Biology subjects

Grant, S. G. N.

Publications and source records attributed to Grant, S. G. N..

3 recordsLinked to original sources

bioRxiv2018

Regional diversity in the postsynaptic proteome of the mouse brain

The proteome of the postsynaptic terminal of excitatory synapses comprises over one thousand proteins in vertebrate species and plays a central role in behavior and brain disease. The brain is organized into anatomically distinct regions and whether the synapse proteome differs across these regions is poorly understood. Postsynaptic proteomes were isolated from seven forebrain and hindbrain regions in mice and their composition determined using proteomic mass spectrometry. Seventy-four percent of proteins showed differential expression and each region displayed a unique compositional signature. These signatures correlated with the anatomical divisions of the brain and their embryological origins. Biochemical pathways controlling plasticity and disease, protein interaction networks and individual proteins involved with cognition all showed differential regional expression. Combining proteomic and connectomic data shows that interconnected regions have specific proteome signatures. Diversity in synapse proteome composition is key feature of mouse and human brain structure.

neuroscience↗

bioRxiv2018

Cell-type specific visualization and biochemical isolation of endogenous synaptic proteins in mice

In recent years, the remarkable molecular complexity of synapses has been revealed, with over 1000 proteins identified in the synapse proteome. Although it is known that different receptors and other synaptic proteins are present in different types of neurons and synapses, the extent of synapse diversity across the brain is largely unknown, mainly owing to technical limitations. Combining mouse genetics and proteomics we have previously reported highly efficient methods for purification of synaptic protein complexes under native conditions. In that approach, tandem affinity purification (TAP) tags were fused to the carboxyl terminus of PSD95 using gene targeting in mice. Here we report an approach that restricts tagging of endogenous PSD95 to cells expressing Cre recombinase. In addition, we developed a labelling strategy enabling visualization of endogenous PSD95 tagged by fluorescent proteins in Cre-expressing cells. We demonstrate the feasibility of proteomic characterisation of synapse proteomes and visualization of synapse proteins in specific cell types. We find that composition of PSD95 complexes purified from specific cell types differs from those extracted from tissues with diverse cellular composition. Therefore, these novel conditional PSD95 tagging lines will not only serve as powerful tools for precisely dissecting synapse diversity in specific subsets of regions/neuronal cells, but also provide an opportunity to better understand brain region-specific alterations associated with various psychiatric/neurological diseases. The newly developed conditional gene tagging methods can be applied to many different synaptic proteins and will thus facilitate research on the molecular complexity of synapses.

neuroscience↗

bioRxiv2016

TrkB signaling underlies the rapid antidepressant effects of isoflurane

A brief burst-suppressing isoflurane anesthesia has been shown to rapidly alleviate symptoms of depression in a subset of patients, but the neurobiological basis of these observations remains obscure. We show that a single isoflurane anesthesia produces antidepressant-like behavioural effects in the learned helplessness paradigm and regulates molecular events implicated in the mechanism of action of rapid-acting antidepressant ketamine: activation of brain-derived neurotrophic factor (BDNF) receptor TrkB, facilitation of mammalian target of rapamycin (mTOR) signaling pathway and inhibition of glycogen synthase kinase 3{beta} (GSK3{beta}). Moreover, isoflurane affected neuronal plasticity by facilitating long-term potentiation in the hippocampus. We also found that isoflurane increased activity of the parvalbumin interneurons, and facilitated GABAergic transmission in wild type mice but not in transgenic mice with reduced TrkB expression in parvalbumin interneurons. Our findings strengthen the role of TrkB signaling in the antidepressant responses and encourage further evaluation of isoflurane as a rapid-acting antidepressant devoid of the psychotomimetic effects and abuse potential of ketamine.

neuroscience↗