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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/10277/739

Autori: Tramarin, Marco
Titolo: Critical role of CDKL5 in AMPA receptor composition: underlying mechanism and functional outcome.
Abstract: Neurological disorders associated with the X-linked kinase CDKL5 are characterized by the early onset of seizures, severe cognitive deficits and autistic traits. Loss of Cdkl5 affects spine density and stabilization as well as synaptic activity, but the underlying molecular mechanisms are still far from fully understood. Here we show several pieces of evidence linking Cdkl5-associated synaptic defects to AMPA receptor (R) expression and subunit composition. In particular, primary hippocampal neurons devoid of Cdkl5 have defective GluA2-subunit expression, as well as a hyper-phosphorylation of Serine 880 (S880). Moreover, Cdkl5-downregulation skews the composition of membrane-inserted AMPARs towards the GluA2-depleted calcium-permeable form. The depletion of membrane-inserted GluA2 is likely to rely on defective recycling. Indeed, at the molecular level, we find that CDKL5 interacts with GRASP-1, a neuron-enriched protein that coordinates the endosomal sorting of AMPARs towards the plasma membrane. Against this background, we assume that the resulting alterations can underlie, at least in part, the synaptic dysfunctions and cognitive deficits in CDKL5 disorder. Finally, we provide evidence that tianeptine, a promising drug previously reported to modulate AMPAR-mediated glutamatergic neurotransmission, is capable of restoring GluA2 expression and S880 phosphorylation in neurons devoid of CDKL5. These results places tianeptine as an interesting candidate drug for CDKL5-disorder.
Parole chiave: CDKL5, autism, AMPA receptor, synaptic plasticity
Data: 2017
Lingua: eng
Corso di dottorato: Medicina sperimentale e traslazionale
Ciclo di dottorato: 29
Università di conseguimento titolo: Università degli Studi dell'Insubria
Citazione: Tramarin, M.Critical role of CDKL5 in AMPA receptor composition: underlying mechanism and functional outcome. (Doctoral Thesis, Università degli Studi dell'Insubria, 2017).

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