The familial dysautonomia disease gene IKBKAP is required in the developing and adult mouse central nervous system.

Hereditary sensory and autonomic neuropathies (HSANs) are a genetically and clinically diverse group of disorders defined by peripheral nervous system (PNS) dysfunction. HSAN type III, known as familial dysautonomia (FD), results from a single base mutation in the gene IKBKAP that encodes a scaffolding unit (ELP1) for a multi-subunit complex known as Elongator. Since mutations in other Elongator subunits (ELP2 to ELP4) are associated with central nervous system (CNS) disorders, the goal of this study was to investigate a potential requirement for Ikbkap in the CNS of mice. The sensory and autonomic pathophysiology of FD is fatal, with the majority of patients dying by age 40. While signs and pathology of FD have been noted in the CNS, the clinical and research focus has been on the sensory and autonomic dysfunction, and no genetic model studies have investigated the requirement for Ikbkap in the CNS. Here, we report, using a novel mouse line in which Ikbkap is deleted solely in the nervous system, that not only is Ikbkap widely expressed in the embryonic and adult CNS, but its deletion perturbs both the development of cortical neurons and their survival in adulthood. Primary cilia in embryonic cortical apical progenitors and motile cilia in adult ependymal cells are reduced in number and disorganized. Furthermore, we report that, in the adult CNS, both autonomic and non-autonomic neuronal populations require Ikbkap for survival, including spinal motor and cortical neurons. In addition, the mice developed kyphoscoliosis, an FD hallmark, indicating its neuropathic etiology. Ultimately, these perturbations manifest in a developmental and progressive neurodegenerative condition that includes impairments in learning and memory. Collectively, these data reveal an essential function for Ikbkap that extends beyond the peripheral nervous system to CNS development and function. With the identification of discrete CNS cell types and structures that depend on Ikbkap, novel strategies to thwart the progressive demise of CNS neurons in FD can be developed.

Relative laterality of the N170 to single letter stimuli is predicted by a concurrent neural index of implicit processing of letter names.

While previous research reports a consistently left-lateralized N170 to whole words relative to control stimuli, much less is known about the nature of single letter processing. Yet single letter processing is of both theoretical and practical interest, as letters form an initial unit of literacy learning for alphabetic scripts and may be particularly useful in the study of literacy development. In the present study, adult fluent readers completed an implicit processing one-back task while event-related brain potentials (ERPs) were recorded. Separate blocks included single letter or matched false-font stimuli. Results indicated that single letters elicited a bilateral (rather than left-lateralized) enhancement of the N170 relative to the false font stimuli. Although participants did not make overt rhyming judgments, letters preceded by a rhyming as compared to non-rhyming letter (e.g., e-b versus e-h) also tended to elicit an N450 rhyme effect, as previously reported in explicit letter rhyme tasks. Moreover, individuals with a larger N450 rhyme effect showed greater relative left-lateralization of the response to single letters. Taken together, these findings suggest that early neural specialization for orthographic stimuli extends to the case of single letters and, further, that automatic mappings between visual symbols and phonological codes can account for at least some portion of the relative left-lateralization of early neurophysiological responses to printed text. These findings help resolve discrepancies in the existing literature concerning relative laterality of early neural responses to single letters and provide critical baseline data for future developmental neuroimaging studies.