Understanding GABAergic synapse diversity and its implications for GABAergic pharmacotherapy DOI Creative Commons
Dilja Krueger‐Burg

Trends in Neurosciences, Journal Year: 2025, Volume and Issue: 48(1), P. 47 - 61

Published: Jan. 1, 2025

Despite the substantial contribution of disruptions in GABAergic inhibitory neurotransmission to etiology psychiatric, neurodevelopmental, and neurodegenerative disorders, surprisingly few drugs targeting system are currently available, partly due insufficient understanding circuit-specific synapse biology. In addition GABA receptors, synapses contain an elaborate organizational protein machinery that regulates properties synaptic transmission. Until recently, this remained largely unexplored, but key methodological advances have now led identification a wealth new organizer proteins. Notably, many these proteins appear function only at specific subsets synapses, creating diversity complexes may serve as targets for pharmacotherapies. The present review aims summarize developments underlie newfound knowledge provide current overview synapse-specific complexes, well outlining future avenues challenges translating into clinical applications.

Language: Английский

Structure, Function, and Pharmacology of Glutamate Receptor Ion Channels DOI Open Access
Kasper B. Hansen, Lonnie P. Wollmuth, Derek Bowie

et al.

Pharmacological Reviews, Journal Year: 2021, Volume and Issue: 73(4), P. 1469 - 1658

Published: Oct. 1, 2021

Many physiologic effects of l-glutamate, the major excitatory neurotransmitter in mammalian central nervous system, are mediated via signaling by ionotropic glutamate receptors (iGluRs). These ligand-gated ion channels critical to brain function and centrally implicated numerous psychiatric neurologic disorders. There different classes iGluRs with a variety receptor subtypes each class that play distinct roles neuronal functions. The diversity iGluR subtypes, their unique functional properties roles, has motivated large number studies. Our understanding advanced considerably since first subunit gene was cloned 1989, research focus expanded encompass facets biology have been recently discovered exploit experimental paradigms made possible technological advances. Here, we review insights from more than 3 decades studies an emphasis on progress occurred past decade. We cover structure, function, pharmacology, neurophysiology, therapeutic implications for all assembled subunits encoded 18 genes. SIGNIFICANCE STATEMENT: Glutamate important virtually aspects either involved mediating some clinical features neurological disease or represent target treatment. Therefore, pharmacology this will advance our many at molecular, cellular, system levels provide new opportunities treat patients.

Language: Английский

Citations

461
GABA-receptive microglia selectively sculpt developing inhibitory circuits DOI Creative Commons
Emilia Favuzzi, Shuhan Huang, Giuseppe-Antonio Saldi

et al.

Cell, Journal Year: 2021, Volume and Issue: 184(15), P. 4048 - 4063.e32

Published: July 1, 2021

Language: Английский

Citations

217
Interneuron Types as Attractors and Controllers DOI
Gord Fishell, Ádám Kepecs

Annual Review of Neuroscience, Journal Year: 2019, Volume and Issue: 43(1), P. 1 - 30

Published: July 12, 2019

Cortical interneurons display striking differences in shape, physiology, and other attributes, challenging us to appropriately classify them. We previously suggested that interneuron types should be defined by their role cortical processing. Here, we revisit the question of how codify diversity based upon division labor function as controllers information flow. suggest developmental trajectories provide a guide for appreciating argue subtype identity is generated using configurational (rather than combinatorial) code transcription factors produce attractor states underlying gene regulatory network. present our updated three-stage model specification: an initial cardinal step, allocating into few major classes, followed definitive refinement, creating subclasses settling within cortex, lastly, state determination, reflecting incorporation functional circuit ensembles. close discussing findings indicating classes are both evolutionarily ancient conserved. propose complexity circuits phylogenetically old types, complemented evolutionary increase principal neuron diversity. This suggests natural neurobiological definition might derived from match between origin computational function.

Language: Английский

Citations

173
Cortical interneurons in autism DOI
Anis Contractor, Iryna M. Ethell, Carlos Portera‐Cailliau

et al.

Nature Neuroscience, Journal Year: 2021, Volume and Issue: 24(12), P. 1648 - 1659

Published: Nov. 29, 2021

Language: Английский

Citations

118
An increase of inhibition drives the developmental decorrelation of neural activity DOI Creative Commons
Mattia Chini, Thomas Pfeffer, Ileana L. Hanganu‐Opatz

et al.

eLife, Journal Year: 2022, Volume and Issue: 11

Published: Aug. 17, 2022

Throughout development, the brain transits from early highly synchronous activity patterns to a mature state with sparse and decorrelated neural activity, yet mechanisms underlying this process are poorly understood. The developmental transition has important functional consequences, as latter is thought allow for more efficient storage, retrieval, processing of information. Here, we show that, in mouse medial prefrontal cortex (mPFC), during first two postnatal weeks decorrelates following specific spatial patterns. This accompanied by concomitant tilting excitation-inhibition (E-I) ratio toward inhibition. Using optogenetic manipulations network modeling, that phenomena mechanistically linked, relative increase inhibition drives decorrelation activity. Accordingly, mice mimicking etiology neurodevelopmental disorders, subtle alterations E-I associated impairments correlational structure spike trains. Finally, capitalizing on EEG data newborn babies, an analogous takes place also human brain. Thus, changes control (de)correlation and, these means, its imbalance might contribute pathogenesis disorders.

Language: Английский

Citations

118
Cortical somatostatin interneuron subtypes form cell-type-specific circuits DOI
Jingjing Sherry Wu, Elaine Sevier, Deepanjali Dwivedi

et al.

Neuron, Journal Year: 2023, Volume and Issue: 111(17), P. 2675 - 2692.e9

Published: June 29, 2023

Language: Английский

Citations

73
The proteomic landscape of synaptic diversity across brain regions and cell types DOI Creative Commons
Marc van Oostrum, Thomas M. Blok, Stefano L. Giandomenico

et al.

Cell, Journal Year: 2023, Volume and Issue: 186(24), P. 5411 - 5427.e23

Published: Nov. 1, 2023

Neurons build synaptic contacts using different protein combinations that define the specificity, function, and plasticity potential of synapses; however, diversity proteomes remains largely unexplored. We prepared synaptosomes from 7 transgenic mouse lines with fluorescently labeled presynaptic terminals. Combining microdissection 5 brain regions fluorescent-activated synaptosome sorting (FASS), we isolated analyzed 18 synapse types. discovered ∼1,800 unique synapse-type-enriched proteins allocated thousands to types synapses (https://syndive.org/). identify shared modules highlight proteomic hotspots for specialization. reveal common features striatal dopaminergic proteome discover signatures relate functional properties interneuron classes. This study provides a molecular systems-biology analysis framework integrate information subtypes interest cellular or circuit-level experiments.

Language: Английский

Citations

58
Neuronal types in the mouse amygdala and their transcriptional response to fear conditioning DOI Creative Commons
Hannah Hochgerner, Shelly Singh, Muhammad Tibi

et al.

Nature Neuroscience, Journal Year: 2023, Volume and Issue: 26(12), P. 2237 - 2249

Published: Oct. 26, 2023

Abstract The amygdala is a brain region primarily associated with emotional response. use of genetic markers and single-cell transcriptomics can provide insights into behavior-associated cell state changes. Here we present detailed cell-type taxonomy the adult mouse during fear learning memory consolidation. We perform RNA sequencing on naïve fear-conditioned mice, identify 130 neuronal types validate their spatial distributions. A subset all transcriptionally responsive to retrieval. activated engram cells upregulate activity-response genes coordinate expression neurite outgrowth, synaptic signaling, plasticity development. known previously undescribed candidate learning. Our molecular atlas may be used generate hypotheses unveil neuron neural circuits regulating component memory.

Language: Английский

Citations

55
Molecularly targetable cell types in mouse visual cortex have distinguishable prediction error responses DOI Creative Commons

Sean M. O’Toole,

Hassana K. Oyibo, Georg B. Keller

et al.

Neuron, Journal Year: 2023, Volume and Issue: 111(18), P. 2918 - 2928.e8

Published: Sept. 1, 2023

Predictive processing postulates the existence of prediction error neurons in cortex. Neurons with both negative and positive response properties have been identified layer 2/3 visual cortex, but whether they correspond to transcriptionally defined subpopulations is unclear. Here we used activity-dependent, photoconvertible marker CaMPARI2 tag mouse cortex during stimuli behaviors designed evoke errors. We performed single-cell RNA-sequencing on these populations found that previously annotated Adamts2 Rrad transcriptional cell types were enriched when photolabeling drive or responses, respectively. Finally, validated results functionally by designing artificial promoters for use AAV vectors express genetically encoded calcium indicators. Thus, distinct can be targeted using exhibit distinguishable responses.

Language: Английский

Citations

43
Astrocyte-secreted neurocan controls inhibitory synapse formation and function DOI Creative Commons
Dolores Irala, Shiyi Wang, Kristina Sakers

et al.

Neuron, Journal Year: 2024, Volume and Issue: 112(10), P. 1657 - 1675.e10

Published: April 3, 2024

Astrocytes strongly promote the formation and maturation of synapses by secreted proteins. Several astrocyte-secreted synaptogenic proteins controlling excitatory synapse development were identified; however, those that induce inhibitory synaptogenesis remain elusive. Here, we identify neurocan as an protein. After secretion from astrocytes, is cleaved into N- C-terminal fragments. We found these fragments have distinct localizations in extracellular matrix. The fragment localizes to controls cortical function. Neurocan knockout mice lacking whole protein or only its domain reduced numbers Through super-resolution microscopy, vivo proximity labeling TurboID, astrocyte-specific rescue approaches, discovered somatostatin-positive regulates their formation. Together, our results unveil a mechanism through which astrocytes control circuit-specific mammalian brain.

Language: Английский

Citations

26