Autism spectrum disorder Flashcards
What is ASD?
ASD is defined by deficits in two core domains: atypical social behaviour and disrupted verbal and non-verbal communication. It also involves restrictive interests and repetitive behaviours.
What are the only approved drugs?
The atypical antipsychotics Risperidone, which is effective in treating aggressive and repetitive behaviour, and Aripiprazole, which reduces irritability.
These act on dopamine receptors as well as 5-HT, α1, H1 and M1 receptors.
Do not treat the core social deficit
Comorbidities
Motor deficits, sleep abnormalities, gastrointestinal disturbances (50%) and epilepsy.
Genetics - inheritance
Rare genetic conditions contribute to 3% of ASD cases.
20% of children with autistic siblings develop ASD.
5% of cases have chromosome anomalies and copy number variations (CNVs).
Genetics - neuroanatomical and systems changes
Neuroanatomical level - children with ASD have larger brains, but this normalises during development → due to disorders in neuronal connectivity in the cerebral cortex, due to subtle differences in the neuronal cortical columns.
Systems level - imbalance in genes affecting excitatory and inhibitory neurons → affects prenatal neuronal migration and axonal pathfinding and postnatal dendritic development, synaptic pruning and neurogenesis. Involves neuroligin, neurexin and SHANK3, amongst others.
Genetics - de novo mutations and susceptibility genes
De novo mutations contribute to 5-10% of cases and include those in the protein Trio found in dendric spines of glutamatergic neurons.
>100 susceptibility genes converging on pathways involving synaptic transmission, neuronal activity and neuronal cell adhesion.
Genetics - Neuroligin and Neurexin
Neuroligins - synaptic cell-adhesion molecules that bind postsynaptic neuronal membranes and interact with NMDA or GABA receptors to maintain synaptic functions and the excitatory/inhibitory balance.
Neurexins - components of the presynaptic membrane whose intracellular domain interacts with proteins involved in exocytosis.
Neuroligin and neurexin link across.
A small % of ASD patients present with mutations in genes encoding neuroligin-neurexin cell adhesion molecules → disrupted excitatory/inhibitory balance.
Neuroligin-3 mutant mice have increased GABAergic signalling and reduced social behaviour.
Genetics - Dopamine
Increased expression of Gi-coupled D2 receptors in the dorsal striatum → links to the only approved treatment being antipsychotics (D2 antagonists).
De novo mutations in DAT resulting in a reduced ability to transport dopamine are associated with ASD. In Drosophila, this causes hyperactivity and disturbances in the circadian rhythm.
Risk factors
Glutamate/GABA imbalance
Dysregulation of monoamine transmission
Chronic neuroinflammation.
Hormonal imbalances.
Dysregulation of the immune system of the mother and developing foetus affect neurodevelopment.
Mitochondrial dysfunction and oxidative stress.
Rate of ASD doubles as maternal age increases from 25 to >40. There is also an increased risk when the male is >10 years older than the female.
Maternal use of the antiepileptic drug valproic acid.
Role of serotonin
Serotonergic dysfunction is a feature of ASD.
Hyperserotonaemia, increased blood serotonin, in 25% of children with ASD.
Tryptophan depletion, which decreases synaptic 5-HT, worsens repetitive behaviours and irritability.
Decreased 5-HT2A receptor binding.
Alteration in the 5-HT inactivation mechanism SERT and MAO-A.
SERT (SLC6A4) mutations change transporter function. Promoter can exist as a short (14) or long (16) repeat - 14 repeat reduces transcription and is associated with anxiety.
Gut-brain axis pathology
Microbiota changes can cause immune over-activation and increased oxidative stress.
Changes in the microbiota are correlated to altered tryptophan-serotonin levels.
Microbiome changes stimulate enterochromaffin cells to release neuroinflammatory molecules which signal to the brain via the vagus nerve, enteric nervous system and bloodstream and can interfere with neuronal function and induce microglia activation.
Beneficial microbiota
Lactobacillus reuteri upregulate plasma and brain oxytocin, which increases social behaviour in mouse models of ASD.
L. rhamnosus produces GABA and regulates GABA receptors in the brain.
Bifidobacterium longum upregulates BDNF, augments neuronal plasticity in the enteric nervous system, and reduces anxiety and depression-like behaviours in mice.
Bacteroides fragilis improves anxiety-like behaviour, repetitive behaviour and communication in mice.
