The proteomic landscape of synaptic diversity across brain regions and cell types

Cell, Год журнала: 2023, Номер 186(24), С. 5411 - 5427.e23

Опубликована: Ноя. 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.

Язык: Английский

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Somatostatin interneurons control the timing of developmental desynchronization in cortical networks

Neuron, Год журнала: 2024, Номер 112(12), С. 2015 - 2030.e5

Опубликована: Апрель 9, 2024

Synchronous neuronal activity is a hallmark of the developing brain. In mouse cerebral cortex, decorrelates during second week postnatal development, progressively acquiring characteristic sparse pattern underlying integration sensory information. The maturation inhibition seems critical for this process, but interneurons involved in crucial transition network cortex remain unknown. Using vivo longitudinal two-photon calcium imaging period that precedes change from highly synchronous to decorrelated activity, we identify somatostatin-expressing (SST+) as modulators switch mice. Modulation SST+ cells accelerates or delays decorrelation cortical process involves regulating parvalbumin-expressing (PV+) interneurons. critically link inputs with local circuits, controlling neural dynamics while modulating other into nascent circuits.

Язык: Английский

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Control of neuronal excitation–inhibition balance by BMP–SMAD1 signalling

Nature, Год журнала: 2024, Номер 629(8011), С. 402 - 409

Опубликована: Апрель 17, 2024

Abstract Throughout life, neuronal networks in the mammalian neocortex maintain a balance of excitation and inhibition, which is essential for computation 1,2 . Deviations from balanced state have been linked to neurodevelopmental disorders, severe disruptions result epilepsy 3–5 To balance, microcircuits composed excitatory inhibitory neurons sense alterations neural activity adjust connectivity function. Here we identify signalling pathway adult mouse that activated response increased network activity. Overactivation signalled through an increase levels BMP2, growth factor well known its role as morphogen embryonic development. BMP2 acts on parvalbumin-expressing (PV) interneurons transcription SMAD1, controls array glutamatergic synapse proteins components perineuronal nets. PV-interneuron-specific disruption BMP2–SMAD1 accompanied by loss innervation PV cells, underdeveloped nets decreased excitability. Ultimately, this impairment functional recruitment disrupts cortical excitation–inhibition with mice exhibiting spontaneous epileptic seizures. Our findings suggest developmental repurposed stabilize brain.

Язык: Английский

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Parvalbumin interneuron deficits in schizophrenia

European Neuropsychopharmacology, Год журнала: 2024, Номер 82, С. 44 - 52

Опубликована: Март 14, 2024

Parvalbumin-expressing (PV+) interneurons represent one of the most abundant subclasses cortical interneurons. Owing to their specific electrophysiological and synaptic properties, PV+ are essential for gating pacing activity excitatory neurons. In particular, critically involved in generating maintaining rhythms gamma frequency, which complex cognitive functions. Deficits have been frequently reported postmortem studies schizophrenia patients, alterations oscillations a prominent feature disease. Here, I summarise main features review clinical preclinical linking developmental dysfunction with pathophysiology schizophrenia.

Язык: Английский

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Differential nanoscale organization of excitatory synapses onto excitatory vs. inhibitory neurons

Proceedings of the National Academy of Sciences, Год журнала: 2024, Номер 121(17)

Опубликована: Апрель 16, 2024

A key feature of excitatory synapses is the existence subsynaptic protein nanoclusters (NCs) whose precise alignment across cleft in a transsynaptic nanocolumn influences strength synaptic transmission. However, whether properties vary between functioning different cellular contexts unknown. We used combination confocal and DNA-PAINT super-resolution microscopy to directly compare organization shared scaffold proteins at two important synapses—those forming onto principal neurons (Ex→Ex synapses) those parvalbumin-expressing interneurons (Ex→PV synapses). As Ex→Ex synapses, we find that Ex→PV presynaptic Munc13-1 postsynaptic PSD-95 both form NCs demonstrate alignment, underscoring nanostructure as conserved organizational principles synapses. Despite general conservation these features, observed specific differences characteristics pre- nanostructure. contained larger PSDs with fewer when accounting for size than Furthermore, were denser. The identity cell was also represented organization, hosted puncta less dense but more numerous NCs. Moreover, measured spatial variability synapse types, revealing over distinct range distances compared conclude while are shared, cell-specific elements nanodomain likely contribute functional diversity

Язык: Английский

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Synapse-type-specific competitive Hebbian learning forms functional recurrent networks

Proceedings of the National Academy of Sciences, Год журнала: 2024, Номер 121(25)

Опубликована: Июнь 13, 2024

Cortical networks exhibit complex stimulus–response patterns that are based on specific recurrent interactions between neurons. For example, the balance excitatory and inhibitory currents has been identified as a central component of cortical computations. However, it remains unclear how required synaptic connectivity can emerge in developing circuits where synapses neurons simultaneously plastic. Using theory modeling, we propose wide range response properties arise from single plasticity paradigm acts at all connections—Hebbian learning is stabilized by synapse-type-specific competition for limited supply resources. In plastic circuits, this enables formation decorrelation inhibition-balanced receptive fields. Networks develop an assembly structure with stronger connections similarly tuned normalization orientation-specific center-surround suppression, reflecting stimulus statistics during training. These results demonstrate self-organize into functional suggest essential role competitive development circuits.

Язык: Английский

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Prefrontal ErbB4-positive interneurons for avoidance

Cell Reports, Год журнала: 2025, Номер 44(5), С. 115628 - 115628

Опубликована: Апрель 30, 2025

Язык: Английский

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Circuit-level theories for sensory dysfunction in autism: convergence across mouse models

Frontiers in Neurology, Год журнала: 2023, Номер 14

Опубликована: Сен. 7, 2023

Individuals with autism spectrum disorder (ASD) exhibit a diverse range of behavioral features and genetic backgrounds, but whether different forms involve convergent pathophysiology brain function is unknown. Here, we analyze evidence for deficits in neural circuit across multiple transgenic mouse models ASD. We focus on sensory areas neocortex, where differences may underlie atypical processing, central feature autism. Many distinct circuit-level theories ASD have been proposed, including increased excitation–inhibition (E–I) ratio hyperexcitability, hypofunction parvalbumin (PV) interneuron circuits, impaired homeostatic plasticity, degraded coding, others. review these assess the degree convergence each. Behaviorally, our analysis reveals that innate detection behavior heightened discrimination many models. Neurophysiologically, PV E–I are prevalent only rarely generate hyperexcitability excess spiking. Instead, tuning other aspects coding commonly explain behavior. Two phenotypic clusters opposing signatures evident Such clustering could suggest physiological subtypes autism, which facilitate development tailored therapeutic approaches.

Язык: Английский

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Astrocytic crosstalk with brain and immune cells in healthy and diseased conditions

Current Opinion in Neurobiology, Год журнала: 2024, Номер 84, С. 102840 - 102840

Опубликована: Янв. 29, 2024

Astrocytes interact with various cell types, including neurons, vascular cells, microglia, and peripheral immune cells. These interactions are crucial for regulating normal brain functions as well modulating neuroinflammation in pathological conditions. Recent transcriptomic proteomic studies have identified critical molecules involved astrocytic crosstalk other shedding light on their roles maintaining homeostasis both healthy diseased perform these through either direct or indirect physical associations neuronal synapses vasculature. Furthermore, astrocytes can communicate such T natural killer secreted during neuroinflammation. In this review, we discuss the molecular basis of underlying mechanisms astrocyte communication We propose that function a central hub inter-connecting vasculatures, cells brains.

Язык: Английский

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Syngap1Disruption Induced by Recombination between Inverted loxP Sites Is Associated with Hippocampal Interneuron Dysfunction

eNeuro, Год журнала: 2023, Номер 10(5), С. ENEURO.0475 - 22.2023

Опубликована: Апрель 18, 2023

SYNGAP1 haploinsufficiency in humans causes intellectual disability (ID). is highly expressed cortical excitatory neurons and, reducing its expression mice accelerates the maturation of synapses during sensitive developmental periods, restricts critical period window for plasticity, and impairs cognition. However, specific role interneurons remains largely undetermined. In this study, we investigated effects conditional Syngap1 disruption medial ganglionic eminence (MGE)-derived on hippocampal interneuron firing properties synaptic inputs, as well pyramidal cell inhibition integration. We show that MGE-derived results cell-specific impairment Nkx2.1 fast-spiking interneurons, with enhancement their AMPA receptor (AMPAR)-mediated inputs but compromised short-term plasticity. contrast, regular-spiking are unaffected. These changes associated impaired enhanced summation responses. Unexpectedly, found Syngap1flox allele used study contains inverted loxP sites targeted recombination induces some loss embryonic development reversible inversion sequence flanked by postmitotic cells. Together, these suggest plays a regulation function cells mice. because our finding sites, it will be important to further investigate using different allele.

Язык: Английский

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