Altered proliferation and networks in neural cells derived from idiopathic autistic individuals

Abstract

Autism spectrum disorders (ASD) are common, complex and heterogeneous neurodevelopmental disorders. Cellular and molecular mechanisms responsible for ASD pathogenesis have been proposed based on genetic studies, brain pathology, and imaging, but a major impediment to testing ASD hypotheses is the lack of human cell models. Here, we reprogrammed fibroblasts to generate induced pluripotent stem cells (iPSCs), neural progenitor cells (NPCs) and neurons from ASD individuals with early brain overgrowth and non-ASD controls with normal brain size. ASD-derived NPCs display increased cell proliferation due to dysregulation of a β-catenin/BRN2 transcriptional cascade. ASD-derived neurons display abnormal neurogenesis and reduced synaptogenesis leading to functional defects in neuronal networks. Interestingly, defects in neuronal networks could be rescued by IGF-1, a drug that is currently in clinical trials for ASD. This work demonstrates that selection of ASD subjects based on endophenotypes unraveled biologically relevant pathway disruption and revealed a potential cellular mechanism for the therapeutic effect of IGF-1.

Neuroimmune Alterations in Autism: A Translational Analysis Focusing on the Animal Model of Autism Induced by Prenatal Exposure to Valproic Acid

“…Valproate, a well-known HDAC inhibitor drug, induces important delays in neuronal maturation [34], already described in ASD [35]. Moreover, VPA prenatal exposure alters the postnatal histone 3 (H3) acetylation levels in the cerebellum [36], stimulates glial cell proliferation in the developing rat brain [37], and also induces changes in acetylation levels in the astrocytes of the hippocampus and cortex in cell culture more than other antidepressants and mood stabilizers do [38].…”

Neurodevelopmental Perspectives on Wnt Signaling in Psychiatry

“…Prenatal administration of a specific GSK3 inhibitor to these animals corrected developmental brain growth abnormalities as well as adult ASD-like behavioral phenotypes [341]. A parallel study examined cellular and molecular defects in hiPSC lines derived from ASD patients with accelerated early brain growth, and similarly found a hyperproliferative NPC phenotype responsive to lithium [342]. Finally, cortical pyramidal neurons from a mouse line mutant for the neuronally expressed Wnt/β-catenin pathway activator and DISC1 partner Dixdc1 have reduced dendritic spine and excitatory synapse density correlating with phenotypes in the affective domain (behavioral despair) and social domain (reciprocal social interaction); administration of either lithium or a selective GKS3 inhibitor corrects both the neurodevelopmental and behavioral phenotypes in these animals [343].…”

Human induced pluripotent stem cells for modelling neurodevelopmental disorders

“…Increased density of cortical neuron minicolumns 141 and areas of aberrant cortical neuron layering 142,143 have been shown to occur in autism, but there are as yet no neuropathological studies with sufficient number of cases to demonstrate an imbalance of inhibitory over excitatory neurons in the cortex. Remarkably, the increase in FOXG1 expression in idiopathic ASD with macrocephaly has been replicated in an independent set of cases using a non-organoid neuronal differentiation protocol, along with the increase in GABAergic neuronal progenitors 144 , consolidating the idea of an involvement of FOXG1-mediated GABAergic disturbance in ASD and suggesting that hiPSC modeling is robust and can yield reproducible data across hiPSC lines, patients, and laboratories. The above mentioned study 144 has also hypothesized that the Wnt signalling pathway, which when elevated causes excessive proliferation of NPCs 145,146 , is paradoxically reduced in ASD with macrocephaly, and somehow this is related to the aberrantly increased proliferative activity, as agents that increased the canonical b-catenin/BRN2 cascade normalized cell proliferation.…”