Excessive trial-by-trial and inter-individual neural variability of sensory responses are hallmarks of atypical sensory processing in autistic individuals with cascading effects on other core autism symptoms. The neurobiological substrate of this exaggerated variability is unknown. Here, by recording neocortical single neuron activity in a well-established mouse model of autism, we characterized atypical sensory processing and probed the role of endogenous noise sources as a driver for response variability. The analysis of sensory stimulus evoked activity and spontaneous dynamics, as well as neuronal features, reveals a complex phenotype composed of both cellular and circuit alterations. Neocortical sensory information processing in autistic animals is more variable, unreliable, and temporally imprecise. This increased trial-by-trial and inter-neuronal response variability is strongly related with key endogenous noise features. We provide a novel preclinical framework for understanding the sources of endogenous noise and its contribution to core symptoms in autism, and for testing the functional consequences for mechanism-based manipulation of this noise.

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The mouse primary somatosensory cortex (S1) processes tactile sensory information and is the largest neocortex area emphasizing the importance of this sensory modality for rodent behavior. Most of our knowledge regarding information processing in S1 stems from studies of the whisker-related barrel cortex (S1–BC), yet the processing of tactile inputs from the hind-paws is poorly understood. We used in vivo whole-cell patch-clamp recordings from layer (L) 2/3 pyramidal neurons (PNs) of the S1 hind-paw (S1-HP) region of anaesthetized wild type (WT) mice to investigate their evoked sub- and supra-threshold activity, intrinsic properties, and spontaneous activity. Approximately 45% of these L2/3 PNs responded to brief contralateral HP stimulation in a subthreshold manner, ~5% fired action potentials, and ~50% of L2/3 PNs did not respond at all. The evoked subthreshold responses had long onset- (~23 ms) and peak-latencies (~61 ms). The majority (86%) of these L2/3 PNs responded to prolonged (stance-like) HP stimulation with both on- and off-responses. HP stimulation responsive L2/3 PNs had a greater intrinsic excitability compared to non-responsive ones, possibly reflecting differences in their physiological role. Similar to S1-BC, L2/3 PNs displayed up- and down-states, and low spontaneous firing rates (~0.1 Hz). Our findings support a sparse coding scheme of operation for S1–HP L2/3 PNs and highlight both differences and similarities with L2/3 PNs from other somatosensory cortex areas.KEY POINTSResponses of layer (L) 2/3 pyramidal neurons (PNs) of the primary somatosensory hind-paw cortex (S1-HP) to contralateral hind-paw stimulation reveal both differences and similarities compared to those of somatosensory neurons responding to other tactile (e.g. whiskers, forepaw, tongue) modalities.Similar to whisker-related barrel cortex (S1-BC) and forepaw cortex (S1-FP) S1-HP L2/3 PNs show a low spontaneous firing rate and a sparse action potential coding of evoked activity.In contrast to S1-BC, brief hind-paw stimulus evoked responses display a long latency in S1-HP neurons consistent with their different functional role.The great majority of L 2/3 PNs respond to prolonged hind-paw stimulation with both on- and off-responses.These results help us to better understand sensory information processing within layer 2/3 of the neocortex and the regional differences related to various tactile modalities.