Jean-françois PerrierAssociate professor - University of Copenhagen
- 12 May 2023
- 11 h 30 min - 12 h 30 min
- Neuroscience Seminar Series
Understanding the cellular mechanisms responsible for neurodevelopmental encephalopathies – the example of STXBP1 encephalopathies, by Jean-François Perrier
Understanding the cellular mechanisms responsible for neurodevelopmental encephalopathies – the example of STXBP1 encephalopathies
De novo mutations in Stxbp1 are among the most prevalent causes of neurodevelopmental disorders, and lead to haploinsufficiency, cortical hyperexcitability, epilepsy and other symptoms. Given that Munc18-1, the protein encoded by Stxbp1, is essential for both excitatory and inhibitory synaptic transmission, it is currently not understood why mutations cause hyperexcitability. We discovered that overall inhibition in canonical feedforward microcircuits is defective in a validated mouse model for Stxbp1 haploinsufficiency. However, unexpectedly, we found that inhibitory synapses were largely unaffected. Instead, excitatory synapses failed to recruit inhibitory interneurons. Modelling experiments confirmed that defects in the recruitment of inhibitory neurons in microcircuits cause hyperexcitation. Ampakines, compounds that enhance excitatory synapses, restored interneuron recruitment and prevented hyperexcitability. These findings identify deficits in excitatory synapses in microcircuits as a key underlying mechanism for cortical hyperexcitability in Stxbp1 disorder and identify compounds enhancing excitation as a direction for therapy design.
1993: Master degree in Neuroscience (Paris VI)
1996: PhD in Neuroscience (Paris VI). In vivo studies aiming at understanding the role of cutaneous afferents in motor control (under the supervision of Daniel Zytnicki)
1997-2001: Postdoc in the lab of Jørn Hounsgaard (University of Copenhagen). Study of the intrinsic properties of interneurons and motoneurons in a slice preparation of the spinal cord of an adult vertebrate.
2002: Associate professor at University of Copenhagen with my own group.
Main scientific contributions
– Role of serotonin in motor control. Our work shows that serotonin assists movement by increasing the excitability of motoneurons but intense motor activity, serotonin acts on a contrary as a brake and prevent damages (identification of the cellular mechanism responsible for central fatigue. Our findings were later confirmed in humans (Taylor lab, ECU, Australia).
– Role of glial cells in motor control: we showed that spinal astrocytes respond to endocannabinoids released upon neuronal activity and inhibit excitatory synaptic transmission and thereby decrease motor tremor.
– Ongoing research: We study the cellular mechanisms responsible for neurodevelopmental encephalopathies in the context of cortical and hippocampal microcircuits.