Neurons throughout our brain communicate with each other through synaptic connections. Synapses are essentially comprised by a presynaptic terminal and the postsynapse, connected by a specialized extracellular environment, the synaptic cleft, and surrounded by glial processes. Synaptic strength varies in response to different patterns of neural activity. This remarkable feature, called synaptic plasticity, is thought to be crucial to our brain’s ability to adapt, learn and memorize.
Our research focuses on the mechanisms underlying the dynamic organization of synapses during synaptic plasticity. We are particularly interested in the glutamatergic and endocannabinoid systems, both essential for neuronal communication as well as crucial for learning, memorizing –and forgetting! To address these questions, we combine genetic, proteomic, molecular, electrophysiological, imaging and behavioral approaches. Our goal is to gain understanding on how synapses work in the healthy brain and what pathological mechanisms lead to diseases with an origin at the synapse.
We focus on 2 main projects:
AMPAR synaptic clustering mechanisms involved in synaptic plasticity.
AMPA receptors (AMPARs) mediate most of the fast excitatory synaptic transmission in the brain. The size of the postsynaptic AMPAR pool is dynamically regulated by several forms of synaptic plasticity. For the past few years we have tried to understand how different domains of the AMPAR subunits and their auxiliary proteins contribute to one of the most widely studied forms of synaptic plasticity, long-term potentiation (LTP). LTP is thought to be crucial for learning and memory.
Overall, our previous research suggests that the synaptic docking of AMPARs requires the concerted action of the extracellular amino-terminal domain and the intracellular interactions between AMPAR auxiliary subunits and synaptic scaffolding molecules. In our new project, we aim to identify novel AMPAR complex interactions involved in synaptic docking and assess their role in synaptic plasticity. We focus on both extracellular and intracellular mechanisms. To achieve these goals, we combine mouse genetics and molecular biology with electrophysiology and behavior.
Given the widely accepted contribution of synaptic plasticity to learning and memory processes, we hope that our research will help identify valuable therapeutic entry points for CNS diseases with a cognitive impairment component.
Endocannabinoids, synapses and epilepsy.
The endocannabinoid (eCB) system plays a crucial role in a wide array of synaptic processes, from synaptogenesis to the modulation of synaptic strength and plasticity, and is involved in cognition, learning and memory, mood, temperature regulation, pain, appetite and motor control, among many other brain functions. Not surprisingly, a dysfunctional eCB system is believed to underlie several CNS disorders, including but not limited to epilepsy, schizophrenia, stress, depression and anxiety.
Enzymes controlling eCB synthesis and degradation restrict cannabinoid receptor signaling spatially and temporally. However, their precise arrangement at different synapses is not completely understood. Using proteomics and gene editing, coupled with imaging and electrophysiology, we aim to better understand their localization and the differential regulation of eCB availability at different synapse types.
We hope that this fundamental knowledge will ultimately inform the design of strategies to selectively target the eCB metabolic machinery at specific synapse types, thereby correcting synaptic imbalance in epilepsy and other CNS pathologies.