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ASD Cerebellum Mind Map, Ca2+ enters through AMPAR and NMDAR in PV…
ASD Cerebellum Mind Map
Glial impairments - Astrocytes (BG)
Network Modules... astrocyte markers and markers of activated microglia. Immune, inflammation. Upregulated: ADFP = PLIN2, IFITM2, etc.
PC changes size, density, counts
Less DCN inhibition
Increased DCN output
70% of cases with decreased PC density reported
25% of cases reported decreased PC size
PV expression changes w/in PC
Cell Adhesion: Endoglycan expressed by chicken embryo PCs (and other Cbl cell types to lesser degree) during development. regulator of cell-cell adhesion during commissural axon guidance across the midline + supports cell migration. Sans endolgycan, PCs fail to migrate -> cerebellar folds fail to form. Expression timeframes: PCs until they reach final destination in Cbl folds, GCs only in IGL and maintained until hatch (maybe beyond), MIL until late stages
Developmental cell adhesion hypothesis
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Endoglycan
Del3p deletions -> similar phenotype as ASD: three consecutive genes encoding closely related neuronal immunoglobulin cell adhesion molecules (IgCAMs)
Close Homolog of L1 (CHL1)
Contactin-6 (CNTN6)
Contactin-4 (CNTN4).
NCAM-180
Apoptotic impairments
Mitochondrial stress & impairments
Epigenetic alterations
GABAergic impairments
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Decreased Reelin
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Decreased semaphorins
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Decreased GAD67 (cerebellar, parietal)
Decreased GAD65 (cerebellar, parietal)
GABAergic transmission regulates the formation and refinement of excitatory synaptic inputs, including the elimination of climbing fiber synapses in the cerebellum during development.
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Glutamatergic impairments
Specific altered gene expression
Frontal
Increased: CLDN-3, -5, -12, TSPO, TRIC, MMP-9, FABP7, APP, STEP, RAC1, SLC25A12. Decreased: FMRP, MeCRP2, homer 1, RORA, RNA hypoediting in synaptic genes, minor MAE shift, LRP2B, ZNF-407, mono-to-biallelic switch, alterened miRNA expression levels
Attenuation of expression differences between frontal and temporal lobes (SOX5 diff expr contributes to attenuation)
Cerebellar
Increased: CLDN-5, -12, TSPO, EN-2. Decreased: FMRP, phosphorylated FMRP, NCAM-180, APP, STEP, RNA hypoediting in synaptic genes, minor MAE shift, altered miRNA expression levels
Purkinje cells
Decreased: GAD67 mRNA (40% less)
Basket cells
Increased: GAD67 mRNA (28% more)
Temporal
Decreased: DPRKCB1, RNA hypoediting and synaptic genes, minor MAE shift, increased transcript induction, altered miRNA expression levels
Network Modules.... Decreased: PVALB+ interneuron module and genes involved in synaptic function, vesicle transport, neuronal projection. Increased: known autism genes like CADPS2 AHI1, CNTNAP2, and SLC25A12.
Cingulate
Decreased: EFNB3, PLXNA4A, ROBO2, ZNF804A
Parietal
Increased: FABP7
Amygdala
Increased: miR-155p5
Fusiform gyrus
Decreased: MeCP2, TrkB, PI3K, Akt, phosphorylated and total mTOR, p70S6 kinase, elF4B, truncated BDNF. Increased: pro-BDNF
Bulk/General observations
Downregulation of alternative splicing of activity-dependent neuron-specific exons
Perturbation of splicing factors Rbfox1, SRRM4, and PTBP1 show strong overlap with differential splicing changes in ASD cortex.
Dysregulation of primate-specific lncRNAs
interact with miRNA-protein complexes whose mRNA targets are enriched in ASD genes
A2BP1 = neural- and muscle-specific alternative splicing regulator, downregulated in ASD. Targets involve actin-binding proteins, cytoskeleton reorganization, CAMK2G, NRCAM, GRINI. Synaptogenesis
Dysregulation of genes differentially expressed in left versus right embryonic perisylvian cortex (like FOXP2 and CNTNAP2) could lead to increased RH engagement during language processing
Neuroligin / other synaptic organizers
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PV expression (density) reduction
Calcium changes
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Increased Ca influx in PV-INs (esp. w/ reduced PV)
Disrupted ETC
ROS accumulate
permeability transition pore opens
outer mitochondrial membrane ruptures
cytochrome c released
Prefrontal cortex has decreased numbers of PV interneurons and decreased parvalbumin expression
Parvalbumin mRNA levels are lower in PCs
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PV mRNA decreased in PCs
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PV hypothesis of ASD (decreased PV)
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Increased residual Ca2+
Increased IPSC through facilitation
Increased excitability
Reduced jitter
Reduction of activity-driven genes including Pvalb, Gad1, c-Fos, Arc, Wnt2
Modification of synchrony and larger-scale network oscillations (largely gamma LFPs) and in downstream neurons (cortex example was pyramidal) -- Decreased gamma oscillations have been noted in ASD
Reduced working memory ability in ASD (Gamma-specific)
Relevance w/ multiplexing
Increase in mRNA for mitochondrial biogenesis (e.g. Ppargc1a (mtiochondrial master regulator PGC-1a), Nrf1, Tfam). Increase in MC volume
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Increased ROS production
Increased dendritic branching
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Perturbs expression of other ASD-associated genes: KV, CaV HCN channels, and SK channels
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Responsible for gamma oscillations. Potentially (partially) explanatory of increased comorbidity of seizure disorders, altered EEG readings, and dysmetria of thought when in conjunction with E/I imbalances
Aberrant synapse pruning
Retention of higher CF cell number @ CF-PC synapse (~4 v 1 in NT)
Altered plasticity
LTP
LTD
Fragile X: enhanced LTD induction at PF-PC synapses
Volume/Tract/Cell Number/fMRI changes
Gray matter volume decreases
Vermal in general, reported
lobule VIII, VI
crus I/II (right)
lobule IX
decreased overall cerebellar gray:white ratio due to decrease in gray
Anterior lobe
White matter tract alterations
Underconnectivity between Cbl and Cortex using DTI
Both decreases in FA and increases in MD could result in ASD from reduction in PC size and number and increased inflammation and microglial activation
Decreased FA and increased MD (asymmetry) in:
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Cingulum
Frontal lobe
Corpus callosum
Temporal lobe
Middle cerebellar peduncle (some controversy)
Decrease in cbl outflow might result in loss of modulatory input to sensorimotor and social processing regions. Decreased FA in the right and left SCPs were related to both increased repetitive behaviors and social impairments in ASD, respectively.
Superior cerebellar peduncle
Reduced FA between right cerebellar cortex and right ventral dentate decreased. Found in 70% of children with ASD in meta analysis
Decreased cerebello-thalamic projections
Overconnectivity between ipsilateral cerebellum and cerebrum
Hypoplasia
Vermal (posterior)
Fragile X: DCN loss
Abnormal cognitive and social activation between cerebellar and cortical regions
Regional volume changes
Degree of volumetric change in cerebellar lobule VII, specifically R Crus 1, correlated with degree of ASD severity
Posterior vermal volume changes alter mPFC activty
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Frontal cortex, temporal cortex, and the amygdala have small cell size, increased packing density, white matter volume increases, decreased cortical thickness, and more numerous and narrower minicolumns
Increased total cbl volume
Decreased vermis (VI and VII) volume
fMRI
Crus1 and CrusII have reduced connectivity to dorsolateral and medial prefrontal cortex
RCrus1 has decreased connectivity to parietal cortex
Long-range underconnectivity and short-range overconnectivity
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Reduced canonical activity in cerebro-cerebellar networks related to language and social interaction
Reduced rsFC between R crus I/II and contralateral PFC, posterior parietal, inferior/middle temporal gyrus, middle frontal gyrus, thalamus, anterior cingulate gyrus, and parietal areas in ASD adolescents. Significant associations with ASD behaviors
E/I imbalance
Decreased excitation in mPFC or thalamic projections to mPFC restores greater function, indicating that mPFC is overexcited in ASD, so decreased cerebellar inhibition
Lateralization / Asymmetry
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Asymmetry found in meta: 1,774 individuals with ASD and 1,809 controls, from 54 independent data sets of the ENIGMA consortium
DCN posterior/vermal reversal?
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Reversed asymmetry in lobule VIIIA in language-impaired children in ASD
Reversed lateralization in language regions in cerebral and cerebellar hemispheres. (Left cerebellar and right cerebral hemispheres overly activated) Reduced or absent activation of right Crus I/II in response to vocal stimuli (Groen). Also no activation in right Crus I/II during semantic processing or processing of semantic anomalies (Harris, Tesink, Groen). Thus, hypoactivation during listening and processing.
Increased contralateral activation of language regions in Cbl and cerebral cortices.
compensatory mechanism to make up for decreased GM volumes in right Crus I/II and their cerebro-cortical projection loops, or could be the cause of it?
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Bilateral cerebral hemisphere activation with language is typical in young children, but maladaptive in adults. Normally lateralizes strongly with age, but does not in ASD. Lack of lateralization in adults associated with poorer language function.
Aberrant connectivity between nonmotor regions of cerebellum and motor, premotor, and visual regions of cerebral cortices
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Dendrite alterations
Fragile X: elongated dendritic spines on PCs
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Shaker Kv1.1?
Receptor changes
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NMDAR?
AMPAR?
GABA A
Decreased effectiveness of seizure and anxiety meds in ASD
Benzodiazepine R
Hippocampal
Cerebellar D2R (High expression in vermis and hemispheres, particularly in CrusI/II and in lobules VI and VII.)
If altered in PCs, affect sociability, preference for social novelty in animal models. D2R also found in BCs, SCs, Lugaro cells, and some DCN. PC D2Rs transiently reduces PF-PB EPSC amplitude.
Affecting VTA-Cbl-VTA loop
Disruption of ECM
Decreased PNN density at GP
Decreases with age
Fmr1 KOs and fragile x models
Cytoskeletal integrity
Sleep disturbances
MZMC organization / learning issues
GAD65 antibodies in ASD serum (controversy)
Premie injury, CAS, lesions, etc.
Crossed cerebellar diaschisis
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Damage to cerebellum in infancy is one of the highest risk factors for developing ASD (~40-fold increase), second only to having an identical twin with autism, and conferring a higher risk than having a sibling with ASD. - 40% is a good number, comparison to twins is on Wang's word
Interneurons
Conflicting reports: No difference in density of BC or SC or in the number of BCs or SCs per PC
Reduced PV expression (decreased PV mRNA)
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Decreased GC number reported
Memory connectivity - Hippocampus
Activity in the cerebellum represents coherence of neural oscillations between the hippocampus and PFC and inhibition of the cerebellar cortex disrupts this coherence. May decrease memory task performance.
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Hippocampal GABAergic impairments
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Hippocampal 5-HT impairments (dystrophic serotonin axons)
Hippocampal apoptotic impairments: increased cathespsin D
Ca2+ enters through AMPAR and NMDAR in PV dendrites
PV
Apoptosis initiated in NT
Possible genes implicated in aberrant lateralization of language...
Synaptic organizer differential localization / expression that could be the culprit of changes in synapse number and morphology in ASD. Could result in PC loss via inactivation of synapses and induction of apoptosis and/or altered plasticity (LTP and LTD), as NMDARs are decreased with decreased Neuroligin in development