Metabotropic regulation of dendritic spine structural plasticity

Abstract

Synaptic plasticity is often accompanied by morphological alterations of dendritic spines, small protrusions formed on neuronal dendritic shafts and sites of most excitatory synapses. Changes in dendritic spine morphogenesis are hypothesized to be the physical correlate of memory. Relationship between synaptic structure and function is further underscored by observations that spine dysgenesis accompanies many neurodevelopmental disorders including Fragile X syndrome, autism and schizophrenia, although how abnormal spine morphology contributes to cognitive and behavioral impairments is not known. Understanding how neuronal activity mobilizes molecular effectors that drive structural modifications in dendritic spines will enhance our understanding of basic memory processes and help to identify pharmacological targets for treatment of neurodevelopmental disorders. My thesis research explored molecular mechanisms underlying dendritic spines morphogenesis and their regulation by glutamatergic neurotrasmission via group 1 metabotropic glutamate receptors (Gp1 mGluRs). Gp1 mGluRs are G protein coupled receptors critical to development of brain circuitry, activity-dependent synaptic plasticity and are implicated in neuropsychiatric disorders such as Fragile X syndrome, autism and schizophrenia. Moreover, Gp1 mGluRs participate in dendritic spine remodeling and administration of mGluR antagonists can correct spine abnormalities in Fmr1 knockout mice, an animal model of Fragile X syndrome. Molecular effectors linking receptor activity to plastic changes in spines remain uncharacterized. My research identified the actin-binding protein aactinin-4 (actinin-4) as a novel Gp1 mGluR binding partner that orchestrates spine dynamics and morphogenesis in neurons and plays an essential role in regulation of dendritic spine morphogenesis downstream of Gp1 mGluRs. Actinin-4 overexpression was sufficient to modify spine morphogenesis, the latter function dependent on actinin-4 C-terminal domain that mediates CaMKII binding and I showed that this interaction is regulated by Gp1 mGluRs. Furthermore, I discovered that actinin-4 interacts in the brain with synaptopodin, an actin-binding protein associated with the spine apparatus at a subset of mature, mushroom type dendritic spines that I hypothesized to be the locus of Gpl mGluR-dependent plasticity. I found that Gpl mGluRs and their signaling complex are selectively enriched at synaptic sites containing synaptopodin in mature neurons. Thus, my research enhanced our understanding of how this important class of glutamate receptors can regulate structural plasticity.