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1.
Nat Neurosci ; 23(4): 533-543, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32203497

RESUMO

Learning disabilities are hallmarks of congenital conditions caused by prenatal exposure to harmful agents. These include fetal alcohol spectrum disorders (FASDs) with a wide range of cognitive deficiencies, including impaired motor skill development. Although these effects have been well characterized, the molecular effects that bring about these behavioral consequences remain to be determined. We previously found that the acute molecular responses to alcohol in the embryonic brain are stochastic, varying among neural progenitor cells. However, the pathophysiological consequences stemming from these heterogeneous responses remain unknown. Here we show that acute responses to alcohol in progenitor cells altered gene expression in their descendant neurons. Among the altered genes, an increase of the calcium-activated potassium channel Kcnn2 in the motor cortex correlated with motor learning deficits in a mouse model of FASD. Pharmacologic blockade of Kcnn2 improves these learning deficits, suggesting Kcnn2 blockers as a new intervention for learning disabilities in FASD.


Assuntos
Comportamento Animal/efeitos dos fármacos , Transtornos do Espectro Alcoólico Fetal/tratamento farmacológico , Deficiências da Aprendizagem/tratamento farmacológico , Aprendizagem/efeitos dos fármacos , Córtex Motor/efeitos dos fármacos , Venenos de Escorpião/farmacologia , Canais de Potássio Ativados por Cálcio de Condutância Baixa/antagonistas & inibidores , Animais , Forma Celular/efeitos dos fármacos , Dendritos/efeitos dos fármacos , Dendritos/metabolismo , Modelos Animais de Doenças , Deficiências da Aprendizagem/metabolismo , Camundongos , Atividade Motora/efeitos dos fármacos , Córtex Motor/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Venenos de Escorpião/uso terapêutico , Canais de Potássio Ativados por Cálcio de Condutância Baixa/metabolismo
2.
ACS Chem Neurosci ; 8(5): 1019-1025, 2017 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-28076682

RESUMO

Fetal exposure to selective serotonin reuptake inhibitors (SSRI) has been associated with increased risk of adverse neurodevelopmental outcomes. In the adult brain, SSRI therapy regulates p11 (s100a10) expression and alters neurogenesis. The protein p11 indirectly regulates 5-HT signaling through 5-HT1B/D receptors. In the fetal brain, signaling through these receptors modulates axonal circuit formation. We determined whether p11 is expressed in the fetal mouse brain, and whether maternal SSRI exposure affects fetal p11 expression and neurogenesis. The SSRI ± citalopram was administered to pregnant mice from gestational day 8 to 17. Results show that p11 is expressed in fetal thalamic neurons and thalamocortical axons. Furthermore, p11 protein expression is significantly decreased in the fetal thalamus after in utero ±citalopram exposure compared to untreated controls, and neurogenesis is significantly decreased in specific fetal brain regions. These findings reveal differential regulation of p11 expression and altered neurogenesis in the fetal brain as a result of maternal SSRI exposure.


Assuntos
Citalopram/farmacologia , Neurogênese/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Tálamo/efeitos dos fármacos , Animais , Axônios/efeitos dos fármacos , Feminino , Exposição Materna , Camundongos , Gravidez
3.
J Comp Neurol ; 524(10): 2080-92, 2016 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-26587807

RESUMO

Deciphering the molecular basis for guiding specific aspects of neocortical development remains a challenge because of the complexity of histogenic events and the vast array of protein interactions mediating these events. The Eph family of receptor tyrosine kinases is implicated in a number of neurodevelopmental activities. Eph receptors have been known to be capable of responding to several ephrin ligands within their subgroups, often eliciting similar downstream effects. However, several recent studies have indicated specificity between receptor-ligand pairs within each subfamily, the functional relevance of which is not defined. Here we show that a receptor of the EphA subfamily, EphA4, has effects distinct from those of its close relative, EphA7, in the developing brain. Both EphA4 and EphA7 interact similarly with corresponding ligands expressed in the developing neocortex. However, only EphA7 shows strong interaction with ligands in the somatosensory thalamic nuclei; EphA4 affects only cortical neuronal migration, with no visible effects on the guidance of corticothalamic (CT) axons, whereas EphA7 affects both cortical neuronal migration and CT axon guidance. Our data provide new evidence that Eph receptors in the same subfamily are not simply interchangeable but are functionally specified through selective interactions with distinct ligands in vivo. J. Comp. Neurol. 524:2080-2092, 2016. © 2015 Wiley Periodicals, Inc.


Assuntos
Córtex Cerebral , Vias Neurais/fisiologia , Receptor EphA4/metabolismo , Receptor EphA7/metabolismo , Tálamo , Animais , Animais Recém-Nascidos , Córtex Cerebral/citologia , Córtex Cerebral/embriologia , Córtex Cerebral/crescimento & desenvolvimento , Córtex Cerebral/metabolismo , Embrião de Mamíferos , Regulação da Expressão Gênica no Desenvolvimento/genética , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Camundongos , Camundongos Transgênicos , Neurônios/metabolismo , Receptor EphA4/genética , Receptor EphA7/genética , Tálamo/citologia , Tálamo/embriologia , Tálamo/crescimento & desenvolvimento , Tálamo/metabolismo
4.
Cereb Cortex ; 23(4): 775-85, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22490549

RESUMO

Auditory stimulus representations are dynamically maintained by ascending and descending projections linking the auditory cortex (Actx), medial geniculate body (MGB), and inferior colliculus. Although the extent and topographic specificity of descending auditory corticofugal projections can equal or surpass that of ascending corticopetal projections, little is known about the molecular mechanisms that guide their development. Here, we used in utero gene electroporation to examine the role of EphA receptor signaling in the development of corticothalamic (CT) and corticocollicular connections. Early in postnatal development, CT axons were restricted to a deep dorsal zone (DDZ) within the MGB that expressed low levels of the ephrin-A ligand. By hearing onset, CT axons had innervated surrounding regions of MGB in control-electroporated mice but remained fixed within the DDZ in mice overexpressing EphA7. In vivo neurophysiological recordings demonstrated a corresponding reduction in spontaneous firing rate, but no changes in sound-evoked responsiveness within MGB regions deprived of CT innervation. Structural and functional CT disruption occurred without gross alterations in thalamocortical connectivity. These data demonstrate a potential role for EphA/ephrin-A signaling in the initial guidance of corticofugal axons and suggest that "genetic rewiring" may represent a useful functional tool to alter cortical feedback without silencing Actx.


Assuntos
Córtex Auditivo , Vias Auditivas/fisiologia , Mapeamento Encefálico , Corpos Geniculados/fisiologia , Receptor EphA7/metabolismo , Transdução de Sinais/fisiologia , Estimulação Acústica , Fatores Etários , Aminoácidos , Animais , Animais Recém-Nascidos , Córtex Auditivo/embriologia , Córtex Auditivo/crescimento & desenvolvimento , Córtex Auditivo/metabolismo , Axônios/fisiologia , Eletroencefalografia , Eletroporação , Embrião de Mamíferos , Potenciais Evocados Auditivos/genética , Feminino , Regulação da Expressão Gênica no Desenvolvimento/genética , Proteínas de Fluorescência Verde/genética , Masculino , Camundongos , Camundongos Transgênicos , RNA Mensageiro/metabolismo , Receptor EphA7/genética , Proteína Vesicular 1 de Transporte de Glutamato/metabolismo
5.
J Comp Neurol ; 521(3): 626-37, 2013 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-22821544

RESUMO

Corticothalamic (CT) feedback outnumbers thalamocortical projections and regulates sensory information processing at the level of the thalamus. It is well established that EphA7, a member of EphA receptor family, is involved in the topographic mapping of CT projections. The aim of the present study was to dissect the precise impact of EphA7 on each step of CT growth. We used in utero electroporation-mediated EphA7 overexpression in developing somatosensory CT axons to dissect EphA7/ephrin-A-dependent mechanisms involved in regulating both initial targeting and postnatal growth of the CT projections. Our data revealed that topographic maps of cortical afferents in the ventrobasal complex and medial part of the posterior complex in the thalamus become discernible shortly after birth and are fully established by the second postnatal week. This process starts with the direct ingrowth of the CT axons to the designated areas within target thalamic nuclei and by progressive increase of axonal processes in the terminal zones. Large-scale overproduction and elimination of exuberant widespread axonal branches outside the target zone was not observed. Each developmental event was coordinated by spatially and temporally different responsiveness of CT axons to the ephrin-A gradient in thalamic nuclei, as well as by the matching levels of EphA7 in CT axons and ephrin-As in thalamic nuclei. These results support the concept that the topographic connections between the maps in the cerebral cortex and corresponding thalamic nuclei are genetically prespecified to a large extent, and established by precise spatiotemporal molecular mechanisms that involve the Eph family of genes.


Assuntos
Efrina-A1/metabolismo , Receptor EphA7/metabolismo , Transdução de Sinais/fisiologia , Córtex Somatossensorial/embriologia , Tálamo/embriologia , Vias Aferentes/citologia , Vias Aferentes/embriologia , Vias Aferentes/metabolismo , Animais , Axônios/metabolismo , Mapeamento Encefálico , Feminino , Camundongos , Camundongos Endogâmicos , Gravidez , Córtex Somatossensorial/citologia , Córtex Somatossensorial/metabolismo , Tálamo/citologia , Tálamo/metabolismo
6.
Nat Neurosci ; 10(5): 588-97, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17450135

RESUMO

Modifying serotonin (5-HT) abundance in the embryonic mouse brain disrupts the precision of sensory maps formed by thalamocortical axons (TCAs), suggesting that 5-HT influences their growth. We investigated the mechanism by which 5-HT influences TCAs during development. 5-HT(1B) and 5-HT(1D) receptor expression in the fetal forebrain overlaps with that of the axon guidance receptors DCC and Unc5c. In coculture assays, axons originating from anterior and posterior halves of the embryonic day 14.5 dorsal thalamus responded differently to netrin-1, reflecting the patterns of DCC and Unc5c expression. 5-HT converts the attraction exerted by netrin-1 on posterior TCAs to repulsion. Pharmacological manipulation of 5-HT(1B/1D) receptors and intracellular cAMP showed the signaling cascade through which this modulation occurs. An in vivo correlate of altered TCA pathfinding was obtained by transient manipulation of 5-HT(1B/1D) receptor expression abundance in the dorsal thalamus by in utero electroporation. These data demonstrate that serotonergic signaling has a previously unrecognized role in the modulation of axonal responsiveness to a classic guidance cue.


Assuntos
Axônios/metabolismo , Córtex Cerebral , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Fatores de Crescimento Neural/metabolismo , Serotonina/metabolismo , Tálamo , Proteínas Supressoras de Tumor/metabolismo , Vias Aferentes/citologia , Vias Aferentes/embriologia , Fatores Etários , Animais , Linhagem Celular Transformada , Córtex Cerebral/citologia , Córtex Cerebral/embriologia , Córtex Cerebral/metabolismo , Eletroporação/métodos , Embrião de Mamíferos , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Humanos , Hibridização In Situ/métodos , Técnicas In Vitro , Proteínas Luminescentes/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Netrina-1 , Gravidez , RNA Interferente Pequeno/farmacologia , Receptores de Serotonina/genética , Receptores de Serotonina/metabolismo , Tálamo/citologia , Tálamo/embriologia , Tálamo/metabolismo
7.
Neuron ; 48(4): 563-75, 2005 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-16301174

RESUMO

Molecular mechanisms generating the topographic organization of corticothalamic (CT) circuits, which comprise more than three-quarters of the synaptic inputs onto sensory relay neurons, and their interdependence with thalamocortical (TC) axon development are unknown. Using in utero electroporation-mediated gene transfer, we show that EphA7-mediated signaling on neocortical axons controls the within-nucleus topography of CT projections in the thalamus. Notably, CT axons that mis-express EphA7 do not shift the relative positioning of their pathway within the subcortical telencephalon (ST), indicating that they do not depend upon EphA7/ephrin-A signaling in the ST for establishing this topography. Moreover, mis-expression of cortical EphA7 results in disrupted topography of CT projections, but unchanged inter- and intra-areal topography of TC projections. Our results support a model in which EphA/ephrin-A signaling controls independently the precision with which CT and TC projections develop, yet is essential for establishing their topographic reciprocity.


Assuntos
Axônios/fisiologia , Córtex Cerebral/fisiologia , Receptor EphA7/fisiologia , Tálamo/fisiologia , Animais , Axônios/metabolismo , Mapeamento Encefálico , Córtex Cerebral/metabolismo , Camundongos , Camundongos Endogâmicos , Neocórtex/anatomia & histologia , Neocórtex/metabolismo , Vias Neurais/fisiologia , Receptor EphA5/metabolismo , Receptor EphA7/metabolismo , Transmissão Sináptica/fisiologia , Telencéfalo/fisiologia , Tálamo/metabolismo
8.
J Neurobiol ; 59(1): 82-94, 2004 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15007829

RESUMO

The functional architecture of the cerebral cortex is based on intrinsic connections that precisely link neurons from distinct cortical laminae as well as layer-specific afferent and efferent projections. Experimental strategies using in vitro assays originally developed by Friedrich Bonhoeffer have suggested that positional cues confined to individual layers regulate the assembly of local cortical circuits and the formation of thalamocortical projections. One of these wiring molecules is ephrinA5, a ligand for Eph receptor tyrosine kinases. EphrinA5 and Eph receptors exhibit highly dynamic expression patterns in distinct regions of the cortex and thalamus during early and late stages of thalamocortical and cortical circuit formation. In vitro assays suggest that ephrinA5 is a multifunctional wiring molecule for different populations of cortical and thalamic axons. Additionally, the expression patterns of ephrinA5 during cortical development are consistent with this molecule regulating, in alternative ways, specific components of thalamic and cortical connectivity. To test this directly, the organization of thalamocortical projections was examined in mice lacking ephrinA5 gene expression. The anatomical studies in ephrinA5 knockout animals revealed a miswiring of limbic thalamic projections and changes in neocortical circuits that were predicted from the expression pattern and the in vitro analysis of ephrinA5 function.


Assuntos
Córtex Cerebral/fisiologia , Efrina-A5/fisiologia , Vias Neurais/fisiologia , Receptor EphA1/fisiologia , Tálamo/fisiologia , Animais , Axônios/fisiologia , Córtex Cerebral/citologia , Embrião de Mamíferos , Embrião não Mamífero , Técnicas In Vitro , Vias Neurais/citologia , Neurônios/fisiologia , Tálamo/citologia
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