Glutamate dehydrogenase deficiency disrupts glutamate homeostasis in hippocampus and prefrontal cortex and impairs recognition memory
| Autor: | Sharon S Lander, Amit Gross, Inna Gaisler-Salomon, Herman Wolosker, Sergiy Chornyy, Hazem Safory |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male Glutamate decarboxylase Hippocampus Glutamic Acid Prefrontal Cortex Hippocampal formation 03 medical and health sciences Behavioral Neuroscience Mice 0302 clinical medicine Glutamate homeostasis Glutamate Dehydrogenase Genetics Animals Homeostasis CA1 Region Hippocampal Spatial Memory biology Glutamate dehydrogenase Glutamate receptor Synaptic Potentials Mice Inbred C57BL 030104 developmental biology nervous system Neurology Glutamate dehydrogenase 1 Pattern Recognition Visual biology.protein NMDA receptor Female Neuroscience 030217 neurology & neurosurgery |
| Zdroj: | Genes, brain, and behaviorREFERENCES. 19(6) |
| ISSN: | 1601-183X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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