Matrix Metalloproteinase 2 Controls Trans-Synaptic Homeostatic Plasticity in Drosophila

ABSTRACT
Synapses in the nervous system are key in signal transmission, computation, and learning. They adaptively
modify during information processing and storage, influencing behavioral responses while maintaining synaptic
stability. Homeostatic signaling plays a crucial role at synaptic, neuronal and circuit levels, ensuring stable
neuronal function and network activity within physiological limits, essential for consistent brain functionality.
Disruptions in these homeostatic signaling pathways are linked to neurological disorders including epilepsy,
schizophrenia, and neurodegeneration. The molecular architecture of homeostatic signaling in the nervous
system remains to be elucidated. Our research focuses on the Drosophila neuromuscular junction (NMJ) as a
model synapse for understanding synaptic homeostatic control mechanisms. At this glutamatergic synapse,
inhibiting postsynaptic glutamate receptors triggers a compensatory increase in presynaptic neurotransmitter
release, maintaining synaptic strength. This process, known as Presynaptic Homeostatic Potentiation (PHP), is
a conserved phenomenon across species. PHP begins with reduced glutamate receptor activity on the
postsynaptic side, but manifests as enhanced presynaptic neurotransmitter release. This indicates a need for
retrograde signaling to counteract postsynaptic changes and restore baseline muscle excitation. Previous
studies highlight the role of the extracellular matrix (ECM) protein Multiplexin, Drosophila homologue to
mammalian collagen XV/XVIII, in PHP. Particularly, its C-terminal domain, Endostatin, released upon proteolytic
cleavage, facilitates neurotransmitter release during PHP via presynaptic calcium channels. The protease
responsible for releasing Endostatin from Multiplexin is still unknown. Drosophila has two matrix
metalloproteinases, MMP1 and MMP2. Our preliminary data, derived from a CRISPR-generated mmp2null mutant,
indicate MMP2's essential role in PHP induction and maintenance. This project aims to systematically investigate
the role of MMP2 in PHP, employing multifaceted techniques including electrophysiology, immunohistochemistry,
biochemistry, confocal calcium imaging, and super resolution imaging. AIM1 focuses on dissecting MMP2's cell-
specific function in PHP and whether MMP2 directly cleaves Multiplexin to release Endostatin during PHP. AIM2
delves into the cellular mechanisms of MMP2 in modulating presynaptic calcium influx and calcium channel
localization during PHP. This study will elucidate key signaling elements in the dynamic regulation of ECM during
PHP and provide valuable insights into synaptic stabilization mechanisms.

Grant Number: 5F31NS139658-02
NIH Institute/Center: NIH
Principal Investigator: Yimei Cai