Plasmin-mediated cleavage of EphA4 at central amygdala inhibitory synapses controls anxiety [article]

Mariusz Mucha, Alberto Labrador-Ramos, Benjamin Attwood, Malorzata Bajor, Jaison Kolenchery, Anna Skrzypiec, Valentina Brambilla, Marta Magnowska, Izabela Figiel, Michal Swiatek, Lucja Wiktorowska, Rahul S Shah (+8 others)
2021 bioRxiv   pre-print
Severe stress can trigger complex behavioural changes such as high anxiety (1). Inhibitory GABA-ergic interneurons in the lateral division of the central amygdala (CEl) control anxiety through feedforward inhibition of their target cells in the medial division (CEm) (2, 3). In particular, PKCδ-positive (PKCδ+) interneurons in CEl are critical elements of the neuronal circuitry of fear and anxiety (3-5), but the molecular mechanisms they employ are poorly understood. Here, we show that, during
more » ... ress, GABA-ergic synapses of amygdala PKCδ+ interneurons are regulated by a serine protease plasmin. On stress, plasmin cleaves the extracellular portion of the tyrosine kinase receptor EphA4 triggering its dissociation from gephyrin, a postsynaptic GABA-receptor anchoring protein. Dynamic EphA4/gephyrin interaction leads to modification of dendritic spine morphology and synaptic GABA-receptor expression profile. Consistent with the critical role for the plasmin/EphA4/gephyrin signalling axis in anxiogenesis, viral delivery of plasmin-resistant (prEphA4) form of EphA4 into the central amygdala prevents the development of stress-induced anxiety in mice, while the delivery of plasmin-truncated EphA4 (tEphA4) dramatically enhances this effect. Thus, our studies identify a novel, critical molecular cascade regulating GABA-ergic signalling in the central amygdala synapses that allows bidirectional switching of animal behaviour from high to low anxiety states.
doi:10.1101/2021.07.16.452595 fatcat:x3supoy5n5b2rebl3s75mclmfq