Format

Send to

Choose Destination
J Neurosci. 2018 Dec 28. pii: 0612-18. doi: 10.1523/JNEUROSCI.0612-18.2018. [Epub ahead of print]

Aberrant somatosensory processing and connectivity in mice lacking Engrailed-2.

Author information

1
Center for Integrative Biology (CIBIO), University of Trento, via Sommarive 9, 38123 Trento, Italy.
2
Neural Control of Movement Lab, HEST, ETH Zürich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
3
Center for Mind/Brain Sciences (CIMeC), University of Trento, Corso Bettini 31, 38068 Rovereto, Italy.
4
Model Organisms Facility, Center for Integrative Biology (CIBIO), University of Trento, via Sommarive 9, 38123 Trento, Italy.
5
Functional Neuroimaging Laboratory, Center for Neuroscience and Cognitive Systems, Istituto Italiano di Tecnologia, Corso Bettini 31, 38068 Rovereto, Italy.
6
CNR Neuroscience Institute, via Moruzzi 1, 56124 Pisa, Italy.
7
Center for Integrative Biology (CIBIO), University of Trento, via Sommarive 9, 38123 Trento, Italy giovanni.provenzano@unitn.it yuri.bozzi@unitn.it.

Abstract

Over-reactivity and defensive behaviors in response to tactile stimuli are common symptoms in autism spectrum disorder (ASD) patients. Similarly, somatosensory hypersensitivity has also been described in mice lacking ASD-associated genes such as Fmr1 (fragile X mental retardation protein 1). Fmr1 knockout mice also show reduced functional connectivity between sensory cortical areas, which may represent an endogenous biomarker for their hypersensitivity. Here, we measured whole-brain functional connectivity in Engrailed-2 knockout (En2-/- ) adult mice, which show a lower expression of Fmr1 and anatomical defects common to Fmr1 knockouts. MRI-based resting-state functional connectivity in adult En2-/- mice revealed significantly reduced synchronization in somatosensory-auditory/associative cortices and dorsal thalamus, suggesting the presence of aberrant somatosensory processing in these mutants. Accordingly, when tested in the whisker nuisance test, En2-/- but not wild-type (WT) mice of both sexes showed fear behavior in response to repeated whisker stimulation. En2-/- mice undergoing this test exhibited decreased c-Fos-positive neurons (a marker of neuronal activity) in layer IV of the primary somatosensory cortex and increased immunoreactive cells in the basolateral amygdala as compared to WT littermates. Conversely, when tested in a sensory maze, En2-/- and WT mice spent a comparable time in whisker-guided exploration, indicating that whisker-mediated behaviors are otherwise preserved in En2 mutants. Thus, fearful responses to somatosensory stimuli in En2-/- mice are accompanied by reduced basal connectivity of sensory regions, reduced activation of somatosensory cortex and increased activation of the basolateral amygdala, suggesting that impaired somatosensory processing is a common feature in mice lacking ASD-related genes.SIGNIFICANCE STATEMENTOver-reactivity to tactile stimuli is a common symptom in autism spectrum disorders (ASD). Recent studies performed in mice bearing ASD-related mutations confirmed these findings. Here we evaluated the behavioral response to whisker stimulation in mice lacking the ASD-related gene Engrailed-2 (En2-/- mice). When compared to wild-type controls, En2-/- mice showed reduced functional connectivity in the somatosensory cortex, which was paralleled by fear behavior, reduced activation of somatosensory cortex and increased activation of the basolateral amygdala in response to repeated whisker stimulation. These results suggest that impaired somatosensory signal processing is a common feature in mice harboring ASD-related mutations.

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center