Dyslexia is a prevalent reading disability whose underlying mechanisms are still disputed. We studied the neural mechanisms underlying dyslexia using a simple frequency-discrimination task. Though participants were asked to compare the two tones in each trial, implicit memory of previous trials affected their responses. We hypothesized that implicit memory decays faster among dyslexics. We tested this by increasing the temporal intervals between consecutive trials, and measuring the behavioral impact and ERP responses from the auditory cortex. Dyslexics showed a faster decay of implicit memory effects on both measures, with similar time constants. Finally, faster decay also characterized dyslexics' benefits in oral reading rate. It decreased faster as a function of the time interval from the previous reading of the same non-word. We propose that dyslexics' shorter neural adaptation paradoxically accounts for their longer reading times, since it induces noisier and less reliable predictions for both simple and complex stimuli.
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Human subjects: Informed consent was acquired from all participants. The study was approved by The Hebrew University Committee for the Use of Human Subject in Research.
© 2017, Jaffe-Dax et al.
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Dense core vesicles (DCVs) transport and release various neuropeptides and neurotrophins that control diverse brain functions, but the DCV secretory pathway remains poorly understood. Here, we tested a prediction emerging from invertebrate studies about the crucial role of the intracellular trafficking GTPase Rab10, by assessing DCV exocytosis at single-cell resolution upon acute Rab10 depletion in mature mouse hippocampal neurons, to circumvent potential confounding effects of Rab10’s established role in neurite outgrowth. We observed a significant inhibition of DCV exocytosis in Rab10-depleted neurons, whereas synaptic vesicle exocytosis was unaffected. However, rather than a direct involvement in DCV trafficking, this effect was attributed to two ER-dependent processes, ER-regulated intracellular Ca2+ dynamics, and protein synthesis. Gene Ontology analysis of differentially expressed proteins upon Rab10 depletion identified substantial alterations in synaptic and ER/ribosomal proteins, including the Ca2+ pump SERCA2. In addition, ER morphology and dynamics were altered, ER Ca2+ levels were depleted, and Ca2+ homeostasis was impaired in Rab10-depleted neurons. However, Ca2+ entry using a Ca2+ ionophore still triggered less DCV exocytosis. Instead, leucine supplementation, which enhances protein synthesis, largely rescued DCV exocytosis deficiency. We conclude that Rab10 is required for neuropeptide release by maintaining Ca2+ dynamics and regulating protein synthesis. Furthermore, DCV exocytosis appeared more dependent on (acute) protein synthesis than synaptic vesicle exocytosis.
By influencing calcium homeostasis, local protein synthesis and the endoplasmic reticulum, a small protein called Rab10 emerges as a crucial cytoplasmic regulator of neuropeptide secretion.