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ISCTM ~ ECNP Joint Conference ▪ 1 September 2017 ▪ Paris ▪ France
Martien Kas From diagnose to biology ISCTM ~ ECNP Joint Conference - - PowerPoint PPT Presentation
Martien Kas From diagnose to biology ISCTM ~ ECNP Joint Conference - - PowerPoint PPT Presentation
Preclinical models of negative symptoms and their implications for clinical trials Martien Kas From diagnose to biology ISCTM ~ ECNP Joint Conference 1 September 2017 Paris France The road to restoring neuronal circuits Canter et
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The road to restoring neuronal circuits…
Canter et al., Nature, 2016
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The puzzle of schizophrenia
stahlonline.cambridge.org
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Integrated experimental approaches
Dolmetsch and Geschwind, Cell, 2011
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How to provide cross-species clinically relevant and quantitative endpoint measures?
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Kas et al., Molecular Psychiatry, 2007
Behavioural domains across the neuropsychiatric spectrum
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Behavioural domains: negative symptoms
Modeling positive versus negative symptoms in animals
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Social withdrawal is a common (early) symptom across neuropsychiatric disorders
Autism Spectrum Disorder Bipolar Depression Major Depression Schizophrenia Alzheimer’s Disease
Social withdrawal
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Social withdrawal is influenced by several processes
Social withdrawal
Social learning Mentalizing activities Social information processing Social perception Emotionality Cognitive performance Reward processing
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Social withdrawal is influenced by several processes
Social withdrawal
Social learning Mentalizing activities Social information processing Social perception Emotionality Cognitive performance Reward processing
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Brunelin et al., 2013
The dopamine hypothesis
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- Striatal D2R overexpression mouse model
- Amphetamine model
- Dopamine transporter knock-out mice
- Neonatal ventral hippocampal lesion
- Isolation rearing
Rodent models to alter dopamine signalling
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Recombinant technologies to delete or
- verexpress the Dopamine-2 receptor in mice
Drew et al. J. Neuroscience, 2007
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Reward processing: testing motivation
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Performance in the progressive ratio task
Drew et al. J. Neuroscience, 2007
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Evolutionary conserved biological processes?
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Social withdrawal is influenced by several processes
Social withdrawal
Social learning Mentalizing activities Social information processing Social perception Emotionality Cognitive performance Reward processing
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Social information processing
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10 20 30 40 50 60 70 5 minutes 24 hours duration (s)
Social recognition
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Mapping a locus on mouse chromosome 14 for social recognition
Mapping a locus on mouse chromosome 14 for long-term social recognition
Bruining et al., Biological Psychiatry, 2015
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Pcdh9: associated to social behavioural deficits in human and dogs
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Pcdh9-deficient mice: impaired social recognition
Bruining et al. Biol. Psychiatry, 2015
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Sensory processing deficits in Pcdh9 KO mice
Touch evoked biting response Sensorimotor performance Prepulse inhibition
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Cortical thinning of sensory cortex, and local dendritic and spine malformations
Bruining et al., Biological Psychiatry, 2015
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Sensory information processing
Mouse and human
Genetic variations Cortical integrity
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From genetic variation to behavioural output
Temporal & Spatial Synaptic density
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Coupling sensory processing to neural biomarkers integrated EEG – behavioural analyses
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Sensory deficits: auditory mismatch negativity
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Disease diversity
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Precision medicine
Insel and Cuthbert, Science, 2015
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The project leading to this application has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115916. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA.
PRISM: Psychiatric Ratings using Intermediate Stratified Markers
Project coordinator: Martien Kas, University of Groningen, the Netherlands Project leader: Hugh Marston, Eli Lilly and Company, United Kingdom
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The project leading to this application has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115916. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA.
PRISM’s general concept:
“Providing quantitative biological measures to facilitate the discovery and development of new treatments for social and cognitive deficits in Alzheimer’s disease, schizophrenia and depression”
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The project leading to this application has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115916. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA.
23 partners, including major EU Academic Centres, SME’s and pharmaceutical industry
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The project leading to this application has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115916. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA.
Human and rodent homologies
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The project leading to this application has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115916. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA.
Longitudinal and objective measures of rodent and human social withdrawal
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The project leading to this application has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115916. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA.
BeHapp – passive remote behavioural monitoring
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The project leading to this application has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115916. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA.
MMS messages SMS messages Outgoing calls Returned calls Incoming calls Missed calls Twitter events GPS location Bluetooth signals in the area WiFi signals Application activity, such as:
Collected Data – smartphone app
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The project leading to this application has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115916. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA.
Smartphone passive behavioural monitoring
Movement trajectory extraction
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The project leading to this application has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115916. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA.
Longitudinal and objective measures of rodent and human social withdrawal
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The project leading to this application has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115916. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA.
Mimicking natural burrowing behaviour
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The project leading to this application has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115916. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA.
Visible Burrow System: studying social interaction in a semi-natural environment
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The project leading to this application has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115916. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA.
BTBR: Reduced social interaction and huddling
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The project leading to this application has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115916. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA.
Summary
- Improving treatment efficacy in schizophrenia will benefit from advancing our
knowledge on target neural circuitries and representative core readout.
- Understanding clinical heterogeneity requires the development and
application of quantitative biological parameters that can be applied across the diagnostic boundaries.
- Implementation of homologous clinical and preclinical testing paradigms to
assess quantitative biological parameters allow for the development of preclinical model systems to back-translate human findings and further expand our neurobiological knowledge.
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The project leading to this application has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115916. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA.