Touching cognition : somatosensory processing and plasticity deficits in mouse barrel cortex

Senses together with thoughts and experience are key factors that shape our cognition. Touch is an important source of sensory information. Disturbances to the development of the somatosensory system have serious consequences for social behaviour and may lead to many neurodevelopmental disorders. In our studies we used three different mouse models of disease. DISC1-cc transgenic mouse with transient disruption of the DISC1 protein signalling was used in the project related to the pathophysiology of schizophrenia. DISC1 is a molecule implicated in psychiatric disorders, which was discovered in a large Scottish family whose several members over four generations exhibited schizophrenia, bipolar disorder and major depression.

In the following projects we focused on the fragile-X-syndrome-related problems. We analysed Fmr1 KO mouse with a knock-out gene Fmr1 coding the FMR1 protein and the BC1 KO mouse with a knock out gene coding BC1 non-protein-coding RNA. Fmr1 KO mouse constitutes the most popular mouse model of fragile X syndrome mimicking many of its phenotypes that occur in humans. In contrast, BC1 KO mouse was created to study a specific role of this molecule rather than mimic symptoms of the fragile X syndrome. Both the FMR1 protein and BC1 non-protein-coding RNA are involved in control of a protein translation process and they are found in similar molecular complexes side by side.

In DISC1-cc mice we expressed the truncated protein DISC1-cc for a controlled period of time at different points during the early postnatal development. Development is shaped by sensory experience, especially during phases known as critical periods. Disruption of experience in the critical period normally produces neurons that lack specificity for sensory experience in adulthood. We found that transient disruption of DISC1 signalling during a critical period of development produced neurons that lack plasticity in adulthood. Adult plasticity deficits may be associated with cognitive deficits and the delayed onset of psychiatric symptoms in late adolescence. In Fmr1 KO mice, we focused on analysing somatosensory processing defects that lead to hypersensitivity to touch in fragile X syndrome patients. We showed neuronal mechanisms that appear to underlie hypersensitivity to somatosensory stimuli (whisker deflections) thus causing an altered behaviour observed in Fmr1 KO mice. In further studies on BC1 KO mice, we characterized electrophysiological aspects of whisker-stimulation-evoked cortical responses and spontaneous activity of recorded neurons. We used similar recording protocols to the ones optimized by us for previous recordings in Fmr1 KO mice therefore these experiments might be informative for future studies on specific roles and interactions between the FMR1 protein and the BC1 non-protein-coding RNA. Furthermore, our experiments on BC1 KO mice were a part of a larger project that provides a broader overview of the phenotypes represented in this mouse.

To sum up, using the whisker somatosensory circuit as a model system we have obtained insight into potential disease mechanism involving sensory processing that could contribute to human brain disorders.

List of scientific papers

I. Greenhill SD, Juczewski K, de Haan AM, Seaton G, Fox K, Hardingham NR. NEURODEVELOPMENT. Adult cortical plasticity depends on an early postnatal critical period. Science. 2015;349:424-7.
https://doi.org/10.1126/science.aaa8481

II. Juczewski K, von Richthofen H, Bagni C, Celikel T, Fisone G, Krieger P. Somatosensory map expansion and altered processing of tactile inputs in a mouse model of fragile X syndrome. Neurobiology of disease. 2016;96:201-15.
https://doi.org/10.1016/j.nbd.2016.09.007

III. Briz V, Restivo L, Pasciuto E, Juczewski K, Mercaldo V, Baatsen P, Gunko NV, Borreca A, Girardi T, Luca R, Nys J, Lo AC, Poorthuis R, Mansevelder H, Fisone G, Ammassari-Teule M, Arckens L, Krieger P, Meredith R, Bagni C. [Submitted]