Jean-Claude Lacaille
Département de neurosciences, Univ Montréal, Montréal, Canada
Title
Neurodevelopmental disorders: Troubled translation in inhibitory interneurons
Abstract
Long term synaptic changes in hippocampal networks underlie spatial and contextual fear learning and memory. However, in neurodevelopmental disorders, the protein synthesis mechanisms that control long-term synaptic plasticity and memory are disrupted. In this context, much attention has been devoted to excitatory principal cells, however inhibitory interneurons also play important roles. I will present our recent work on the involvement of somatostatin (SOM) interneurons in spatial and contextual learning.
In previous work, we used molecular genetics to dissect the neuronal circuits by which protein synthesis gates memory and cognitive processing. We found that learning reduces eIF2α phosphorylation in excitatory neurons and a subset of inhibitory neurons that express somatostatin. Ablation of p-eIF2α in either excitatory or somatostatin (but not parvalbumin) inhibitory neurons increased general mRNA translation, bolstered synaptic plasticity and enhanced long-term memory. Thus, eIF2α-dependent mRNA translation controls memory consolidation via autonomous mechanisms in excitatory and somatostatin inhibitory neurons.
In more recent work, we use optogenetics to determine the role of LTP at PC-SOM synapses in network plasticity and memory. We found that optogenetic stimulation of pyramidal cells induces LTP at PC-SOM synapses in slices. Optogenetic induction of LTP at PC-SOM synapses bi-directionally controls the plasticity of the two inputs of pyramidal cells, the Schaffer collateral and temporo-ammonic pathways. Finally, optogenetic induction of LTP at PC-SOM synapses in vivo regulates learning-induced LTP at these synapses and contextual fear memory.
Thus, LTP at PC-SOM synapses is sufficient to control the state of plasticity in the CA1 network and the consolidation of contextual fear memory, uncovering a long-term feedback control mechanism via PC-SOM synapses necessary and sufficient for regulation of CA1 pyramidal cell metaplasticity and hippocampus-dependent memory. Disruption of such translational control mechanisms in selective inhibitory cells may thus contribute in part to neurodevelopmental disorders.
Biosketch
Dr. Jean-Claude Lacaille is Professor of Neurosciences at Université de Montréal and a Fellow of the Canadian Academy of Health Sciences. He was the founding director of the Department of Neurosciences (2013-14). He was previously in the Department of Physiology from 1987-2013 and was director from 2001-05. He is also a founding member of the Research Group on the Central Nervous System at Université de Montréal. He holds the Canada Research Chair in Cellular and Molecular Neurophysiology and his research focuses on the organization and function of synaptic networks in the hippocampus at molecular, cellular and system levels; on the cellular and molecular mechanisms of synaptic plasticity underlying learning and memory; and on synaptic dysfunction in epilepsy and neurodevelopmental brain disorders (autism, intellectual deficiency, Fragile X). His laboratory is specialized in the use of behavioral tests, electrophysiological, cellular imaging and molecular biological techniques in brain slices and cultured neurons from transgenic mice to investigate the function of hippocampal cells and synaptic circuits.
Website: https://neurosciences.umontreal.ca/recherche/les-chercheurs/jean-claude-lacaille