Originally from Chile, Dr Patricio Opazo completed undergraduate training in biochemistry at the Universidad de Concepcion. Given a general interest in the molecular basis of cognition, he pursued a PhD at the University of California, Los Angeles in the laboratory of Dr Thomas O’Dell investigating the signaling pathways driving long-term potentiation (LTP) of synaptic transmission, an electrophysiological signature of memory formation. For his postdoctoral training, he joined the lab of Dr Daniel Choquet at the Université de Bordeaux to take a more reductionist approach in the study of memory by investigating the trafficking of individual AMPA receptors to synapses, a critical step for synaptic potentiation, using single-particle tracking microscopy. Dr Opazo then joined the lab of Dr Tobias Bonhoeffer at the Max-Planck Institute in Munich and took a more integrative approach to memory by investigating the role of subcellular structural changes underlying behavioral memory. In April 2016, Dr Opazo joined the Queensland Brain Institute’s Clem Jones Centre for Ageing Dementia Research to continue investigating the basis of memory and at the same time, take advantage of this basic knowledge to elucidate the alterations leading to memory dysfunction in Alzheimer’s disease.
The main direction of our research is to understand how memories are stored in the brain and how they are lost during the progression of Alzheimer’s disease. Given the long-lasting nature of memories, we focus in the long-lasting structural modifications in the brain that might serve as a substrate for memory storage. In the last decade, the advancement of 2-photon imaging microscopy has allowed the in vivo visualisation of subcellular structural modifications in the brain as animals learn a given memory task. This technological breakthrough has revealed that memory formation and performance is strongly associated with the structural plasticity of dendritic spines, dendritic protrusions that serve as placeholders for excitatory synapses in the brain. In particular, learning has been strongly associated with a rapid increase in the formation of new dendritic spines as well as to a delayed increase in the elimination of dendritic spines. Importantly, both the formation and elimination of dendritic spines are thought to drive the connectivity re-arrangement underlying memory storage. Given these insights, dendritic spines are considered to be the structural units of memory.
Molecular Mechanisms underlying the structural plasticity of dendritic spines
Although dendritic spine formation and elimination are strongly correlated to memory formation, their causal relationship remain to be determined. The main obstacle in assessing causality between dendritic spine plasticity and memory correspond to our lack of knowledge regarding their molecular mechanisms. An understanding of the molecular events leading to spine formation/elimination will allow us to identify molecular marker for newly formed spines or spines tagged for elimination. By manipulating these markers, we hope to be able to selectively interfere with these structural plasticity events and thus be able to evaluate their causal role in memory. To this end, we will first attempt to elucidate the molecular basis of spine formation /elimination using in vitro models to subsequently manipulate these processes in vivo in a behaving animal and thus assess their causative role in memory formation. We will meet these goals using a combination of in vitro/in vivo genetic manipulations and 2-photon imaging microscopy.
Alzheimer disease targets dendritic spines
Given that dendritic spines seem to correspond to the most basic unit of memory storage, it is possible that Alzheimer’s disease (AD) might trigger memory dysfunction by targeting dendritic spines. As of today, numerous studies have shown that Alzheimer disease is strongly associated with a decrease in the number of dendritic spines in both transgenic animal model of AD and human AD patients. More importantly, dendritic spine loss is strongly correlated with the cognitive deficits associated to AD suggesting a causal relationship. It is less clear, however, what aspect of dendritic spine plasticity is affected during the progression of the disease as both a decrease in dendritic spine formation or increase in dendritic spine elimination might lead to the overall loss in dendritic spines. Again, progress in this area have been hindered by the lack of knowledge regarding the molecular mechanisms underlying dendritic spine plasticity. In this project, we will take advantage of the insights gained in the previous section to elucidate the particular molecules and events leading to the net loss of dendritic spines. The ultimate goal is to correct these alterations in dendritic spine plasticity as a way to prevent or halt the progression of Alzheimer’s disease.
Hafner AS., Penn AC., Grillo-Bosch D., Retailleau N., Poujol C., Philippat A., Coussen, F., Sainlos M., Opazo P.# and Choquet D. # (2015) Lengthening of the stargazin cytoplasmic tail increases synaptic transmission by promoting interaction to deeper domains of PSD-95. Neuron 86: 475-489. (# Co-senior and corresponding authors)
Carta M, Opazo P, Veran J, Athané A, Choquet D, Coussen F, Mulle C. (2013) CaMKII-dependent phosphorylation of GluK5 mediates plasticity of kainate receptors. EMBO J. 32: 496-510.
Opazo P., Sainlos M., Choquet D. (2012) Regulation of AMPA receptor surface diffusion by PSD- 95 slots. Curr Opin Neurobiol. 22: 453-60
Opazo P. and Choquet D. (2011) A three-step model for the synaptic recruitment of AMPA receptors Mol. Cell Neurosci. 46: 1-8
Opazo P, Labrecque S, Tigaret CM, Frouin A, Wiseman PW, De Koninck P and Choquet D. (2010) CaMKII triggers the diffusional trapping of surface AMPARs through phosphorylation of stargazin. Neuron, 67:239-52