| 1. |
- Bulovaite, Edita, et al.
(author)
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A brain atlas of synapse protein lifetime across the mouse lifespan
- 2022
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In: Neuron. - : Elsevier BV. - 0896-6273 .- 1097-4199. ; 110:24, s. 4057-
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Journal article (peer-reviewed)abstract
- The lifetime of proteins in synapses is important for their signaling, maintenance, and remodeling, and for memory duration. We quantified the lifetime of endogenous PSD95, an abundant postsynaptic protein in excitatory synapses, at single-synapse resolution across the mouse brain and lifespan, generating the Protein Lifetime Synaptome Atlas. Excitatory synapses have a wide range of PSD95 lifetimes extending from hours to several months, with distinct spatial distributions in dendrites, neurons, and brain regions. Synapses with short protein lifetimes are enriched in young animals and in brain regions controlling innate behaviors, whereas synapses with long protein lifetimes accumulate during development, are enriched in the cortex and CA1 where memories are stored, and are preferentially preserved in old age. Synapse protein lifetime increases throughout the brain in a mouse model of autism and schizophrenia. Protein lifetime adds a further layer to synapse diversity and enriches prevailing concepts in brain development, aging, and disease.
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| 2. |
- Cowgill, John, et al.
(author)
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Structure and dynamics of differential ligand binding in the human ρ-type GABAA receptor
- 2023
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In: Neuron. - : Elsevier BV. - 0896-6273 .- 1097-4199. ; 111:21, s. 5-3450
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Journal article (peer-reviewed)abstract
- The neurotransmitter γ-aminobutyric acid (GABA) drives critical inhibitory processes in and beyond the nervous system, partly via ionotropic type-A receptors (GABAARs). Pharmacological properties of ρ-type GABAARs are particularly distinctive, yet the structural basis for their specialization remains unclear. Here, we present cryo-EM structures of a lipid-embedded human ρ1 GABAAR, including a partial intracellular domain, under apo, inhibited, and desensitized conditions. An apparent resting state, determined first in the absence of modulators, was recapitulated with the specific inhibitor (1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid and blocker picrotoxin and provided a rationale for bicuculline insensitivity. Comparative structures, mutant recordings, and molecular simulations with and without GABA further explained the sensitized but slower activation of ρ1 relative to canonical subtypes. Combining GABA with picrotoxin also captured an apparent uncoupled intermediate state. This work reveals structural mechanisms of gating and modulation with applications to ρ-specific pharmaceutical design and to our biophysical understanding of ligand-gated ion channels.
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| 3. |
- Fransén, Erik, 1962-, et al.
(author)
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Mechanism of graded persistent cellular activity of entorhinal cortex layer V neurons
- 2006
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In: Neuron. - : Elsevier BV. - 0896-6273 .- 1097-4199. ; 49:5, s. 735-746
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Journal article (peer-reviewed)abstract
- Working memory is an emergent property of neuronal networks, but its cellular basis remains elusive. Recent data show that principal neurons of the entorhinal cortex display persistent firing at graded firing rates that can be shifted up or down in response to brief excitatory or inhibitory stimuli. Here, we present a model of a potential mechanism for graded firing. Our multicompartmental model provides stable plateau firing generated by a nonspecific calcium-sensitive cationic (CAN) current. Sustained firing is insensitive to small variations in Ca2+ concentration in a neutral zone. However, both high and low Ca2+ levels alter firing rates. Specifically, increases in persistent firing rate are triggered only during high levels of calcium, while decreases in rate occur in the presence of low levels of calcium. The model is consistent with detailed experimental observations and provides a mechanism for maintenance of memory-related activity in individual neurons.
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| 4. |
- Gharpure, Anant, et al.
(author)
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Agonist Selectivity and Ion Permeation in the alpha 3 beta 4 Ganglionic Nicotinic Receptor
- 2019
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In: Neuron. - : CELL PRESS. - 0896-6273 .- 1097-4199. ; 104:3, s. 501-
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Journal article (peer-reviewed)abstract
- Nicotinic acetylcholine receptors are pentameric ion channels that mediate fast chemical neurotransmission. The alpha 3 beta 4 nicotinic receptor subtype forms the principal relay between the central and peripheral nervous systems in the autonomic ganglia. This receptor is also expressed focally in brain areas that affect reward circuits and addiction. Here, we present structures of the alpha 3 beta 4 nicotinic receptor in lipidic and detergent environments, using functional reconstitution to define lipids appropriate for structural analysis. The structures of the receptor in complex with nicotine, as well as the alpha 3 beta 4-selective ligand AT-1001, complemented by molecular dynamics, suggest principles of agonist selectivity. The structures further reveal much of the architecture of the intracellular domain, where mutagenesis experiments and simulations define residues governing ion conductance.
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| 5. |
- Lindén, Henrik, et al.
(author)
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Modeling the spatial reach of the LFP
- 2011
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In: Neuron. - : Elsevier BV. - 0896-6273 .- 1097-4199. ; 72:5, s. 859-872
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Journal article (peer-reviewed)abstract
- The local field potential (LFP) reflects activity of many neurons in the vicinity of the recording electrode and is therefore useful for studying local network dynamics. Much of the nature of the LFP is, however, still unknown. There are, for instance, contradicting reports on the spatial extent of the region generating the LFP. Here, we use a detailed biophysical modeling approach to investigate the size of the contributing region by simulating the LFP from a large number of neurons around the electrode. We find that the size of the generating region depends on the neuron morphology, the synapse distribution, and the correlation in synaptic activity. For uncorrelated activity, the LFP represents cells in a small region (within a radius of a few hundred micrometers). If the LFP contributions from different cells are correlated, the size of the generating region is determined by the spatial extent of the correlated activity.
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| 6. |
- Lundqvist, Mikael, et al.
(author)
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Gamma and Beta Bursts Underlie Working Memory
- 2016
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In: Neuron. - : Elsevier BV. - 0896-6273 .- 1097-4199. ; 90:1, s. 152-164
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Journal article (peer-reviewed)abstract
- Working memory is thought to result from sustained neuron spiking. However, computational models suggest complex dynamics with discrete oscillatory bursts. We analyzed local field potential (LFP) and spiking from the prefrontal cortex (PFC) of monkeys performing a working memory task. There were brief bursts of narrow-band gamma oscillations (45-100 Hz), varied in time and frequency, accompanying encoding and re-activation of sensory information. They appeared at a minority of recording sites associated with spiking reflecting the to-be-remembered items. Beta oscillations (20-35 Hz) also occurred in brief, variable bursts but reflected a default state interrupted by encoding and decoding. Only activity of neurons reflecting encoding/decoding correlated with changes in gamma burst rate. Thus, gamma bursts could gate access to, and prevent sensory interference with, working memory. This supports the hypothesis that working memory is manifested by discrete oscillatory dynamics and spiking, not sustained activity.
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| 7. |
- Zhu, Fei, et al.
(author)
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Architecture of the Mouse Brain Synaptome
- 2018
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In: Neuron. - : CELL PRESS. - 0896-6273 .- 1097-4199. ; 99:4, s. 781-
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Journal article (peer-reviewed)abstract
- Synapses are found in vast numbers in the brain and contain complex proteomes. We developed genetic labeling and imaging methods to examine synaptic proteins in individual excitatory synapses across all regions of the mouse brain. Synapse catalogs were generated from the molecular and morphological features of a billion synapses. Each synapse subtype showed a unique anatomical distribution, and each brain region showed a distinct signature of synapse subtypes. Whole-brain synaptome cartography revealed spatial architecture from dendritic to global systems levels and previously unknown anatomical features. Synaptome mapping of circuits showed correspondence between synapse diversity and structural and functional connectomes. Behaviorally relevant patterns of neuronal activity trigger spatio-temporal postsynaptic responses sensitive to the structure of synaptome maps. Areas controlling higher cognitive function contain the greatest synapse diversity, and mutations causing cognitive disorders reorganized synaptome maps. Synaptome technology and resources have wide-ranging application in studies of the normal and diseased brain.
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