Autism Spectrum Disorder

Topic 1: Genetic and Cellular Theories of ASD

Autism Spectrum Disorder (ASD) has a strong genetic component, possibly up to 90%, which can lead to mutations in neuroligin-3 and neuroligin-4 genes.

Neuroligin is a protein located at the synapse:

  • Neuroligin-3 and Neuroligin-4 are associated with ASD & play important roles in synapse formation and function

The common disease, common variant hypothesis suggests that risk of developing ASD is due to multiple genetic variants, each having a small impact.

GWAS (Genome-Wide Association Studies)

  • Look for SNPs (Single Nucleotide Polymorphisms)

  • Compare Danny of cases and controls

  • Associations indicate regions of the genome contributing to ASD risk

Many ASD-related CNVs (Copy Number Variations) are found at the synapse or other synaptic elements along the neuron.

Genomic Findings

  • CNVs are deleted or duplicated DNA segments in chromosomes

  • Many ASD-related CNVs are widespread throughout the genome

  • 50-70% of the genes associated with ASD CNVs are found at the synapse

Strong genetic component of ASD, the involvement of synapse-related proteins like Neuroligin, and the wide distribution of ASD-related CNVs, many of which are found to be synaptic genes.

Results from copy number variation studies

  • De novo copy number variations might be responsible for some cases of autism, especially in families with no significant family history

  • Whole exome sequencing was introduced to address the limitations of this technology, as it allows for sequencing of the most important parts of the genome

Review of results

  • A series of three Nature papers were published with the results from the exome sequencing studies

  • Despite identifying many mutations that may be associated with autism, hardly any of them appeared more than once

  • A few candidate genes were identified, including those related to transcriptional regulation, chromatin remodelling, and synaptic function

Cellular theories of pathogenesis

  • Abnormalities in synapses have an impact on neurons and their connections, leading onto the behavioural changes seen in ASD

  • Changes in dendritic spines, which indicate excitatory synapses, have been observed in ASD patients, suggesting a failure in the normal "pruning away" of synapses that usually occurs during childhood and adolescence

  • Heterogeneity in ASD presents a challenge in identifying the specific cellular and molecular mechanisms underlying the disease

To understand Autism Spectrum Disorder (ASD) better, scientists are exploring the use of animal models like mice, and even growing human brains in labs.

  • Animals can help us study the impact of genetic changes on the structure and function of synapses, those tiny communication points between brain cells.

  • Researchers have found that many genes related to ASD are involved in the synapse and can lead to changes in the balance between excitatory and inhibitory synapses. This, in turn, may result in reduced synaptic density and strength, which seems to align with findings from mouse models and human brain samples.

Using animal models for ASD research

  • Scientists consider using animal models like mice to study ASD

  • Animal studies can help us understand the impact of gene deletion/mutation on synaptic & neuronal structure and function

Synapse-related genes and ASD

  • Many genes implicated in ASD are part of two main groups: transcriptional control & synapse

  • Synaptic genes - such as those associated with the postsynaptic density - play a significant role, potentially causing features of Phelan-McDermid Syndrome (PMS)

Impact on synapses and neuronal activity

  • Deletion of PDZ domain in mice leads to repetitive grooming & enlarged striatum, reminiscent of ASD features

  • Researchers find synapses smaller and with reduced function in mouse models and human brain samples

  • Excitatory synaptic function is impaired in human ASD patients with one copy of a particular gene mutated

Changes in the balance of excitation and inhibition

  • Changes to synapses can appear in excitatory, inhibitory, or both forms, and may occur in either direction

  • Balance between excitation and inhibition (E/I balance) is thought to be crucial, with imbalances possibly leading to ASD

Growing human brains in labs

  • Aim is to use invasive technologies to understand neuron and synapse changes without issues seen in human research

  • Researchers have successfully cultured human brains from stem cells in a lab dish

Examples of recent findings in human brain structures

  • Neurons from PMS patients show fewer synapses and are smaller than control group samples

  • Reduction in excitatory synapses correlates with impaired electrical recordings in PMS patients

Autism Spectrum Disorder (ASD) is mostly sporadic, not linked to a syndrome. And recently, scientists have used brain scans and cells from ASD patients to learn more about it.

Findings of the study

  • People with ASD tend to have a larger total brain volume than the average person

  • This could be due to the fact that there are fewer inhibitory neurons in cells from ASD patients

  • Additionally, there are decreased excitatory synapses in the ASD group

  • Abnormal structure and function of synapses were observed in ASD group

  • Long-range connections and theories about connectivity weren't discussed in this slide deck but they are also important to the understanding of ASD

Correlation between brain volume and ASD

  • Increase in brain volume could be related to the early growth stage of the brain in ASD patients

Topic 2: A Spectrum Within a Spectrum: Finding New Treatments for Autism

ASD encompasses a diverse range of presentations, meaning individuals with ASD can exhibit vastly different symptoms and levels of impairment.

  • Heterogeneity: The variability in ASD presentation is due to a combination of genetic, environmental, and neurological factors.

Given the spectrum nature of ASD, effective interventions must be tailored to the individual's specific needs and challenges.

Many neurodevelopmental disorders share common symptoms and underlying causes, making differential diagnosis challenging.

  • Individuals with ASD often experience co-occurring conditions such as anxiety, depression, and ADHD, further complicating diagnosis and treatment.

  • he interplay of genetic and environmental factors increases an individual's vulnerability to neurodevelopmental disorders.

Traditional diagnostic approaches often rely on categorical classifications, which may not fully capture the complexity of neurodevelopmental disorders like ASD. A dimensional approach, which considers the severity of symptoms along a continuum, may provide a more nuanced understanding.

  • Categorical Approach: Classifies individuals into distinct diagnostic categories based on the presence or absence of specific symptoms.

    • Limitations:

      • May oversimplify complex conditions

      • Fails to capture the heterogeneity within diagnostic categories.

  • Dimensional Approach: Views symptoms as existing on a continuum, allowing for a more nuanced assessment of severity and individual differences.

The causes of ASD are diverse and not fully understood. Genetic factors, environmental influences, and neurological abnormalities all play a role. Certain infections during pregnancy, such as rubella, have been linked to an increased risk of ASD.

  • Multifactorial Etiology: ASD is likely caused by a combination of genetic and environmental factors.

  • Genetic Predisposition: Individuals with a family history of ASD are at a higher risk of developing the condition.

  • Environmental Risk Factors: Exposure to certain environmental toxins or infections during pregnancy may increase the risk of ASD.

  • Congenital Rubella: Infection with the rubella virus during pregnancy can cause congenital rubella syndrome, which is associated with an increased risk of ASD.

Research into ASD involves a variety of techniques to study the brain and behavior of individuals with the condition. These techniques include neuroimaging, genetic analysis, and behavioural assessments. (Slide 3)

Techniques such as MRI and fMRI are used to study brain structure and function in individuals with ASD.

Identifying genes associated with ASD can provide insights into the underlying biological mechanisms.

Standardized tests are also used to assess social communication, repetitive behaviours, and other characteristics of ASD.

Disruptions in the balance between excitatory and inhibitory neurotransmission in the brain are thought to play a role in the development of ASD. This imbalance can affect neuronal communication and contribute to the symptoms of ASD.

  • Excitatory Neurotransmission: Involves the release of neurotransmitters that stimulate neuronal activity.

  • Inhibitory Neurotransmission: Involves the release of neurotransmitters that suppress neuronal activity.

  • Glutamate: The primary excitatory neurotransmitter in the brain.

  • GABA: The primary inhibitory neurotransmitter in the brain.

  • Synaptic Dysfunction: Disruptions in synaptic function can lead to an imbalance between excitation and inhibition.

Studies have investigated the levels of glutamate, an excitatory neurotransmitter, in the brains of individuals with ASD. Some research suggests that glutamate levels may be elevated in certain brain regions, such as the basal ganglia and frontal lobe.

  • Creatinine: A compound used to normalize glutamate levels in neurochemical studies.

⚠ Increased glutamate levels may contribute to neuronal hyperexcitability and the symptoms of ASD.

Microglia, the brain's resident immune cells, may play a role in the pathophysiology of ASD. Activated microglia can release cytokines, which are inflammatory molecules that can affect neuronal function and glutamate levels.

  • Evidence suggests that microglia are more active in the brains of individuals with ASD.

  • Cytokines released by activated microglia can increase glutamate levels in the brain.

The heterogeneity of ASD and the complex interplay of biological factors have important implications for drug development. It cannot be assumed that drugs will work the same way in all individuals with ASD, or that they will have the same mechanism of action in everyone.

  • Personalized Medicine: Tailoring treatment to the individual's specific biological and clinical characteristics.

  • Mechanism of Action: The specific way in which a drug produces its therapeutic effect.

  • Drug Response Variability: Individuals with ASD may respond differently to the same drug due to differences in genetics, brain function, and other factors.

Topic 3: Concepts And Challenges For 'Precision Medicine Approaches' For Autism Spectrum Disorders

Precision medicine for autism is crucial to understand each individual's unique condition to develop effective treatments.

Precision Medicine Approach to Autism

  • Goal: understand each individual's unique condition to develop effective treatments

  • Challenges: identifying causes, treatment biomarkers, and personalizing therapies

  • Prognosis: variable, with intellectual abilities and language as best predictors for adult comorbidities (e.g., ADHD, anxiety, depression)

  • Treatment options: behavioral interventions (which can be time-consuming) and medical treatments for associate/comorbid symptoms like epilepsy, anxiety, or depression

  • Cause: previously considered idiopathic, but recent studies identify common and rare genetic links (affecting 10-20% of individuals)

Integrated Translational Approach

  • Animal models to identify new treatment targets

  • New technologies (patient-derived induced pluripotent stem cells) to identify treatment targets

  • Large-scale studies to identify biological risk markers

Genetic Impact

  • Some individuals' autism seems to be caused by specific genes, impacting synapse development

  • Ongoing research for neurobiological causes

Key takeaway: So, here's what stands out: scientists can now study the brain and behavior in autism using different methods. Some focus on gene manipulation in animals, while others study the brain and its functions directly in humans through neuroimaging and stem cell technology. The aim is to find personalized treatment targets, but there's a long way to go even if successful.

Animal models in autism research

  • Gene knockout in animals helps understand cellular development and behavior

  • Finds roles of synaptic abnormalities in brain development and their impact on cognitive functions

Neuroimaging technologies for translatable methods

  • Comparable areas in the brain between animals and humans studied through MRI

  • Neurotransmitter studies (glutamate, GABA) done in mice, rat, and human beings

  • EEG studies to analyze brain function during rest or while performing tasks

Patient-derived induced pluripotent stem cells (IPSCs)

  • Turn any kind of cell type into pluripotency and program into any fate (liver cell, neuron)

  • Derive neurons from autism patients and compare to relatives, controls, or other test subjects

  • Test new drugs using these cells for electrophysiological, growth, and morphology assessments

Challenges in precision medicine approaches for autism

  • Even with successful identification of treatment targets, there are still major clinical barriers to face

Need for biomarkers as surrogate outcome measures and better understanding of autism development and etiologies

  • Comprehensive assessments in research institutes to evaluate autism symptoms, adaptive function, developmental trajectories, and etiologies