Glutamate dehydrogenase deficiency disrupts glutamate homeostasis in hippocampus and prefrontal cortex and impairs recognition memory.
Genes Brain Behav
; 19(6): e12636, 2020 07.
Article
em En
| MEDLINE
| ID: mdl-31898404
ABSTRACT
Glutamate Dehydrogenase 1 (GDH), encoded by the Glud1 gene in rodents, is a mitochondrial enzyme critical for maintaining glutamate homeostasis at the tripartite synapse. Our previous studies indicate that the hippocampus may be particularly vulnerable to GDH deficiency in central nervous system (CNS). Here, we first asked whether mice with a homozygous deletion of Glud1 in CNS (CNS-Glud1 -/- mice) express different levels of glutamate in hippocampus, and found elevated glutamate as well as glutamine in dorsal and ventral hippocampus, and increased glutamine in medial prefrontal cortex (mPFC). l-serine and d-serine, which contribute to glutamate homeostasis and NMDA receptor function, are increased in ventral but not dorsal hippocampus, and in mPFC. Protein expression levels of the GABA synthesis enzyme glutamate decarboxylase (GAD) GAD67 were decreased in the ventral hippocampus as well. Behavioral analysis revealed deficits in visual, spatial and social novelty recognition abilities, which require intact hippocampal-prefrontal cortex circuitry. Finally, hippocampus-dependent contextual fear retrieval was deficient in CNS-Glud1 -/- mice, and c-Fos expression (indicative of neuronal activation) in the CA1 pyramidal layer was reduced immediately following this task. These data point to hippocampal subregion-dependent disruption in glutamate homeostasis and excitatory/inhibitory balance, and to behavioral deficits that support a decline in hippocampal-prefrontal cortex connectivity. Together with our previous data, these findings also point to different patterns of basal and activity-induced hippocampal abnormalities in these mice. In sum, GDH contributes to healthy hippocampal and PFC function; disturbed GDH function is relevant to several psychiatric and neurological disorders.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Reconhecimento Visual de Modelos
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Córtex Pré-Frontal
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Ácido Glutâmico
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Região CA1 Hipocampal
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Glutamato Desidrogenase
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Genes Brain Behav
Ano de publicação:
2020
Tipo de documento:
Article