Medial septal dysfunction by Aβ-induced KCNQ channel-block in glutamatergic neurons
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Premovement neuronal activity
Excitotoxicity
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Excitatory amino acids, such as glutamate, exert a profound stimulatory effect on the reproductive axis of several mammals. Although glutamate receptor agonists stimulate GnRH secretion, both in vivo and in vitro, it is unclear whether GnRH neurones respond directly to glutamatergic excitation. Immortalized GnRH neurones (GT1 cells) express glutamate receptors when grown in culture and also show enhanced GnRH secretion in response to glutamate receptor agonists. In addition, immunocytochemical evidence at the electron microscope level supports the possibility of a direct interaction between glutamatergic and GnRH neurones. In general, however, double-label histochemical studies (using immunocytochemistry, in situ hybridization, or a combination of these techniques) have not shown significant glutamate receptor gene expression in GnRH neurones of adult animals. It remains to be determined whether a higher degree of glutamate receptor gene expression occurs during development. This general lack, or very low amount, of glutamate receptor gene expression in the GnRH neurones of adults supports the view that excitatory amino acids exert their stimulatory action on the reproductive axis primarily through interneuronal pathways that impinge on the GnRH neurones, rather than by stimulating GnRH release directly.
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Regionally specific neuronal loss is a distinguishing feature of Alzheimer disease (AD). Excitotoxicity is a mechanism commonly invoked to explain this. We review the accumulating evidence for such a hypothesis, particularly the altered expression and pharmacology of glutamate receptors and transporters in pathologically susceptible regions of the AD brain. Loss of neurons would be expected to lead to the retrograde degeneration of their afferents, which should be reflected in a loss of presynaptic markers such as synaptophysin. We discuss the possibility that neurons may be destroyed locally, but that glutamatergic presynaptic terminals may remain, or even re-proliferate. The reduced glutamate uptake site density in AD brain may signify a loss of the transporters on otherwise intact terminals, rather than the loss of glutamatergic afferents. Neuronal death may follow if cells are exposed to excessive amounts of glutamate; the loss of transporters from functioning, but defective, glutamate terminals would mean they could continue to release glutamate to exacerbate excitotoxicity. We discuss experimental methods to quantitate synapses, which are crucial for deciding between the various possibilities.
Excitotoxicity
Synaptophysin
Neuronal Degeneration
Neurotoxicity
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Aging brain
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Glutamic acid
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Excitatory amino acids, such as glutamate, exert a profound stimulatory effect on the reproductive axis of several mammals. Although glutamate receptor agonists stimulate GnRH secretion, both in vivo and in vitro, it is unclear whether GnRH neurones respond directly to glutamatergic excitation. Immortalized GnRH neurones (GT1 cells) express glutamate receptors when grown in culture and also show enhanced GnRH secretion in response to glutamate receptor agonists. In addition, immunocytochemical evidence at the electron microscope level supports the possibility of a direct interaction between glutamatergic and GnRH neurones. In general, however, double-label histochemical studies (using immunocytochemistry, in situ hybridization, or a combination of these techniques) have not shown significant glutamate receptor gene expression in GnRH neurones of adult animals. It remains to be determined whether a higher degree of glutamate receptor gene expression occurs during development. This general lack, or very low amount, of glutamate receptor gene expression in the GnRH neurones of adults supports the view that excitatory amino acids exert their stimulatory action on the reproductive axis primarily through interneuronal pathways that impinge on the GnRH neurones, rather than by stimulating GnRH release directly.
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Background:
Schizophrenia has been hypothesized to be caused by a hypofunction of glutamatergic neurons. Findings of reduced concentrations of glutamate in the cerebrospinal fluid of patients with schizophrenia and the ability of glutamate-receptor antagonists to cause psychotic symptoms lend support to this hypothesis.N-acetylaspartylglutamate (NAAG), a neuropeptide that is highly concentrated in glutamatergic neurons, antagonizes the effects of glutamate atN-methyl-d-aspartate receptors. Moreover, NAAG is cleaved to glutamate andN-acetylaspartate by a specific peptidase,N-acetyl-α—linked acidic dipeptidase (NAALADase). To test the glutamatergic hypothesis of schizophrenia, we studied the NAAG-related glutamatergic variables in postmortem brains from patients with schizophrenia, neuroleptic-treated controls, and normal individuals, with particular emphasis on the prefrontal cortex and hippocampus.Method:
Different regions of frozen brain tissue from three different groups (patients with schizophrenia, neuroleptictreated controls, and normal controls) were assayed to determine levels of NAAG,N-acetylaspartate, NAALADase, and several amino acids, including aspartate and glutamate.Results:
Our study demonstrates alterations in brain levels of aspartate, glutamate, and NAAG and in NAALADase activity. Levels of NAAG were increased and NAALADase activity and glutamate levels were decreased in the schizophrenic brains. Notably, the changes in NAAG level and NAALADase activity in schizophrenic brains were more selective than those for aspartate and glutamate. In neuroleptic-treated control brains, levels of aspartate, glutamate, and glycine were found to be increased.Conclusions:
The changes in levels of aspartate, glutamate, NAAG, and NAALADase are prominent in the prefrontal and hippocampal regions, where previous neuropathological studies of schizophrenic brains demonstrate consistent changes. These findings support the hypothesis that schizophrenia results from a hypofunction of certain glutamatergic neuronal systems. They also suggest that the therapeutic efficacy of neuroleptics may be related to increased glutamatergic activity.Glutamate carboxypeptidase II
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