Up-Regulation of Oligodendrocyte Lineage Markers in the Cerebellum of Autistic Patients: Evidence from Network Analysis of Gene Expression

Abstract

Autism is a neurodevelopmental disorder manifested by impaired social interaction, deficits in communication skills, restricted interests, and repetitive behaviors. In neurodevelopmental, neurodegenerative, and psychiatric disorders, glial cells undergo morphological, biochemical, and functional rearrangements, which are critical for neuronal development, neurotransmission, and synaptic connectivity. Cerebellar function is not limited to motor coordination but also contributes to cognition and may be affected in autism. Oligodendrocytes and specifically oligodendroglial precursors are highly susceptible to oxidative stress and excitotoxic insult. In the present study, we searched for evidence for developmental oligodendropathy in the context of autism by performing a network analysis of gene expression of cerebellar tissue. We created an in silico network model (OLIGO) showing the landscape of interactions between oligodendrocyte markers and demonstrated that more than 50 % (16 out of 30) of the genes within this model displayed significant changes of expression (corrected p value <0.05) in the cerebellum of autistic patients. In particular, we found up-regulation of OLIG2-, MBP-, OLIG1-, and MAG-specific oligodendrocyte markers. We postulate that aberrant expression of oligodendrocyte-specific genes, potentially related to changes in oligodendrogenesis, may contribute to abnormal cerebellar development, impaired myelination, and anomalous synaptic connectivity in autism spectrum disorders (ASD).

Hyper-excitability and hyper-plasticity disrupt cerebellar signal transfer in the IB2 KO mouse model of autism

“…Cerebellar lesions often cause autistic-like symptoms (Hampson and Blatt, 2015), and perinatal cerebellar injuries are the greatest nongenetic risk factor for ASDs (Bolduc and Limperopoulos, 2009;Limperopoulos et al, 2009;Bolduc et al, 2011;Wang et al, 2014;Mosconi et al, 2015). Moreover, cerebellar alterations are found in several syndromic forms of ASDs, like Phelan-McDermid, Fragile X, Tuberous Sclerosis, and Rett syndrome (for review, see Courchesne and Allen, 1997;Schmahmann, 2004;Allen, 2006;Ito, 2008;D'Angelo and Casali, 2013;Broussard, 2014;Hampson and Blatt, 2015;Mosconi et al, 2015;Zeidán-Chuliá et al, 2016). This raises a main question: are there any alterations of cerebellar microcircuit functions in ASDs?…”

Schizophrenia and Human Self-Domestication: An Evolutionary Linguistics Approach

“…OLIG2 is also associated with psychotic symptoms in Alzheimer's disease [Sims et al, 2009] and it is upregulated in the cerebellum of ASD patients [Zeidán-Chuliá et al, 2016].…”

Gene-set analysis shows association between FMRP targets and autism spectrum disorder

“…Synaptic genes have been implicated to be among the top genes harboring variants associated with ASD 14,16 and other psychiatric disorders. 28 The glial sets are an exploratory approach to provide general insights and starting points for more specific hypothesis formation although previous research has pointed in the direction of a role for astrocytes 29 and oligodendrocytes 30 in ASD, and for oligodendrocytes in schizophrenia (SCZ). 31 The third category we selected consists of genes which gene-transcripts are targeted by fragile X mental retardation protein (FMRP).…”