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1.
Hum Mol Genet ; 2024 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-39146503

RESUMO

CD2-Associated protein (CD2AP) is a candidate susceptibility gene for Alzheimer's disease, but its role in the mammalian central nervous system remains largely unknown. We show that CD2AP protein is broadly expressed in the adult mouse brain, including within cortical and hippocampal neurons, where it is detected at pre-synaptic terminals. Deletion of Cd2ap altered dendritic branching and spine density, and impaired ubiquitin-proteasome system activity. Moreover, in mice harboring either one or two copies of a germline Cd2ap null allele, we noted increased paired-pulse facilitation at hippocampal Schaffer-collateral synapses, consistent with a haploinsufficient requirement for pre-synaptic release. Whereas conditional Cd2ap knockout in the brain revealed no gross behavioral deficits in either 3.5- or 12-month-old mice, Cd2ap heterozygous mice demonstrated subtle impairments in discrimination learning using a touchscreen task. Based on unbiased proteomics, partial or complete loss of Cd2ap triggered perturbation of proteins with roles in protein folding, lipid metabolism, proteostasis, and synaptic function. Overall, our results reveal conserved, dose-sensitive requirements for CD2AP in the maintenance of neuronal structure and function, including synaptic homeostasis and plasticity, and inform our understanding of possible cell-type specific mechanisms in Alzheimer's Disease.

2.
Cells ; 11(23)2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36497147

RESUMO

Tremor is the most common movement disorder. Several drugs reduce tremor severity, but no cures are available. Propranolol, a ß-adrenergic receptor blocker, is the leading treatment for tremor. However, the in vivo circuit mechanisms by which propranolol decreases tremor remain unclear. Here, we test whether propranolol modulates activity in the cerebellum, a key node in the tremor network. We investigated the effects of propranolol in healthy control mice and Car8wdl/wdl mice, which exhibit pathophysiological tremor and ataxia due to cerebellar dysfunction. Propranolol reduced physiological tremor in control mice and reduced pathophysiological tremor in Car8wdl/wdl mice to control levels. Open field and footprinting assays showed that propranolol did not correct ataxia in Car8wdl/wdl mice. In vivo recordings in awake mice revealed that propranolol modulates the spiking activity of control and Car8wdl/wdl Purkinje cells. Recordings in cerebellar nuclei neurons, the targets of Purkinje cells, also revealed altered activity in propranolol-treated control and Car8wdl/wdl mice. Next, we tested whether propranolol reduces tremor through ß1 and ß2 adrenergic receptors. Propranolol did not change tremor amplitude or cerebellar nuclei activity in ß1 and ß2 null mice or Car8wdl/wdl mice lacking ß1 and ß2 receptor function. These data show that propranolol can modulate cerebellar circuit activity through ß-adrenergic receptors and may contribute to tremor therapeutics.


Assuntos
Cerebelo , Propranolol , Camundongos , Animais , Propranolol/farmacologia , Cerebelo/metabolismo , Células de Purkinje , Ataxia , Neurônios/metabolismo , Antagonistas Adrenérgicos beta/farmacologia , Camundongos Knockout , Proteínas do Tecido Nervoso/metabolismo , Biomarcadores Tumorais
3.
Neuro Oncol ; 20(5): 655-665, 2018 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-29112734

RESUMO

Background: Memantine has shown clinical utility in preventing radiation-induced cognitive impairment, but the mechanisms underlying its protective effects remain unknown. We hypothesized that abnormal glutamate signaling causes radiation-induced abnormalities in neuronal structure and that memantine prevents synaptic toxicity. Methods: Hippocampal cultures expressing enhanced green fluorescent protein were irradiated or sham-treated and their dendritic spine morphology assessed at acute (minutes) and later (days) times using high-resolution confocal microscopy. Excitatory synapses, defined by co-localization of the pre- and postsynaptic markers vesicular glutamate transporter 1 and postsynaptic density protein 95, were also analyzed. Neurons were pretreated with vehicle, the N-methyl-d-aspartate-type glutamate receptor antagonist memantine, or the glutamate scavenger glutamate pyruvate transaminase to assess glutamate signaling. For animal studies, Thy-1-YFP mice were treated with whole-brain radiotherapy or sham with or without memantine. Results: Unlike previously reported long-term losses of dendritic spines, we found that the acute response to radiation is an initial increase in spines and excitatory synapses followed by a decrease in spine/synapse density with altered spine dynamics. Memantine pre-administration prevented this radiation-induced synaptic remodeling. Conclusion: These results demonstrate that radiation causes rapid, dynamic changes in synaptic structural plasticity, implicate abnormal glutamate signaling in cognitive dysfunction following brain irradiation, and describe a protective mechanism of memantine.


Assuntos
Anormalidades Induzidas por Radiação/prevenção & controle , Espinhas Dendríticas/efeitos dos fármacos , Raios gama/efeitos adversos , Hipocampo/efeitos dos fármacos , Memantina/farmacologia , Sinapses/efeitos dos fármacos , Anormalidades Induzidas por Radiação/etiologia , Anormalidades Induzidas por Radiação/patologia , Animais , Células Cultivadas , Espinhas Dendríticas/patologia , Espinhas Dendríticas/efeitos da radiação , Antagonistas de Aminoácidos Excitatórios/farmacologia , Hipocampo/patologia , Hipocampo/efeitos da radiação , Ratos , Ratos Long-Evans , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapses/patologia , Sinapses/efeitos da radiação
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