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1.
EMBO J ; 41(4): e106523, 2022 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-34935159

RESUMO

Excitatory synapses of principal hippocampal neurons are frequently located on dendritic spines. The dynamic strengthening or weakening of individual inputs results in structural and molecular diversity of dendritic spines. Active spines with large calcium ion (Ca2+ ) transients are frequently invaded by a single protrusion from the endoplasmic reticulum (ER), which is dynamically transported into spines via the actin-based motor myosin V. An increase in synaptic strength correlates with stable anchoring of the ER, followed by the formation of an organelle referred to as the spine apparatus. Here, we show that myosin V binds the Ca2+ sensor caldendrin, a brain-specific homolog of the well-known myosin V interactor calmodulin. While calmodulin is an essential activator of myosin V motor function, we found that caldendrin acts as an inhibitor of processive myosin V movement. In mouse and rat hippocampal neurons, caldendrin regulates spine apparatus localization to a subset of dendritic spines through a myosin V-dependent pathway. We propose that caldendrin transforms myosin into a stationary F-actin tether that enables the localization of ER tubules and formation of the spine apparatus in dendritic spines.


Assuntos
Proteínas de Ligação ao Cálcio/metabolismo , Espinhas Dendríticas/metabolismo , Retículo Endoplasmático/metabolismo , Miosina Tipo V/metabolismo , Actinas/metabolismo , Animais , Proteínas de Ligação ao Cálcio/genética , Calmodulina/metabolismo , Retículo Endoplasmático Liso/metabolismo , Células HEK293 , Hipocampo/citologia , Hipocampo/metabolismo , Humanos , Espectrometria de Massas , Camundongos Knockout , Miosina Tipo V/genética , Domínios e Motivos de Interação entre Proteínas , Ratos Wistar
2.
J Neurosci ; 39(41): 8149-8163, 2019 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-31488612

RESUMO

Arc/Arg3.1, an activity regulated immediate early gene, is essential for learning and memory, synaptic plasticity, and maturation of neural networks. It has also been implicated in several neurodevelopmental disorders, including schizophrenia. Here, we used male and female constitutive and conditional Arc/Arg3.1 knock-out (KO) mice to investigate the causal relationship between Arc/Arg3.1 deletion and schizophrenia-linked neurophysiological and behavioral phenotypes. Using in vivo local field potential recordings, we observed dampened oscillatory activity in the prefrontal cortex (PFC) of the KO and early conditional KO (early-cKO) mice, in which Arc/Arg3.1 was deleted perinatally. Whole-cell patch-clamp recordings from neurons in PFC slices revealed altered synaptic properties and reduced network gain in the KO mice as possible mechanisms underlying the oscillation deficits. In contrast, we measured normal oscillatory activity in the PFC of late conditional KO (late-cKO) mice, in which Arc/Arg3.1 was deleted during late postnatal development. Our data show that constitutive Arc/Arg3.1 KO mice exhibit no deficit in social engagement, working memory, sensorimotor gating, native locomotor activity, and dopaminergic innervation. Moreover, adolescent social isolation, an environmental stressor, failed to induce deficits in sociability or sensorimotor gating in adult KO mice. Thus, genetic removal of Arc/Arg3.1 per se does not cause schizophrenia-like behavior. Prenatal or perinatal deletion of Arc/Arg3.1 alters cortical network activity, however, without overtly disrupting the balance of excitation and inhibition in the brain and not promoting schizophrenia. Misregulation of Arc/Arg3.1 rather than deletion could potentially tip this balance and thereby promote emergence of schizophrenia and other neuropsychiatric disorders.SIGNIFICANCE STATEMENT The activity-regulated and memory-linked gene Arc/Arg3.1 has been implicated in the pathogenesis of schizophrenia, but direct evidence and a mechanistic link are still missing. The current study asks whether loss of Arc/Arg3.1 can affect brain circuitry and cause schizophrenia-like symptoms in mice. The findings demonstrate that genetic deletion of Arc/Arg3.1 before puberty alters synaptic function and prefrontal cortex activity. Although brain networks are disturbed, genetic deletion of Arc/Arg3.1 does not cause schizophrenia-like behavior, even when combined with an environmental insult. It remains to be seen whether misregulation of Arc/Arg3.1 might critically imbalance brain networks and lead to emergence of schizophrenia.


Assuntos
Proteínas do Citoesqueleto/genética , Proteínas do Tecido Nervoso/genética , Córtex Pré-Frontal/fisiopatologia , Psicologia do Esquizofrênico , Animais , Proteínas do Citoesqueleto/deficiência , Neurônios Dopaminérgicos , Eletroencefalografia/efeitos dos fármacos , Potenciais Evocados , Potenciais Pós-Sinápticos Excitadores , Feminino , Masculino , Memória de Curto Prazo/efeitos dos fármacos , Camundongos , Camundongos Knockout , Atividade Motora/efeitos dos fármacos , Proteínas do Tecido Nervoso/deficiência , Neurônios , Técnicas de Patch-Clamp , Reflexo de Sobressalto/efeitos dos fármacos , Convulsões/induzido quimicamente , Convulsões/genética , Filtro Sensorial , Comportamento Social
3.
Proc Natl Acad Sci U S A ; 115(49): 12531-12536, 2018 12 04.
Artigo em Inglês | MEDLINE | ID: mdl-30442670

RESUMO

During early postnatal development, sensory regions of the brain undergo periods of heightened plasticity which sculpt neural networks and lay the foundation for adult sensory perception. Such critical periods were also postulated for learning and memory but remain elusive and poorly understood. Here, we present evidence that the activity-regulated and memory-linked gene Arc/Arg3.1 is transiently up-regulated in the hippocampus during the first postnatal month. Conditional removal of Arc/Arg3.1 during this period permanently alters hippocampal oscillations and diminishes spatial learning capacity throughout adulthood. In contrast, post developmental removal of Arc/Arg3.1 leaves learning and network activity patterns intact. Long-term memory storage continues to rely on Arc/Arg3.1 expression throughout life. These results demonstrate that Arc/Arg3.1 mediates a critical period for spatial learning, during which Arc/Arg3.1 fosters maturation of hippocampal network activity necessary for future learning and memory storage.


Assuntos
Proteínas do Citoesqueleto/metabolismo , Hipocampo/fisiologia , Memória de Longo Prazo/fisiologia , Proteínas do Tecido Nervoso/metabolismo , Aprendizagem Espacial/fisiologia , Animais , Comportamento Animal , Inibidor de Quinase Dependente de Ciclina p21/genética , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Proteínas do Citoesqueleto/genética , Deleção de Genes , Regulação da Expressão Gênica/fisiologia , Camundongos , Proteínas do Tecido Nervoso/genética , Plasticidade Neuronal , Neurônios/fisiologia
4.
Exp Neurol ; 295: 88-103, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28576568

RESUMO

The consumption of psychoactive drugs during pregnancy can have deleterious effects on newborns. It remains unclear whether early-life exposure to caffeine, the most widely consumed psychoactive substance, alters brain development. We hypothesized that maternal caffeine ingestion during pregnancy and the early postnatal period in mice affects the construction and activity of cortical networks in offspring. To test this hypothesis, we focused on primary visual cortex (V1) as a model neocortical region. In a study design mimicking the daily consumption of approximately three cups of coffee during pregnancy in humans, caffeine was added to the drinking water of female mice and their offspring were compared to control offspring. Caffeine altered the construction of GABAergic neuronal networks in V1, as reflected by a reduced number of somatostatin-containing GABA neurons at postnatal days 6-7, with the remaining ones showing poorly developed dendritic arbors. These findings were accompanied by increased synaptic activity in vitro and elevated network activity in vivo in V1. Similarly, in vivo hippocampal network activity was altered from the neonatal period until adulthood. Finally, caffeine-exposed offspring showed increased seizure susceptibility in a hyperthermia-induced seizure model. In summary, our results indicate detrimental effects of developmental caffeine exposure on mouse brain development.


Assuntos
Cafeína/toxicidade , Estimulantes do Sistema Nervoso Central/toxicidade , Córtex Cerebral/crescimento & desenvolvimento , Rede Nervosa/crescimento & desenvolvimento , Animais , Animais Recém-Nascidos , Córtex Cerebral/efeitos dos fármacos , Dendritos/efeitos dos fármacos , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Feminino , Técnicas In Vitro , Masculino , Camundongos , Neocórtex/efeitos dos fármacos , Neocórtex/crescimento & desenvolvimento , Rede Nervosa/efeitos dos fármacos , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Convulsões Febris/induzido quimicamente , Convulsões Febris/fisiopatologia , Somatostatina/metabolismo , Córtex Visual/efeitos dos fármacos , Córtex Visual/crescimento & desenvolvimento , Ácido gama-Aminobutírico/fisiologia
5.
J Neurosci ; 33(32): 12915-28, 12928a, 2013 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-23926248

RESUMO

The metalloproteinase ADAM10 is of importance for Notch-dependent cortical brain development. The protease is tightly linked with α-secretase activity toward the amyloid precursor protein (APP) substrate. Increasing ADAM10 activity is suggested as a therapy to prevent the production of the neurotoxic amyloid ß (Aß) peptide in Alzheimer's disease. To investigate the function of ADAM10 in postnatal brain, we generated Adam10 conditional knock-out (A10cKO) mice using a CaMKIIα-Cre deleter strain. The lack of ADAM10 protein expression was evident in the brain cortex leading to a reduced generation of sAPPα and increased levels of sAPPß and endogenous Aß peptides. The A10cKO mice are characterized by weight loss and increased mortality after weaning associated with seizures. Behavioral comparison of adult mice revealed that the loss of ADAM10 in the A10cKO mice resulted in decreased neuromotor abilities and reduced learning performance, which were associated with altered in vivo network activities in the hippocampal CA1 region and impaired synaptic function. Histological and ultrastructural analysis of ADAM10-depleted brain revealed astrogliosis, microglia activation, and impaired number and altered morphology of postsynaptic spine structures. A defect in spine morphology was further supported by a reduction of the expression of NMDA receptors subunit 2A and 2B. The reduced shedding of essential postsynaptic cell adhesion proteins such as N-Cadherin, Nectin-1, and APP may explain the postsynaptic defects and the impaired learning, altered network activity, and synaptic plasticity of the A10cKO mice. Our study reveals that ADAM10 is instrumental for synaptic and neuronal network function in the adult murine brain.


Assuntos
Proteínas ADAM/deficiência , Secretases da Proteína Precursora do Amiloide/deficiência , Encéfalo/ultraestrutura , Espinhas Dendríticas/patologia , Epilepsia/genética , Epilepsia/patologia , Deficiências da Aprendizagem/patologia , Proteínas de Membrana/deficiência , Sinapses/patologia , Proteína ADAM10 , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Animais Recém-Nascidos , Encéfalo/patologia , Caderinas/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Moléculas de Adesão Celular/metabolismo , Espinhas Dendríticas/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica no Desenvolvimento/genética , Gliose/genética , Deficiências da Aprendizagem/genética , Camundongos , Camundongos Transgênicos , Nectinas , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapses/metabolismo , Sinapses/ultraestrutura
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