ORCID Profile
0000-0003-0121-8514
Current Organisation
Trinity College Dublin
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Publisher: Springer Science and Business Media LLC
Date: 09-09-2009
DOI: 10.1038/NRN2717
Abstract: Understanding the evolutionary origins of behaviour is a central aim in the study of biology and may lead to insights into human disorders. Synaptic transmission is observed in a wide range of invertebrate and vertebrate organisms and underlies their behaviour. Proteomic studies of the molecular components of the highly complex mammalian postsynaptic machinery point to an ancestral molecular machinery in unicellular organisms--the protosynapse--that existed before the evolution of metazoans and neurons, and hence challenges existing views on the origins of the brain. The phylogeny of the molecular components of the synapse provides a new model for studying synapse ersity and complexity, and their implications for brain evolution.
Publisher: eLife Sciences Publications, Ltd
Date: 21-07-2017
DOI: 10.7554/ELIFE.17161
Abstract: Aberrant NMDA receptor (NMDAR) activity contributes to several neurological disorders, but direct antagonism is poorly tolerated therapeutically. The GluN2B cytoplasmic C-terminal domain (CTD) represents an alternative therapeutic target since it potentiates excitotoxic signaling. The key GluN2B CTD-centred event in excitotoxicity is proposed to involve its phosphorylation at Ser-1303 by Dapk1, that is blocked by a neuroprotective cell-permeable peptide mimetic of the region. Contrary to this model, we find that excitotoxicity can proceed without increased Ser-1303 phosphorylation, and is unaffected by Dapk1 deficiency in vitro or following ischemia in vivo. Pharmacological analysis of the aforementioned neuroprotective peptide revealed that it acts in a sequence-independent manner as an open-channel NMDAR antagonist at or near the Mg2+ site, due to its high net positive charge. Thus, GluN2B-driven excitotoxic signaling can proceed independently of Dapk1 or altered Ser-1303 phosphorylation.
Publisher: Springer Science and Business Media LLC
Date: 27-04-2016
DOI: 10.1038/NCOMMS11264
Abstract: How neuronal proteomes self-organize is poorly understood because of their inherent molecular and cellular complexity. Here, focusing on mammalian synapses we use blue-native PAGE and ‘gene-tagging’ of GluN1 to report the first biochemical purification of endogenous NMDA receptors (NMDARs) directly from adult mouse brain. We show that NMDARs partition between two discrete populations of receptor complexes and ∼1.5 MDa supercomplexes. We tested the assembly mechanism with six mouse mutants, which indicates a tripartite requirement of GluN2B, PSD93 and PSD95 gate the incorporation of receptors into ∼1.5 MDa supercomplexes, independent of either canonical PDZ-ligands or GluN2A. Supporting the essential role of GluN2B, quantitative gene-tagging revealed a fourfold molar excess of GluN2B over GluN2A in adult forebrain. NMDAR supercomplexes are assembled late in postnatal development and triggered by synapse maturation involving epigenetic and activity-dependent mechanisms. Finally, screening the quaternary organization of 60 native proteins identified numerous discrete supercomplexes that populate the mammalian synapse.
Publisher: Cold Spring Harbor Laboratory
Date: 19-12-2018
DOI: 10.1101/500389
Abstract: Although molecular mechanisms underpinning specific behaviors have been described, whether there are mechanisms that orchestrate a behavioral repertoire is unknown. To test if the postsynaptic proteome of excitatory synapses could impart such a mechanism we conducted the largest genetic study of mammalian synapses yet undertaken. A repertoire of sixteen innate and learned behaviors was assessed from 290,850 measures in 55 lines of mutant mice carrying targeted mutations in the principal classes of postsynaptic proteins. Each innate and learned behavior used a different combination of proteins. These combinations were comprised of proteins that lified or attenuated the magnitude of each behavioral response. All behaviors required proteins found in PSD95 supercomplexes. We show the vertebrate increase in proteome complexity drove an expansion in behavioral repertoires and generated susceptibility to a wide range of diseases. Our results reveal a molecular mechanism that generates a versatile and complex behavioral repertoire that is central to human behavioral disorders.
Publisher: eLife Sciences Publications, Ltd
Date: 08-03-2022
DOI: 10.7554/ELIFE.77177
Abstract: The thalamus is a gateway to the cortex. Cortical encoding of complex behavior can therefore only be understood by considering the thalamic processing of sensory and internally generated information. Here, we use two-photon Ca 2+ imaging and optogenetics to investigate the role of axonal projections from the posteromedial nucleus of the thalamus (POm) to the forepaw area of the mouse primary somatosensory cortex (forepaw S1). By recording the activity of POm axonal projections within forepaw S1 during expert and chance performance in two tactile goal-directed tasks, we demonstrate that POm axons increase activity in the response and, to a lesser extent, reward epochs specifically during correct HIT performance. When performing at chance level during learning of a new behavior, POm axonal activity was decreased to naive rates and did not correlate with task performance. However, once evoked, the Ca 2+ transients were larger than during expert performance, suggesting POm input to S1 differentially encodes chance and expert performance. Furthermore, the POm influences goal-directed behavior, as photoinactivation of archaerhodopsin-expressing neurons in the POm decreased the learning rate and overall success in the behavioral task. Taken together, these findings expand the known roles of the higher-thalamic nuclei, illustrating the POm encodes and influences correct action during learning and performance in a sensory-based goal-directed behavior.
Publisher: Elsevier BV
Date: 05-2012
Publisher: Springer Science and Business Media LLC
Date: 15-01-2008
Abstract: Glutamate gated postsynaptic receptors in the central nervous system (CNS) are essential for environmentally stimulated behaviours including learning and memory in both invertebrates and vertebrates. Though their genetics, biochemistry, physiology, and role in behaviour have been intensely studied in vitro and in vivo , their molecular evolution and structural aspects remain poorly understood. To understand how these receptors have evolved different physiological requirements we have investigated the molecular evolution of glutamate gated receptors and ion channels, in particular the N -methyl- D -aspartate (NMDA) receptor, which is essential for higher cognitive function. Studies of rodent NMDA receptors show that the C-terminal intracellular domain forms a signalling complex with enzymes and scaffold proteins, which is important for neuronal and behavioural plasticity The vertebrate NMDA receptor was found to have subunits with C-terminal domains up to 500 amino acids longer than invertebrates. This extension was specific to the NR2 subunit and occurred before the duplication and subsequent ergence of NR2 in the vertebrate lineage. The shorter invertebrate C-terminus lacked vertebrate protein interaction motifs involved with forming a signaling complex although the terminal PDZ interaction domain was conserved. The vertebrate NR2 C-terminal domain was predicted to be intrinsically disordered but with a conserved secondary structure. We highlight an evolutionary adaptation specific to vertebrate NMDA receptor NR2 subunits. Using in silico methods we find that evolution has shaped the NMDA receptor C-terminus into an unstructured but modular intracellular domain that parallels the expansion in complexity of an NMDA receptor signalling complex in the vertebrate lineage. We propose the NR2 C-terminus has evolved to be a natively unstructured yet flexible hub organising postsynaptic signalling. The evolution of the NR2 C-terminus and its associated signalling complex may contribute to species differences in behaviour and in particular cognitive function.
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United States of America
No related grants have been discovered for Tomás Ryan.