Synaptic circuits of memory

The team aims at characterizing the function and dysfunction of synaptic transmission and circuits in the central nervous system. The projects have a strong focus on the CA3 region of the hippocampus, which is key for the initial steps in episodic and spatial memory encoding. A majority of projects relate to the less well characterized presynaptic plasticity mechanisms, in relation to the activity of neural circuits and memory encoding. The team combines molecular, cellular and circuit level approaches in physiological conditions as well as in relation to Alzheimer disease.

• Presynaptic plasticity We hypothesize that structural and functional plasticity on the presynaptic side, acting in a concerted fashion, shape the dynamics of neural processing in cortical circuits, which ultimately underlies mechanisms of information processing in the context of memory encoding and sensory perception. We interrogate the molecular mechanisms of presynaptic facilitation at excitatory and inhibitory synapses. We characterize the role of mitochondria and mitochondria-ER contacts in presynaptic mechanisms. We explore the consequences of presynaptic facilitation in the operation of CA3 circuits and memory encoding.
• Operation and plasticity of CA3 circuits. Using electrophysiological and live imaging methods in vitro and in vivo, combined with gene transfer techniques and novel optogenetic toolkits, we characterize the mechanisms of synaptic specification and plasticity within CA3 circuits. We develop parallel methods to interrogate the relationship between the intracellular dynamics of CA3 pyramidal cells in mice, brain states and memory encoding. We have for instance discovered that within theta, an activity and memory related brain state, a majority of CA3 pyramidal cells hyperpolarize, creating the neuronal context for the emergence of engram cells.
• Alzheimer disease (AD) and synaptic physiopathology. During the past years, the team has characterized the impairment of intrinsic and synaptic plasticity in DG and CA3 cells in mouse models of AD. We explore the physiological role for presenilin and APP in presynaptic mechanisms at excitarory and inhibitory synpases and in synapse function. We develop and use models for assessing the role of pathological Tau in the alteration of synaptic circuits in organotypic cultures, including the role of mitochondria.