New connections: Signaling in learning disability

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Sci. Signal.  16 Jan 2018:
Vol. 11, Issue 513, eaas9779
DOI: 10.1126/scisignal.aas9779

Research in this issue of Science Signaling and the Archives brings us steps closer to understanding the origins of learning disability.

Learning disabilities can be devastating to both the affected individuals and their families. Fragile X syndrome (FXS) is an intellectual disability disorder associated with changes in neuronal function and circuitry in the brain that impair synaptic plasticity, which is critical to learning and various other behaviors. Among these changes are increased neuronal excitability, impaired maturation of neural structures, and altered differentiation of neural stem cells. Studying these phenotypes is generally limited to the use of animal (most often fly, mouse, or rat) neurons, which can introduce complex species differences into the molecular framework. Achuta et al. engineered neuronal progenitors from human fibroblasts. In those derived from boys with FXS, the expression of the AMPA receptor subunit GluA2 was decreased, resulting in a greater number of AMPA receptors that lacked GluA2, which facilitate calcium influx into the cells, thereby contributing to the abnormal excitation and differentiation phenotypes associated with FXS. Pharmacologically blocking GluA2-lacking AMPA receptors in FXS-derived cultures and in FXS mouse models restored normal neuronal function. Future work will reveal whether that intervention restores learning and other FXS-altered behaviors, and what precisely causes the decrease in GluA2, although it appears to be at the posttranscriptional level. Nonetheless, these findings add to a body of work published in the Archives of Science Signaling that provides insight into the mechanisms underlying FXS, highlighted in a 2017 Focus Issue (see Ferrarelli).

Patients with FXS often exhibit behaviors that are characteristic of autism spectrum disorder (ASD), a neurodevelopmental disorder that impairs various behaviors, most commonly the processing of social cues and interactions. It is not clear what causes ASD; changes in the expression of some protein-coding genes are implicated, but the answer may lie rather in the epigenetic code. The molecular mechanisms necessary for learning and memory are increasingly shown to be under the control of epigenetics, modifications to the DNA or chromatin that alter gene expression without changing the underlying DNA sequence. Koberstein et al. developed a high-throughput sequencing method called DEScan to analyze the epigenetic landscape of the hippocampus (a region critical for memory) in mice. DEScan identified many learning-regulated regions in the DNA in the hippocampus in mice. Learning exercises in mice induced changes to regions outside of the protein-coding genes, particularly the activation of alternative promoters, many of which were located near ASD-associated genes. One of these alternative promoters was near the ASD-associated gene Shank3; loss of SHANK3 alters the organization of the synapse, thereby impairing neuronal function and response (see Li et al. in the Archives). This method could help identify critical genetic regions that are involved in autism and other learning and neurodevelopmental disorders. Learning disabilities cannot be cured, but these studies may lead to the development of therapeutics that restore neuronal function to improve the quality of life for patients and their caregivers.

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