Editors' ChoiceAutism

Seeing the Big Picture in Fragile X Syndrome

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Science Translational Medicine  04 Sep 2013:
Vol. 5, Issue 201, pp. 201ec146
DOI: 10.1126/scitranslmed.3007371

Autism is a heterogeneous disorder caused by diverse genetic, developmental, and environmental factors. Many of these factors are thought to converge at some level to elicit overlapping behavioral symptoms. In particular, cortical circuits composed of numerous interacting cells and synapses represent plausible loci for such convergence. Nevertheless, specific circuit-level abnormalities in autism remain largely unknown. In a recent study, Gonçalves et al. describe abnormal patterns of activity in the somatosensory cortex of Fmr1–/– mice, which model Fragile X syndrome (FXS), the most common single-gene cause of autism.

Gonçalves et al. used two-photon calcium imaging to measure simultaneous activity from many neurons in the somatosensory cortex of awake, head-fixed mice. They compared neuron activity recorded at different ages in wild-type and Fmr1–/– mice. Typically, cortical activity is highly synchronized across neurons early in postnatal life and then transitions to a more desynchronized pattern by adolescence. Gonçalves et al. found that the correlations between neurons were stronger in Fmr1–/– mice than in wild-type mice at an age (P14 to P16) that represents a key time point in the development of somatosensory circuits. These differences were less pronounced at younger and older ages, when activity is more and less synchronized, respectively, suggesting that the differences at ages P14 to P16 represent delayed cortical desynchronization. Gonçalves et al. went on to show how these increased correlations result from increased neuronal participation in Up states, brief (1 to 2 s) periods of circuit-wide increases in neuronal excitability and activity that occur every few seconds during sleep or quiet wakefulness. This is notable because increased neuronal activity, possibly as a consequence of decreased synaptic inhibition, has long been hypothesized to play a role in autism. Furthermore, abnormal patterns of activity during Up states could plausibly alter cortical circuit development in ways that contribute to autism and intellectual disability.

Future studies should test whether similar alterations in circuit activity are present in other mouse models of autism. Identifying the specific changes in genetic and cellular pathways that drive increased neuronal participation in Up states may lead to novel therapies that restore normal cortical circuit development in FXS and related conditions.

J. T. Gonçalves et al., Circuit level defects in the developing neocortex of Fragile X mice. Nat. Neurosci. 16, 903–909 (2013). [Abstract]

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