A critical period of neuronal activity results in aberrant neurogenesis rewiring hippocampal circuitry in a mouse model of epilepsy

AbstractIn the mammalian hippocampus, adult-born granule cells (abGCs) contribute to the function of the dentate gyrus (DG). Disruption of the DG circuitry causes spontaneous recurrent seizures (SRS), which can lead to epilepsy. Although abGCs contribute to local inhibitory feedback circuitry, whether they are involved in epileptogenesis remains elusive. Here, we identify a critical window of activity associated with the aberrant maturation of abGCs characterized by abnormal dendrite morphology, ectopic migration, and SRS. Importantly, in a mouse model of temporal lobe epilepsy, silencing aberrant abGCs during this critical period reduces abnormal dendrite morphology, cell migration, and SRS. Using mono-synaptic tracers, we show silencing aberrant abGCs decreases recurrent CA3 back-projections and restores proper cortical connections to the hippocampus. Furthermore, we show that GABA-mediated amplification of intracellular calcium regulates the early critical period of activity. Our results demonstrate that aberrant neurogenesis rewires hippocampal circuitry aggravating epilepsy in mice.

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Faculty Opinions recommendation of Delayed coupling to feedback inhibition during a critical period for the integration of adult-born granule cells.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.725287920.793567630 ◽

2019 ◽

Author(s):

Linda Overstreet-Wadiche ◽

Jose Gonzalez

Keyword(s):

Critical Period ◽

Granule Cells ◽

Feedback Inhibition ◽

Delayed Coupling

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Early changes in synaptic and intrinsic properties of dentate gyrus granule cells in a mouse model of Alzheimer's disease neuropathology and atypical effects of the cholinergic antagonist atropine

Neurobiology of Disease ◽

10.1016/j.nbd.2021.105274 ◽

2021 ◽

Vol 152 ◽

pp. 105274

Author(s):

David Alcantara-Gonzalez ◽

Elissavet Chartampila ◽

Chiara Criscuolo ◽

Helen E. Scharfman

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Dentate Gyrus ◽

Granule Cells ◽

Intrinsic Properties ◽

Cholinergic Antagonist ◽

Model Of Alzheimer’S Disease

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Role of Pax6 in development of the cerebellar system

Development ◽

10.1242/dev.126.16.3585 ◽

1999 ◽

Vol 126 (16) ◽

pp. 3585-3596 ◽

Cited By ~ 11

Author(s):

D. Engelkamp ◽

P. Rashbass ◽

A. Seawright ◽

V. van Heyningen

Keyword(s):

Cell Proliferation ◽

Cell Migration ◽

Granule Cell ◽

Granule Cells ◽

Cerebellar Granule Cells ◽

Long Distance ◽

Cerebellar Granule ◽

Precerebellar Nuclei ◽

Rhombic Lip

Post-mitotic neurons generated at the rhombic lip undertake long distance migration to widely dispersed destinations, giving rise to cerebellar granule cells and the precerebellar nuclei. Here we show that Pax6, a key regulator in CNS and eye development, is strongly expressed in rhombic lip and in cells migrating away from it. Development of some structures derived from these cells is severely affected in Pax6-null Small eye (Pax6(Sey)/Pax6(Sey)) embryos. Cell proliferation and initial differentiation seem unaffected, but cell migration and neurite extension are disrupted in mutant embryos. Three of the five precerebellar nuclei fail to form correctly. In the cerebellum the pre-migratory granule cell sub-layer and fissures are absent. Some granule cells are found in ectopic positions in the inferior colliculus which may result from the complete absence of Unc5h3 expression in Pax6(Sey)/Pax6(Sey) granule cells. Our results suggest that Pax6 plays a strong role during hindbrain migration processes and at least part of its activity is mediated through regulation of the netrin receptor Unc5h3.

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Early adolescent Rai1 reactivation reverses transcriptional and social interaction deficits in a mouse model of Smith–Magenis syndrome

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1806796115 ◽

2018 ◽

Vol 115 (42) ◽

pp. 10744-10749 ◽

Cited By ~ 9

Author(s):

Wei-Hsiang Huang ◽

David C. Wang ◽

William E. Allen ◽

Matthew Klope ◽

Hailan Hu ◽

...

Keyword(s):

Social Interaction ◽

Mouse Model ◽

Behavioral Problems ◽

Autism Spectrum ◽

Inhibitory Neurons ◽

Critical Window ◽

Genetic Mouse Model ◽

Expression Of Genes ◽

Syndromic Autism ◽

Level 3

Haploinsufficiency of Retinoic Acid Induced 1 (RAI1) causes Smith–Magenis syndrome (SMS), a syndromic autism spectrum disorder associated with craniofacial abnormalities, intellectual disability, and behavioral problems. There is currently no cure for SMS. Here, we generated a genetic mouse model to determine the reversibility of SMS-like neurobehavioral phenotypes in Rai1 heterozygous mice. We show that normalizing the Rai1 level 3–4 wk after birth corrected the expression of genes related to neural developmental pathways and fully reversed a social interaction deficit caused by Rai1 haploinsufficiency. In contrast, Rai1 reactivation 7–8 wk after birth was not beneficial. We also demonstrated that the correct Rai1 dose is required in both excitatory and inhibitory neurons for proper social interactions. Finally, we found that Rai1 heterozygous mice exhibited a reduction of dendritic spines in the medial prefrontal cortex (mPFC) and that optogenetic activation of mPFC neurons in adults improved the social interaction deficit of Rai1 heterozygous mice. Together, these results suggest the existence of a postnatal temporal window during which restoring Rai1 can improve the transcriptional and social behavioral deficits in a mouse model of SMS. It is possible that circuit-level interventions would be beneficial beyond this critical window.

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The chemokine SDF1 regulates migration of dentate granule cells

Development ◽

10.1242/dev.129.18.4249 ◽

2002 ◽

Vol 129 (18) ◽

pp. 4249-4260 ◽

Cited By ~ 6

Author(s):

Anil Bagri ◽

Theresa Gurney ◽

Xiaoping He ◽

Yong-Rui Zou ◽

Dan R. Littman ◽

...

Keyword(s):

Cell Migration ◽

Dentate Gyrus ◽

Granule Cell ◽

Granule Cells ◽

Ectopic Expression ◽

Dentate Granule Cell ◽

Vitro Assay ◽

Dentate Granule Cells ◽

Cell Position

The dentate gyrus is the primary afferent pathway into the hippocampus, but there is little information concerning the molecular influences that govern its formation. In particular, the control of migration and cell positioning of dentate granule cells is not clear. We have characterized more fully the timing and route of granule cell migration during embryogenesis using in utero retroviral injections. Using this information, we developed an in vitro assay that faithfully recapitulates important events in dentate gyrus morphogenesis. In searching for candidate ligands that may regulate dentate granule cell migration, we found that SDF1, a chemokine that regulates cerebellar and leukocyte migration, and its receptor CXCR4 are expressed in patterns that suggest a role in dentate granule cell migration. Furthermore, CXCR4 mutant mice have a defect in granule cell position. Ectopic expression of SDF1 in our explant assay showed that it directly regulates dentate granule cell migration. Our study shows that a chemokine is necessary for the normal development of the dentate gyrus, a forebrain structure crucial for learning and memory.

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Functioning of the rat circadian system is modified by light applied in critical postnatal days

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.2001.280.4.r1023 ◽

2001 ◽

Vol 280 (4) ◽

pp. R1023-R1030 ◽

Cited By ~ 28

Author(s):

M. M. Canal-Corretger ◽

J. Vilaplana ◽

T. Cambras ◽

A. Díez-Noguera

Keyword(s):

Light Pulse ◽

Critical Period ◽

Decisive Role ◽

Circadian System ◽

Constant Darkness ◽

Biological Clocks ◽

Critical Window ◽

Lighting Conditions ◽

Lactation Stage ◽

Circadian Organization

Lighting conditions influence biological clocks. The present experiment was designed to test the presence of a critical window of days during the lactation stage of the rat in which light has a decisive role on the development of the circadian system. Rats were exposed to 4, 8, or 12 days of constant light (LL) during the first days of life. Their circadian rhythm was later studied under LL and constant darkness. The response to a light pulse was also examined. Results show that the greater the number of LL days during lactation, the stronger the rhythm under LL and the smaller the phase shift due to the light pulse. These responses are enhanced when rats are exposed to LL days around postnatal day 12. A mathematical model was built to explain the responses of the circadian system with respect to the timing of LL during lactation, and we deduced that between postnatal days 10 to 20there is a critical period of sensitivity to light; consequently, exposure to LL during this time modifies the circadian organization of the motor activity.

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