Dysfunction of cortical GABAergic neurons leads to sensory hyper-reactivity in a Shank3 mouse model of ASD.

Hyper-reactivity to sensory input is a common and debilitating symptom in individuals with autism spectrum disorders (ASD), but the neural basis underlying sensory abnormality is not completely understood. Here we examined the neural representations of sensory perception in the neocortex of a Shank3B-/- mouse model of ASD. Male and female Shank3B-/- mice were more sensitive to relatively weak tactile stimulation in a vibrissa motion detection task. In vivo population calcium imaging in vibrissa primary somatosensory cortex (vS1) revealed increased spontaneous and stimulus-evoked firing in pyramidal neurons but reduced activity in interneurons. Preferential deletion of Shank3 in vS1 inhibitory interneurons led to pyramidal neuron hyperactivity and increased stimulus sensitivity in the vibrissa motion detection task. These findings provide evidence that cortical GABAergic interneuron dysfunction plays a key role in sensory hyper-reactivity in a Shank3 mouse model of ASD and identify a potential cellular target for exploring therapeutic interventions

Liao Yiwu und die Freiheit der Literatur. Mit Beiträgen von Karin Betz, Christoph König, Liao Yiwu und Herbert Wiesner

Textdokumentation zur Podiumsveranstaltung der Osnabrücker Friedensgespräche und des Germanistischen Kolloquiums der Universität Osnabrück am 27. Juni 201

Discovery of Novel Class I Histone Deacetylase Inhibitors with Promising in Vitro and in Vivo Antitumor Activities

A successful structure-based design of novel cyclic depsipeptides that selectively target class I HDAC isoforms is described. Compound <b>11</b> has an IC₅₀ of 2.78 nM for binding to the HDAC1 protein, and the prodrugs <b>12</b> and <b>13</b> also exhibit promising antiproliferative activities in the nanomolar range against various cancer cell lines. Compounds <b>12</b> and <b>13</b> show more than 20-fold selectivity toward human cancer cells over human normal cells in comparison with romidepsin (FK228), demonstrating low probability of toxic side effects. In addition, compound <b>13</b> exhibits excellent in vivo anticancer activities in a human prostate carcinoma (Du145) xenograft model with no observed toxicity. Thus, prodrug <b>13</b> has therapeutic potential as a new class of anticancer agent for further clinical translation

Discovery of Novel Class I Histone Deacetylase Inhibitors with Promising in Vitro and in Vivo Antitumor Activities

A successful structure-based design of novel cyclic depsipeptides that selectively target class I HDAC isoforms is described. Compound <b>11</b> has an IC₅₀ of 2.78 nM for binding to the HDAC1 protein, and the prodrugs <b>12</b> and <b>13</b> also exhibit promising antiproliferative activities in the nanomolar range against various cancer cell lines. Compounds <b>12</b> and <b>13</b> show more than 20-fold selectivity toward human cancer cells over human normal cells in comparison with romidepsin (FK228), demonstrating low probability of toxic side effects. In addition, compound <b>13</b> exhibits excellent in vivo anticancer activities in a human prostate carcinoma (Du145) xenograft model with no observed toxicity. Thus, prodrug <b>13</b> has therapeutic potential as a new class of anticancer agent for further clinical translation

Dysfunction of cortical GABAergic neurons leads to sensory hyper-reactivity in a Shank3 mouse model of ASD

Hyper-reactivity to sensory input is a common and debilitating symptom in individuals with autism spectrum disorders (ASD), but the neural basis underlying sensory abnormality is not completely understood. Here we examined the neural representations of sensory perception in the neocortex of a Shank3B−/− mouse model of ASD. Male and female Shank3B−/− mice were more sensitive to relatively weak tactile stimulation in a vibrissa motion detection task. In vivo population calcium imaging in vibrissa primary somatosensory cortex (vS1) revealed increased spontaneous and stimulus-evoked firing in pyramidal neurons but reduced activity in interneurons. Preferential deletion of Shank3 in vS1 inhibitory interneurons led to pyramidal neuron hyperactivity and increased stimulus sensitivity in the vibrissa motion detection task. These findings provide evidence that cortical GABAergic interneuron dysfunction plays a key role in sensory hyper-reactivity in a Shank3 mouse model of ASD and identify a potential cellular target for exploring therapeutic interventions.National Institutes of Health (Grant R01MH097104)NIMH (Grants P50MH094271, F32MH100749 and R01NS045130