1. McLeod F, Ganley R, Williams L, Selfridge J, Bird A, Cobb SR. {{Reduced seizure threshold and altered network oscillatory properties in a mouse model of Rett syndrome}}. {Neuroscience};2012 (Dec 10)
Rett syndrome (RTT) is a disorder with a pronounced neurological phenotype and is caused mainly by mutations in the X-linked gene MECP2. A common feature of RTT is an abnormal EEG and a propensity for seizures. In the current study we aimed to assess brain network excitability and seizure propensity in a mouse model of RTT. Mice in which Mecp2 expression was silenced (Mecp2(stop/y)) showed a higher seizure score (mean = 6 +/- 0.8 compared to 4 +/- 0.2 in wild-type, WT) and more rapid seizure onset (median onset = 10 mins in Mecp2(stop/y) and 32 mins in WT) when challenged with the convulsant drug kainic acid (25mg/Kg). Hippocampal slices from Mecp2(stop/y) brain displayed no spontaneous field potential activities under control conditions but showed higher power gamma frequency field potential oscillations compared to WT in response to kainic acid (400 nM) in vitro. Brain slices challenged with the GABA(A) receptor antagonist bicuculline (0.1-10muM) and the potassium channel blocker 4-aminopyridine (1-50muM) also revealed differences between genotypes with hippocampal circuits from Mecp2(stop/y) mouse slices showing enhanced epileptiform burst duration and frequency. In contrast to these network level findings, single cell analysis of pyramidal cells by whole-cell patch clamp recording revealed no detectable differences in synaptic or biophysical properties between MeCP2-containing and MeCP2-deficient neurons. These data support the proposal that loss of MeCP2 alters network level excitability in the brain to promote epileptogenesis.
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2. Wang IT, Allen M, Goffin D, Zhu X, Fairless AH, Brodkin ES, Siegel SJ, Marsh ED, Blendy JA, Zhou Z. {{Loss of CDKL5 disrupts kinome profile and event-related potentials leading to autistic-like phenotypes in mice}}. {Proc Natl Acad Sci U S A};2012 (Dec 10)
Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have been identified in neurodevelopmental disorders including atypical Rett syndrome (RTT), autism spectrum disorders (ASDs), and early infantile epileptic encephalopathy. The biological function of CDKL5 and its role in the etiology of these disorders, however, remain unclear. Here we report the development of a unique knockout mouse model of CDKL5-related disorders and demonstrate that mice lacking CDKL5 show autistic-like deficits in social interaction, as well as impairments in motor control and fear memory. Neurophysiological recordings reveal alterations in event-related potentials (ERPs) similar to those observed in RTT and ASDs. Moreover, kinome profiling uncovers disruption of multiple signal transduction pathways, including the AKT-mammalian target of rapamycin (mTOR) cascade, upon Cdkl5 loss-of-function. These data demonstrate that CDKL5 regulates signal transduction pathways and mediates autistic-like phenotypes and together establish a causal role for Cdkl5 loss-of-function in neurodevelopmental disorders.
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3. Winder BM, Wozniak RH, Parlade MV, Iverson JM. {{Spontaneous Initiation of Communication in Infants at Low and Heightened Risk for Autism Spectrum Disorders}}. {Dev Psychol};2012 (Dec 10)
Communication spontaneously initiated by infants at heightened risk (HR; n = 15) for autism spectrum disorders (ASD) is compared with that in low-risk (LR; n = 15) infants at 13 and 18 months of age. Infants were observed longitudinally during naturalistic in-home interaction and semistructured play with caregivers. At both ages, HR infants spontaneously produced Words, Communicative Non-Word Vocalizations, show and point Gestures, and Gesture + Non-Word Vocalization combinations at lower rates than LR peers. This difference also held for Gesture + Word combinations at 18 but not 13 months. At 36 months, all HR children were evaluated for ASD, and 3 received a diagnosis of autistic disorder. At both 13 and 18 months, these 3 children had been at or near the bottom of the distribution on all spontaneous communication variables. (PsycINFO Database Record (c) 2012 APA, all rights reserved).
