MCB 170: Neurodevelopmental Disorders

What are neurodevelopmental disorders?

What are neurodevelopmental disorders?

a group of disorders that affect the development of the nervous system, leading to abnormal brain function which may affect emotion, learning ability, self-control, and memory

What are some neurodevelopmental disorders?

• autism spectrum disorder (ASD)

• attention deficit hyperactivity disorder (ADHD)

• intellectual disabilities (ID)

• communication disorders (CD)

Do neurodevelopmental disorders typically co-occur?

yes

What is the statistic for prevalence of neurodevelopmental disorders in the US?

15% of children

What are autism spectrum disorders?

a group of developmental disabilities that cause significant social, communication, and behavioral challenges

What are the three core deficits of autism spectrum disorders?

• impaired social interaction

• impaired language and communication

• repetitive and stereotyped behaviors with severely restricted interests

What are the four types of ASD identified in the past?

• infantile autism

• Asperger’s syndrome

• childhood disintegrative disorder

• persuasive developmental disorder not otherwise specified (PDD-NOS)

What is ASD diagnosis based on?

behavioral analysis

What are the different levels of autism?

• level 1

• level 2

• level 3

What occurs during level 1 of ASD?

the mildest, most “high-functioning” form of autism

What occurs during level 2 of ASD?

more obvious problems with verbal and social communication than the mild level

What occurs during level 3 of ASD?

the most severe form of autism

What syndrome is present in the film Rain Man?

savant syndrome

What is savant syndrome?

a rare but extraordinary condition in which persons with serious mental disabilities, including autistic disorder, have some ‘island of genius’ which stands in marked, incongruous contrast to an overall handicap

What is the percentage of gifted abilities of autistic individuals?

10%

What are special skills accompanied with?

prodigious memory

What is the prevalence of ASD? (3 things)

• increased 200% since 2000

• ASD is estimated to affect more than 3 million individuals in the US

• autism costs the nation over $268 billion per year

What does the treatment of ASD focus on?

reducing ASD symptoms

What is important to know about the behavioral interventions for ASD?

undertaken early in life, using an intense delivery format, are considered the current gold-standard treatment for behavioral symptoms associated with ASD

What are the two medications associated with reducing ASD symptoms?

risperidone and aripiprazole

What is risperidone?

an adult antipsychotic for the symptomatic treatment of irritability, aggression, deliberate self-injury, and tantrums (in children and adolescents)

What is aripiprazole?

a third-generation atypical antipsychotic for the treatment of irritability associated with ASD in children and adolescents

What is the mind blindness hypothesis?

the inability to attribute mental states to others

What is the inability of mentalizing in ASDs associated with?

impaired neural circuits underlying social cognition

What test is associated with the mind blindness hypothesis?

the sally-anne test

What are the neuroanatomical abnormalities associated with ASD?

• fronto-temporal region

• fronoparietal region

• amygdala

• basal ganglia

• cerebellum

• thalamus

• motor area

What parts of the brain are associated with social impairment in ASDs?

• front-temporal region

• frontoparietal region

• amygdala

What parts of the brain are associated with communication deficits in ASDs

• basal ganglia

• cerebellum

• thalamus

• motor area

What parts of the brain are associated with repetitive behavior in ASDs?

basal ganglia and thalamus

What is important to know about early brain growth in ASDs?

the brain of ASD patients is larger in volume than the brain of typically developing children, suggesting an atypical trajectory of maturation

What is important to know about dendritic spine pathology in ASDs?

there is exaggerated spine formation or incomplete pruning that occurs in childhood leading to increased spine numbers

What is important to know about the surplus of synapses in the brain of children with ASD?

there is increased dendrite spine density in pyramidal neurons of the temporal lobe in the ASD brain, suggesting deficits in synaptic pruning

Does autism have a specific cause?

no

What are the possible causes of autism?

genetic and environmental factors

What is the significance of the “refrigerator mothers” in the twin studies?

studies on identical twins establish the importance of genetics in autism

What is the fragile x syndrome?

the leading monogenic cause of intellectual disability and autism

What are the cognitive dysfunctions of fragile x syndrome?

• language delay

• intellectual disabilities

• learning deficits

What are the social and behavioral problems of fragile x syndrome?

anxiety and autism spectrum disorders

What are the neurological deficits of fragile x syndrome?

seizures and abnormal sleep patterns

What are the morphological abnormalities of fragile x syndrome?

dysmorphic faces and macroorchidsm (enlarged testes)

What is the prevalence of FXS?

• 40,000 cases of FXS in males and 27,000 cases in females in the US in 2017

• 1 in 4,000 males and 1 in 7,000-8,000 females

What is FXS caused by?

mutations in the fragile x mental R1 gene that is located on the x chromosome

What does the FMR1 gene do?

encodes a protein called fragile x mental r protein (FMRP)

What causes hypermethylation and transcriptional silencing of the FMR1 gene?

a trinucleotide repeat expansion within the 5’ untranslated region of the gene

What is FMRP?

an RNA-binding protein that shuttles between the nucleus and the cytoplasm of neuronal cells

What is FMRP involved with?

• the transport of mRNAs and their translation to synapses

• the nuclear RNA interference pathway associated with ncRNAs to suppress gene expression

What is important to know about altered synaptic pruning without FMRP?

• FMRP regulates the synthesis of structural proteins or signaling proteins that is important for stabilizing and maturing developing synapses

• more dendritic spines in FXS patients

What is FXS associated with?

increased excitability and excitation/inhibition imbalance

What is the process of hyperexcitability in FXS?

1. FXS-related hyperexcitability is apparent in elevated neuronal fining frequency

2. FMRP can indirectly regulate neurotransmitter release by controlling the action potential peak and duration, which in turn determines the amplitude and duration of presynaptic calcium influx through voltage-gated calcium channels

3. dendritic excitability is governed mainly by ion channels, a number of which are dysregulated in the absence of FMRP

What occurs to multipotent NSCs in relation to neurodevelopmental disorders?

altered proliferation, false specification, and maintenance

What occurs to oligodendrocytes in relation to neurodevelopmental disorders?

impaired white matter development and myelination

What occurs to astrocytes in relation to neurodevelopmental disorders?

altered astrocyte-neuron interactions

What occurs to immature neurons in relation to neurodevelopmental disorders?

stunted dendritic morphogenesis and altered axon targeting

What occurs to mature neurons in relation to neurodevelopmental disorders?

reduced synaptogenesis and altered circuit integration

What does FXS cause?

a decreased amount of FMRP

Where are NCS found?

the temporal lobe

What is the function of the basal ganglia?

control voluntary movements