Activity-dependent regulation of microglia numbers by pyramidal cells during development shape cortical functions DOI Creative Commons
Sanjana Kumaraguru,

James J. Morgan,

Fong Kuan Wong

et al.

Science Advances, Journal Year: 2025, Volume and Issue: 11(8)

Published: Feb. 19, 2025

Beyond their role as immune sentinels, microglia are actively involved in establishing and maintaining cortical circuits. Alteration microglial numbers has been associated with abnormal behaviors akin to those observed neurodevelopmental disorders. Consequently, the appropriate during development is crucial for ensuring normal function. Here, we uncovered a dynamic relationship between pyramidal cells that tunes through distinct phases of mouse postnatal development. Changes cell activity induce differential release activity-dependent proteins such Activin A, which, turn, adjusts accordingly. Decoupling this not only changes but long-term consequence on synaptic organizers, which ultimately affects Our findings reveal adapt critical time window development, consequently adjusting function demands developing local

Language: Английский

Assembloid CRISPR screens reveal impact of disease genes in human neurodevelopment DOI Creative Commons
Xiang-Ling Meng,

David Yao,

Kent Imaizumi

et al.

Nature, Journal Year: 2023, Volume and Issue: 622(7982), P. 359 - 366

Published: Sept. 27, 2023

Abstract The assembly of cortical circuits involves the generation and migration interneurons from ventral to dorsal forebrain 1–3 , which has been challenging study at inaccessible stages late gestation early postnatal human development 4 . Autism spectrum disorder other neurodevelopmental disorders (NDDs) have associated with abnormal interneuron 5 but these NDD genes affect migration, how they mediate effects remains unknown. We previously developed a platform in subpallial organoids assembloids 6 Here we integrate CRISPR screening investigate involvement 425 development. first screen aimed revealed 13 candidate genes, including CSDE1 SMAD4 subsequently conducted an more than 1,000 that identified 33 cytoskeleton-related endoplasmic reticulum-related gene LNPK discovered that, during reticulum is displaced along leading neuronal branch before nuclear translocation. deletion interfered this displacement resulted migration. These results highlight power CRISPR-assembloid systematically map onto reveal disease mechanisms.

Language: Английский

Citations

69
Somatostatin interneurons control the timing of developmental desynchronization in cortical networks DOI Creative Commons
Laura Mòdol, Monika Moissidis, Martijn Selten

et al.

Neuron, Journal Year: 2024, Volume and Issue: 112(12), P. 2015 - 2030.e5

Published: April 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.

Language: Английский

Citations

19
PTEN mutations impair CSF dynamics and cortical networks by dysregulating periventricular neural progenitors DOI
Tyrone DeSpenza,

Emre Kiziltug,

Garrett Allington

et al.

Nature Neuroscience, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 24, 2025

Language: Английский

Citations

2
The role of the prefrontal cortex in social interactions of animal models and the implications for autism spectrum disorder DOI Creative Commons
Alok Nath Mohapatra, Shlomo Wagner

Frontiers in Psychiatry, Journal Year: 2023, Volume and Issue: 14

Published: June 20, 2023

Social interaction is a complex behavior which requires the individual to integrate various internal processes, such as social motivation, recognition, salience, reward, and emotional state, well external cues informing of others' behavior, state rank. This phenotype susceptible disruption in humans affected by neurodevelopmental psychiatric disorders, including autism spectrum disorder (ASD). Multiple pieces convergent evidence collected from studies rodents suggest that prefrontal cortex (PFC) plays pivotal role interactions, serving hub for affiliation, empathy, hierarchy. Indeed, PFC circuitry results deficits symptomatic ASD. Here, we review this describe ethologically relevant tasks could be employed with rodent models study interactions. We also discuss linking pathologies associated Finally, address specific questions regarding mechanisms may result atypical interactions models, future should address.

Language: Английский

Citations

30
Improvement of sensory deficits in fragile X mice by increasing cortical interneuron activity after the critical period DOI Creative Commons
Nazim Kourdougli, Anand Suresh, Benjamin Liu

et al.

Neuron, Journal Year: 2023, Volume and Issue: 111(18), P. 2863 - 2880.e6

Published: July 13, 2023

Changes in the function of inhibitory interneurons (INs) during cortical development could contribute to pathophysiology neurodevelopmental disorders. Using all-optical vivo approaches, we find that parvalbumin (PV) INs and their immature precursors are hypoactive transiently decoupled from excitatory neurons postnatal mouse somatosensory cortex (S1) Fmr1 KO mice, a model fragile X syndrome (FXS). This leads loss (PV-INs) both mice humans with FXS. Increasing activity future PV-INs neonatal restores PV-IN density ameliorates transcriptional dysregulation S1, but not circuit dysfunction. Critically, administering an allosteric modulator Kv3.1 channels after S1 critical period does rescue dynamics tactile defensiveness. Symptoms FXS related disorders be mitigated by targeting PV-INs.

Language: Английский

Citations

30
VIP interneuron impairment promotes in vivo circuit dysfunction and autism-related behaviors in Dravet syndrome DOI Creative Commons
Kevin M. Goff, Sophie R Liebergall,

Evan Jiang

et al.

Cell Reports, Journal Year: 2023, Volume and Issue: 42(6), P. 112628 - 112628

Published: June 1, 2023

Dravet syndrome (DS) is a severe neurodevelopmental disorder caused by loss-of-function variants in SCN1A, which encodes the voltage-gated sodium channel subunit Nav1.1. We recently showed that neocortical vasoactive intestinal peptide interneurons (VIP-INs) express Nav1.1 and are hypoexcitable DS (Scn1a+/−) mice. Here, we investigate VIP-IN function at circuit behavioral level performing vivo 2-photon calcium imaging awake wild-type (WT) Scn1a+/− pyramidal neuron activation during transition from quiet wakefulness to active running diminished mice, optogenetic of VIP-INs restores activity WT levels locomotion. selective Scn1a deletion reproduces core autism-spectrum-disorder-related behaviors addition cellular- circuit-level deficits function, but without epilepsy, sudden death, or avoidance seen global model. Hence, impaired vivo, may underlie non-seizure cognitive comorbidities DS.

Language: Английский

Citations

25
Network state transitions during cortical development DOI
M. Wu, Nazim Kourdougli, Carlos Portera‐Cailliau

et al.

Nature reviews. Neuroscience, Journal Year: 2024, Volume and Issue: 25(8), P. 535 - 552

Published: May 23, 2024

Language: Английский

Citations

14
Group 2 innate lymphoid cells promote inhibitory synapse development and social behavior DOI
Jerika J. Barron, Nicholas M. Mroz, Sunrae E. Taloma

et al.

Science, Journal Year: 2024, Volume and Issue: 386(6721)

Published: Oct. 31, 2024

The innate immune system shapes brain development and is implicated in neurodevelopmental diseases. It critical to define the relevant cells signals their impact on circuits. In this work, we found that group 2 lymphoid (ILC2s) cytokine interleukin-13 (IL-13) signaled directly inhibitory interneurons increase synapse density developing mouse brain. ILC2s expanded produced IL-13 meninges. Loss of or signaling decreased inhibitory, but not excitatory, cortical synapses. Conversely, were sufficient pathway led selective impairments social interaction. These data a type neuroimmune circuit early life behavior.

Language: Английский

Citations

10
Mediodorsal thalamus regulates task uncertainty to enable cognitive flexibility DOI Creative Commons
Xiaohan Zhang, Arghya Mukherjee, Michael M. Halassa

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: March 18, 2025

The mediodorsal (MD) thalamus is a critical partner for the prefrontal cortex (PFC) in cognitive control. Accumulating evidence has shown that MD regulates task uncertainty decision making and enhance flexibility. However, computational mechanism of this process remains unclear. Here we trained biologically-constrained models to delineate mechanistic role context-dependent making. We show addition feedforward structure recurrent PFC increases robustness low cueing signal-to-noise ratio, enhances working memory, enables rapid context switching. Incorporating genetically identified thalamocortical connectivity interneuron cell types into model replicates key neurophysiological findings task-performing animals. Our reveals mechanisms geometric interpretations regulating cue switching enable makes experimentally testable predictions linking deficits with disrupted connectivity, excitation-inhibition imbalance dysfunctional inhibitory types. by which activity flexibility not fully understood. authors build incorporating Together experimental testing, circuit

Language: Английский

Citations

1
Convergent depression of activity-dependent bulk endocytosis in rodent models of autism spectrum disorder DOI Creative Commons
Katherine Bonnycastle,

Mehwish Nawaz,

Peter C. Kind

et al.

Molecular Autism, Journal Year: 2025, Volume and Issue: 16(1)

Published: April 16, 2025

Abstract Background The key pathological mechanisms underlying autism spectrum disorder (ASD) remain relatively undetermined, potentially due to the heterogenous nature of condition. Targeted studies a series monogenic ASDs have revealed postsynaptic dysfunction as central conserved mechanism. Presynaptic is emerging an additional disease locus in neurodevelopmental disorders; however, it unclear whether this drives ASD or adaptation altered brain microenvironment. Methods To differentiate between these two competing scenarios, we performed high content analysis stages synaptic vesicle lifecycle primary neuronal cultures derived from preclinical rat models ASD. These five independent ( Nrxn1 +/− , Nlgn3 − /y Syngap +/Δ−GAP Pten ) were specifically selected perturbations diverse palette genes that expressed either at pre- post-synapse. Synaptic exocytosis and cargo trafficking triggered via discrete trains activity monitored using genetically-encoded reporter synaptophysin-pHluorin. Activity-dependent bulk endocytosis was assessed during intense fluid phase marker tetramethylrhodamine-dextran. Results Both fusion events unaffected all investigated under stimulation protocols. However, convergent phenotype across neurons revealed, depression activity-dependent endocytosis. Limitations study exclusively conducted hippocampal neurons; therefore, impact on other regions microcircuitry not assessed. No molecular mechanism has been identified for depression. Conclusion This suggests presynaptic homeostatic correct intrinsic neurons.

Language: Английский

Citations

1