Synaptic and Molecular Changes in Autism Flashcards
What is the “missed window” theory of autism?
ASD may emerge through faulty subcortical development: motor development delays, social impairment, autistic seizures
primary sensory alterations underlie higher order cognitive defects
auditory, visual, and somatosensory dysfunction in information processing drive socialization and communication deficits in ASD
In what ways is ASD a critical period disorder?
critical period development is affected by genetic and environmental insults
plasticity demands a precise balance of excitatory and inhibitory neurotransmission (E/I balance)
missed window theory predicts E/I imbalance in ASD
What is excitatory neurotransmission?
activation of postsynaptic cation channels by glutamate
results in postsynaptic depolarization (excitatory postsynaptic potential, EPSP)
What is inhibitory neurotransmission?
activation of postsynaptic anion channels by GABA
results in postsynaptic hyperpolarization (inhibitory postsynaptic potential, IPSP)
reduces or interferes with the ability of postsynaptic cell to trigger an action potential
What is the excitatory and inhibitory neurotransmission balance?
sensitive to genetic and environmental factors
location and severity of imbalance would result in a spectrum of phenotypes
diagnostic window of ASD (first 3 years) correlates with intensive experience-dependent circuit refinement
runaway hyperexcitable
Is there evidence for excitatory/inhibitory imbalance in ASD?
the predictions are:
altered primary sensory function
defects in synaptic pruning
+/- GABA transmission
+/- glutamate transmission
What is the evidence for a excitatory inhibitory imbalance in ASD in sensory dysfunction studies?
evidence for primary sensory dysfunction
age-dependent
strongest effect in age 6-9 group versus control
increase or decrease cortical latency to auditory tones
impairments in ability to resolve vibrotactile stimuli
evidence for multi-sensory processing deficits (integration)
What is the evidence for a excitatory inhibitory imbalance in ASD in GABA levels?
altered plasma GABA levels reported in ASD: relevance to brain GABA unclear
GAD (GABA synthesis): informs GAD65/GAD67 reduced in postmortem ASD parietal cortex and cerebellum
reduced GABA-A, B receptors in ASD
disrupted cortical mini-columns observed in ASD leading to broadened excitatory transmission
What is the evidence for a excitatory inhibitory imbalance in ASD in dendritic spines?
dendritic spine densities are altered in ASD
age-dependent differences (post-mortem samples aged 10-45) were observed that were less severe with increasing age
What is Fragile X Syndrome (FXS)?
CGG trinucleotide repeat in the FMR1 gene (located on the X chromosome): prevents expression of fragile-X mental retardation protein (FMRP)
most widespread single-gene cause of autism and intellectual disability
markedly severe in men (much less severe in heterozygotic females)
What are FXS models?
FXS is easily translatable to animal models by knockout of the FMR1 gene
FMR1 KO mice have cognitive and behavioral deficits relatable to human FXS patients
What is altered inhibition in FMR1 KO mice due to dendrite spines?
altered dendritic spine morphology and decreased dendritic pruning
increased prevalence of immature spines and decreased mature spines (too many spines cause there is no pruning)
What is altered inhibition in FMR1 KO mice due to GABA levels?
developmental alterations of GAD and GABA-A receptor subunits
brain region-specific changes in GABA metabolism
What is altered inhibition in FMR1 KO mice due to electrophysiological deficits?
electrophysical deficits indicating impaired inhibitory neurotransmission
paired pulse is a short-term measure of inhibitory activity: first pulse sensitizes inhibitory circuits leading to a decreased second pulse
What is altered excitation in FMR1 KO mice?
increased excitatory neurotransmission in FMR1 KO mice is well documented
excessive signaling to MGluR proposed to increase downstream activation
exaggerated MGluRR-mediated hippocampal LTD
MGluR antagonists ameliorate behavioral characteristics in FMR1 KO mice
What is the excitatory inhibitory imbalance in FXS?
extensive evidence suggests E/I balance is disrupted in FXS
specific synaptic roles of FMRP have been identified
altered synaptic function can lead to behaviors consistent with autism
What are the limitations of the evidence of the excitatory inhibitory imbalance in FXS?
FXS data is not generalizable
~2-6% of cases of autism are caused by FXS
any pharmacological developments may be too specific to FXS
further evidence of synaptic dysfunction in ASD is required
What are the strengths of the FMR1 KO mice?
FMR1 KO mice is a widely mouse model
high construct validity
good face validity
What are the weaknesses of the FMR1 KO mice?
FMR1 in FXS is present, but silenced by methylation in embryonic development
FMR1 expression in FXS has mosaicism, it is differentially expressed due to methylation specificity: FMR1 KO does not recreate this feature
mouse model has relatively mild phenotype that is very dependent on the strain background
What are cell adhesion molecules (CAMs)?
CAMs are expressed on the pre and post-synaptic membranes of neurons
trans-synaptic binding of cognate CAMs determine the identity and function of excitatory and inhibitory synapses
CAMs provide important cues for development and refinement of synapses
What is neurexin?
located on the presynaptic membrane
3 genes (NRXN1, NRXN2, NRXN3)
What is neuroligin?
located on the postsynaptic membrane
5 genes (NLGN1, 2, 3, 4, 4Y)
NLGN-1, -3, -4 on glutamatergic synapses
NLGN-2 on GABAergic synapses
How is neurexin involved in ASD?
NRXN1 deletions in families with autism
NRXN1 de novo deletion in two affected siblings in one ASD family
NRXN2 truncation identified in ASD patients with family history of SCZ
NRXN3 deletions identified in 4 ASD individuals: one de novo, three inherited
How is neuroligin involved in ASD?
NLGN4 frameshift mutation found in three ASD siblings
NLGN4 frameshift in large French family with multiple ASD, PDD, and mental retardation diagnoses
NLGN3 R451C point mutation in two ASD siblings
minor associations of common variants of NLGN1, 3, 4 with ASD
What are synapsins?
responsible for organization of synaptic vesicles in both inhibitory and excitatory presynaptic terminals
How are synapsins in ASD?
SYN1 nonsense mutations (causing insertion of a stop codon and premature termination of protein synthesis) W356X and Q555X identified in two large families with epilepsy, learning difficulties, and 3 ASD diagnoses
SYN1 missense mutations (A55OT, T567A) found in 6 patients with ASD, epilepsy, or both
SYN2 frameshift and missense mutations found in three affected males
SYN variants expressed in mice reproduce some behavioral aspects of ASD
What is the synaptic refinement hypothesis in ASD?
evidence of conserved genetic risks affecting synaptic strength, organization, and refinement in ASD
deficits in synaptic development lead to E/I imbalance in ASD, resulting in impaired development in critical periods and persistent deficits in connectivity underlying behavioral changes
What is inflammation in ASD?
evidence of persistent inflammation in ASD: microglial activation, astrocyte hypertrophy
associated with degenerating neurons (i.e. cerebellar purkinje neurons)
microglia regulate synapse development through activity-dependent pre-synaptic pruning
