Developmental disorders of the synapse Flashcards
what is a synapse
connection between neurons
overview of ASD
2 core features: persistent deficits in communication(language&eye contact), social interaction & repetitive behaviours
symptoms (intellectual disability/irritability/immune dysfunction/GI disorders) occur in early childhood (heterogenous)
affects 1-2%, more boys (1:4), no treatment for core symptoms
overview of schizophrenia
positive symptoms: delusions/hallucinations/disorganised speech negative symptoms: catonia/avolition/asociality
diagnosis requires: social/occupational dysfunction, >6months of symptoms
Intellectual disability
deficits in mental abilities approx 2SD below IQ
ASD cause
period of overgrowth/arrested growth/possible decline/degeneration
structural changes in ASD brains
ASD babies have a large brain
MRIs show that the frontal regions have large cortical thickness and brain size (Bedford et al., 2020)
ASD pathology
more dendritic spines (failure of synaptic pruning)
difficult to obtain controls since ASD is heterogenous
twin concordance rate in ASD and schizophrenia
ASD - 90%
Schizophrenia - 50%
2 swedish families (NLGN3/4 - postsynaptic transmembrane protein) neurexin is presynaptic
Copy number Variations (CNV)
deletions/duplications in DNA (only unbalanced chromosomal changes)
uses microarray-based comparative genomic hybridization (CGH)
above 0 - duplication
below 0 - deletion
CNVs and de novo mutations
Levy at el., 2011
de novo = mother and father do not have mutation, child is affected
more females have de novo CNVs in ASD
females have larger CNVs
females are resistant to the phenotypic effects of ASD causing mutations
network analysis
node size = importance of gene to the cluster score (how many times it appears)
length width = proportional to the likelihood of sharing the phenotype
percentages of CNVs in ASD
5-10% non syndromic
10-25% syndromic (multiple features occur together)
de novo CNVs contribute to simplex ASD
majority of causes not related to CNVs (multiple genes instead)
ASD exome sequencing
synaptic genes identified are GRIN2B (NMDAR subunit)/SCN1A (sodium channel subunit)
>100 genes involved in synapse formation/transcription regulation/chromatin remodelling
common disease common variant hypothesis
majority of risk comes from several common alleles (>5%) each conferring modest risk
no evidence
GWAS
looks for SNPs by comparing case and controls , SNPs point to an area of the genome which contributes to the disease
3 alleles: 5p (between cadherin 9/10), 80kB from Sema5A gene, MACROD2
limitations: studies are underpowered, each study fails to replicate findings, decreased confidence for all risk alleles, no common variants confer even modest (>1.2 fold) statistical increase in the risk of AD
simplex vs multiplex
simplex = one affected child disorder
multiplex = multiple families
mouse assays to understand behaviour
social interaction assay: 3 chamber task - analyse time spent in object/mouse chamber. If more time spent with object then ASD symptom. Mouse tried to kill other mouse (measure aggression)
repetitive behaviour assay: grooming/bar biting/marble burying. Tests cognitive flexibility, MWM-water must be cold. ultrasonic vocalisations = sqeaks
what does functional imaging show
local hypoconnectivity with loss of long-range connectivity
increased brain volume with rapid overgrowth and decreased white matter imaging
SHANK3 mutant
post synaptic scaffolding protein, binds to Homer and PSD-95, forms a scaffold, binds to glutamate.
Shank3 deletions cause Phelan Mcdermid Syndrome (22q13.3-haploinsufficency)/PDZ domain is deleted.
behavioural phenotypes similar to ASD(excessive grooming and social interaction deficits)
Feng Lab observations of the Shank3 mutants
Peca et al., 2011
observed cortico-striatal synapses only gamma subunits - no trafficking and enlarged striatum (overgrowth), dendrites had more complex dendritic aborisations-longer length of spines but reduced density
Buxbaum lab observations of the Shank3 mutant
Bodzagi et al., 2010
deleted ankyrin repeat domain:
reduced AMPA responses/mEPSPc amplitude, loss of LTP and LTD, decreased GluR1 puncta in hippocampus and impaired social interaction
Rett syndrome
mainly affects girls since males die (heterozygous X)
at 1st year then 12-18 months: regression of speech and motor skills, cognitive/motor-hand/respiratory abnormalities
stereotypic motor behaviour (hand wringing), seizures, ataxia
caused by MeCP2 mutant on the X chromosome
mouse models of rett syndrome
MeCP-/y MeCP308/y (truncated, hypomorph) MeCPTG (duplication) - Dani et al., 2005
in pyramidal neuron cortical slices recordings: reduced spontaneous firing in mutants, reduced excitation (via mEPSPs), increased inhibition (mIPSCs), less dendritic spines in the hippocampus
duplications increased synapses
KO of MeCP2 from GABAergic inhibitory interneurons
(same phenotype as null mice) - stereotyped paw movements/compulsive grooming/impaired coordination
reduced somatic GABA/GAD1/GAD2 levels in neurons - risk of early death
decreased mIPSCs, no change on frequencies
gene therapy and interneurons
MeCP2 null - adult mouse has no movement MeCP2+gene rescue at 3-4wks - movement (Guy et al., 2007)
SST/PV+ altered inhibition
PYR - reduced excitation
rett syndrome treatment
neurons from skin neuroblasts from 4 patients with rett syndrome
add IGF1 - rescues glutamatergic synapse number/promotes excitatory synapse maturation and neuronal survival/crosses BBB
what is (1-3)IGF
synthetic tripeptide
causes extended lifespan and rescues spine density
rhIGF (recombinant IGF1) increases survival and breathing rate
IGF1 trials
2016 Tropea trial (Pini et al., 2016) Rx mecasermin improved disease severity
2018 Sahin group - double blind crossover had no benefit
Trofinetide
novel synthetic analog of N-terminus peptide of IGF-1 phase II had promising results - approved in mar 2023
why does the same pathway/mutations cause differing human phenotypes
2-hit model
genetics - background effect in animal models/epistatic interactions
environmental factors - febrile seizures/head injuries/psychosocial stressors
intrinsic stochastic developmental variation