Endogenous noise of neocortical neurons correlates with atypical sensory response variability in the Fmr1-/y mouse model of autism.

Excessive neural variability of sensory responses is a hallmark of atypical sensory processing in autistic individuals with cascading effects on other core autism symptoms but unknown neurobiological substrate. Here, by recording neocortical single neuron activity in a well-established mouse model of Fragile X syndrome and autism, we characterized atypical sensory processing and probed the role of endogenous noise sources in exaggerated response variability in males. The analysis of sensory stimulus evoked activity and spontaneous dynamics, as well as neuronal features, reveals a complex cellular and network phenotype. Neocortical sensory information processing is more variable and temporally imprecise. Increased trial-by-trial and inter-neuronal response variability is strongly related to key endogenous noise features, and may give rise to behavioural sensory responsiveness variability in autism. We provide a novel preclinical framework for understanding the sources of endogenous noise and its contribution to core autism symptoms, and for testing the functional consequences for mechanism-based manipulation of noise.

Loss of 4E-BP converts cerebellar long-term depression to long-term potentiation.

Genetic perturbances in translational regulation result in defects in cerebellar motor learning; however, little is known about the role of translational mechanisms in the regulation of cerebellar plasticity. We show that genetic removal of 4E-BP, a translational suppressor and target of mammalian target of rapamycin complex 1, results in a striking change in cerebellar synaptic plasticity. We find that cerebellar long-term depression (LTD) at parallel fiber-Purkinje cell synapses is converted to long-term potentiation in 4E-BP knockout mice. Biochemical and pharmacological experiments suggest that increased phosphatase activity largely accounts for the defects in LTD. Our results point to a model in which translational regulation through the action of 4E-BP plays a critical role in establishing the appropriate kinase/phosphatase balance required for normal synaptic plasticity in the cerebellum.