appear secondary to social or verbal dysfunction.
- Social bias in testing methods may obscure clearer separations between traits.
Genetic Studies:
- Twin studies suggest traits have genetic independence.
What are the specific brain regions associated with each component of the autism triad? (5)
Social Traits: Medial frontal cortex, temporoparietal junction, temporal sulcus/poles.
Verbal Traits: Voice-related cortical areas.
Repetitive Traits: Caudate putamen.
What does the Sally-Anne test assess?
Theory of mind – understanding others’ beliefs, desires, and intentions
How does the Sally-Anne test work? (4)
- Sally hides a marble in a basket and leaves.
- Anne moves the marble to a box.
- Question: “Where will Sally look for her marble?”
- Correct answer reflects understanding Sally’s false belief (basket). Incorrect answer suggests difficulty understanding others’ perspectives
What evidence suggests autism has a biological basis? (3)
- Changes in brain structure/function identified in imaging and post-mortem studies.
- EEGs in autistic individuals show unusual electrical activity, often linked with seizures (~30%).
- Abnormal brain size changes: slow neonatal and rapid postnatal growth.
What changes might be observed in different brain regions in autism? (4)
- Cell number increase or decrease
- Cell size changes
- Cell density increases
- Connectivity changes
Why do post-mortem studies have limitations?
They are influenced by a lifetime of experiences (e.g., treatments, medications) and variations in death circumstances.
What are the key stages of early brain development? (4)
- Progenitor cell division (asymmetrical).
- Neurogenesis (formation of new neurons).
- Migration (neurons move to their final positions).
- Cell death (elimination of excess neurons).
What are the later stages of brain development? (5)
- Neuronal differentiation (specialization).
- Neurite outgrowth (axons and dendrites form connections).
- Synapse formation. Retraction and shrinkage can also occur here
- Synapse maturation and stabilization.
- Synaptic pruning (refining connections)
How can these stages of brain development be disrupted in autism? (5)
- Abnormal neurogenesis
- Defective migration
- Impaired neuronal differentiation
- Excessive or reduced synapse formation
- Defective synaptic pruning
What genetic factors are linked to autism? (3)
- Mutations in specific genes.
- Chromosomal rearrangements.
- Polygenic inheritance (many genes with small effects).
What genetic research methods are used to study autism? (3)
- Linkage analysis
- Association studies
- Genome-wide association studies (GWAS)
What does GWAS identify in autism?
Single nucleotide polymorphisms (SNPs) associated with the disorder.
What is synaptopathy in the context of autism?
Abnormalities in the formation, function, or elimination of synapses
Give examples of genes involved in synaptic processes that are linked to autism? (3)
FMR1: Regulates protein synthesis at the synapse (linked to intellectual disability and autism).
NLGN3/NLGN4: Involved in synaptic adhesion and signaling.
What cellular processes do ASD-related genes influence? (7)
- Chromatin remodeling and gene regulation. (e.g. FMRP)
- Actin cytoskeleton dynamics.
- Synaptic scaffolding proteins.
- Receptors and transporters.
- Second-messenger systems.
- Cell adhesion molecules. (e.g. NLGN4 and NLGN3)
- Secreted proteins.
What role do neuroligins and neurexins play in the brain?
They are cell adhesion molecules critical for synapse formation and stabilisation. Disruptions in these proteins can lead to ASD
Where are neuroligins and neurexins located in the synapse?
Neurexins: presynaptic membrane
Neuroligins: postsynaptic membrane
What structural features are associated with neuroligins and neurexins? (3)
Neuroligins
- Share a fold similar to acetylcholinesterase (α/β-hydrolase fold).
Neurexins
- Built around LNS (Laminin-Neurexin-Sex Hormone-Binding Globulin) domains and EGF (Epidermal Growth Factor-like) repeats.
- Produce α-neurexins (long) and β-neurexins (short), both capable of protein-protein interactions.
How many genes encode neuroligins and neurexins and what are its key features? (7)
Neurexins:
- 4 genes
- Independent promoters enable transcription from distinct gene regions.
- Extensively spliced, creating thousands of isoforms for synaptic diversity.
Neuroligins:
- Humans: 5 genes; NLGN1–4X; NLGN4Y on Y chromosome
- Non-human mammals: 4 genes; NLGN1–4 distributed (no NLGN4Y)
- Extensively spliced
- Genetic complexity and redundancy make it difficult to replicate human neuroligin variants.
What happens to synapse numbers in neuroligin-deficient animal models?
Synapse numbers and structure are relatively normal, but synaptic function is disrupted.
How does neuroligin deficiency affect the brain stem in mouse models? (2)
- Normal synapse count, but reduced glutamate (excitatory) and GABA (inhibitory) transmitters.
- Ratio of inhibitory/excitatory transmission is reduced, with excitatory dominance.
Which neuroligin mutations are associated with autism?
Mutations in NLGN3 and NLGN4, particularly on the X chromosome
e.g. R451C mutation in NLGN3
What is the significance of the R451C mutation in NLGN3? (2)
- Found in individuals with autism, varying in severity (e.g., severe symptoms with seizures vs. milder Asperger’s syndrome).
- Suggests complex genetic interactions.
What findings were reported in mouse models with the NLGN3 R451C mutation? (2)
- Tabuchi et al: Strong social deficits
- Chadman et al: Minimal social interaction abnormalities but motor deficiencies
How do NLGN3 knock-out and mutated mice differ in synaptic function? (5)
Knock-out:
- Increased metabotropic glutamate receptor activity
- disrupted cerebellar plasticity and other areas of the brain.
NLGN3-mutated:
- Increased inhibition
- impaired social behavior (disputed)
What were key similarities between both models compared to the wild type? (2)
- Both models showed enhanced motor learning during the more demanding task, suggesting a potential link between with repetitive behaviors in autism.
- Both models showed an imbalance in the activity of striatal neurons
How does the striatum contribute to autism-related behaviors? (2)
- Imbalance between excitation and inhibition in the striatal circuit.
- Reduced GABAergic inhibition onto D1-type neurons leads to repetitive behaviors.
What challenges exist in treating autism? (2)
- Developmental and pervasive nature of the disorder.
- Wide spectrum of symptoms requiring individualized approaches.
What are the goals of behavioural therapies for autism?
To promote behavioural plasticity
What are the strategies of behavioural therapies? (3)
- Sensory or Play Therapies: aim to refine behavior by bringing individuals out of themselves
- Encouraging interaction with the environment (often involve carer programmes)
- Cognitive Therapy: Identifying cognitive deficiencies, instilling self-awareness, and teaching strategies to overcome these challenges.
What types of drug therapies are used in autism treatment? (5)
Neurochemistry-focused:
- Serotonergic and Dopaminergic Drugs: alleviate social impairments and stereotyped behaviors.
- Selective Serotonin Reuptake Inhibitors (SSRIs): Used to target repetitive behaviors.
- Mood Stabilizers: Lithium, valproate, and carbamazepine have shown some success in managing certain symptoms.
Transmitter pathway-focused:
- Adrenergic Antagonists: Propranolol and clonidine can be used to treat sleep disorders and aggressive behavior.
Organic Interventions
- Vitamin and Mineral Supplements: Some individuals with autism may benefit from supplementation with magnesium, vitamin B6, and vitamin B12.
What are the limitations of current autism treatments? (2)
- Lack of rigorous scientific evidence for many treatments.
- Limited efficacy in addressing core symptoms or providing a cure.
