Proline-induced potentiation of glutamate transmission

Cohen, Susan M.; Nadler, J. Victor

doi:10.1016/s0006-8993(97)00352-1

Cited by 84 publications

(69 citation statements)

References 45 publications

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“…Earlier reports 26,27 had implicated potentiation of glutamate excitotoxicity as a possible mechanism for neurological dysfunction in hyperprolinemic subjects. Recently, more insight into the deleterious effect of elevated proline level in brain has been gained with reports showing that proline decreases Na þ , K þ -ATPase and acetylcholinesterase activities and elicits oxidative stress in rat brains.…”

Section: Discussionmentioning

confidence: 98%

Hyperprolinemia is a risk factor for schizoaffective disorder

et al. 2004

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DNA sequence variations within the 22q11 DiGeorge chromosomal region are likely to confer susceptibility to psychotic disorders. In a previous report, we identified several heterozygous alterations, including a complete deletion, of the proline dehydrogenase (PRODH) gene, which were associated with moderate hyperprolinemia in a subset of DSM III schizophrenic patients. Our objective was (i) to determine whether hyperprolinemia is associated with increased susceptibility for any of three psychiatric conditions (schizophrenia, schizoaffective disorder and bipolar disorder) and (ii) to establish a correlation between hyperprolinemia and PRODH genotypes. We have conducted a case-control study including 114 control subjects, 188 patients with schizophrenia, 63 with schizoaffective disorder and 69 with bipolar disorder. We report that, taking into account a confounding effect due to valproate treatment, hyperprolinemia is a risk factor for DSM IIIR schizoaffective disorder (P ¼ 0.02, Odds ratio ¼ 4.6, 95% confidence interval 1.3-16.3). We did not detect 22q11 interstitial deletions associated with the DiGeorge syndrome among the 320 patients of our sample and we found no association between common PRODH polymorphisms and any of the psychotic disorders. In contrast, we found that five rare PRODH alterations (including a complete PRODH deletion and four missense substitutions) were associated with hyperprolinemia. In several cases, two variations were present simultaneously, either in cis or trans in the same subject. A total of 11 from 30 hyperprolinemic subjects bore at least one genetic variation associated with hyperprolinemia. This study demonstrates that moderate hyperprolinemia is an An increased frequency of several psychotic disorders, such as children-onset schizophrenia, 1 schizophrenia, 2 and bipolar disorder, 3 has been observed in patients with the 22q11 deletion syndromes (22q11DS), 4 which include the DiGeorge syndrome (MIM 188400) and the velo-cardio-facial syndrome (MIM 192430). This has led to the hypothesis that sequence variations of one or several genes located within the 3 Mb region commonly deleted in most of the 22q11DS patients 5 might confer susceptibility for psychoses in the general population. In a previous study, we had identified in two schizophrenic relatives (diagnosed according to DSM III criteria) a 350 kb heterozygous deletion within the DiGeorge critical region (DGCR) removing entirely the proline dehydrogenase (PRODH) gene. This deletion was associated in patients with moderate hyperprolinemia. In addition, two heterozygous PRODH missense mutations (L441P and L289M) were detected in three of 63 schizophrenic patients but not in 68 controls, and these mutations were also associated with moderate hyperprolinemia. 6 Interestingly, we subsequently found the same PRODH deletion and the L441P substitution at the homozygous state in children suffering from a severe form of type I hyperprolinemia, a condition characterized by high plasma proline levels, seizures and mental retardation. 7 T...

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Section: Discussionmentioning

confidence: 98%

Hyperprolinemia is a risk factor for schizoaffective disorder

et al. 2004

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“…Selective deletion of PRODH in mice has been shown to lead to deficits in sensorimotor gating, with decreased glutamate, aspartate and GABA levels in the frontal cortex 85 . Proline has been implicated in modulation of neurotransmission especially in the glutamatergic system, which could lead to the psychotic symptoms observed in patients [86][87][88] . 22q11DS mouse models present with a loss of glutamatergic synapses, decreased spine density, decreased CA1 pyramidal neuron complexity and reduced neurogenesis in the subventricular zone.…”

Section: Q11mentioning

confidence: 99%

Estudos traducionais de neuropsiquiatria e esquizofrenia: modelos animais genéticos e de neurodesenvolvimento

Gottschalk

Sarnyai

Guest

et al. 2012

Arch. Clin. Psychiatry (São Paulo)

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Psychiatric symptoms are subjective by nature and tend to overlap between different disorders. The modelling of a neuropsychiatric disorder therefore faces challenges because of missing knowledge of the fundamental pathophysiology and a lack of accurate diagnostics. Animal models are used to test hypotheses of aetiology and to represent the human condition as close as possible to increase our understanding of the disease and to evaluate new targets for drug discovery. In this review, genetic and neurodevelopmental animal models of schizophrenia are discussed with respect to behavioural and neurophysiological findings and their association with the clinical condition. Only specific animal models of schizophrenia may ultimately lead to novel diagnostic approaches and drug discovery. We argue that molecular biomarkers are important to improve animal to human translation since behavioural readouts lack the necessary specificity and reliability to assess human psychiatric symptoms.Gottschalk MG, et al. / Rev Psiq Clín. 2013;40(1):41-50 Keywords: Translational research, neuropsychiatry, genetic, neurodevelopment, animal model, schizophrenia. ResumoSintomas psiquiátricos são subjetivos por natureza e tendem a se sobrepor entre diferentes desordens. Sendo assim, a criação de modelos de uma desordem neuropsiquiátrica encontra desafios pela falta de conhecimento dos fundamentos da fisiopatologia e diagnósticos precisos. Modelos animais são usados para testar hipóteses de etiologia e para representar a condição humana tão próximo quanto possível para aumentar nosso entendimento da doença e avaliar novos alvos para a descoberta de drogas. Nesta revisão, modelos animais genéticos e de neurodesenvolvimento de esquizofrenia são discutidos com respeito a achados comportamentais e neurofisiológicos e sua associação com a condição clínica. Somente modelos animais específicos de esquizofrenia podem, em último caso, levar a novas abordagens diagnósticas e descoberta de drogas. Argumentamos que biomarcadores moleculares são importantes para aumentar a tradução de animais a humanos, já que faltam a especificidade e a fidelidade necessárias às leituras comportamentais para avaliar sintomas psiquiátricos humanos.Gottschalk MG, et al. / Rev Psiq Clín. 2013;40(1):41-50

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“…In high concentrations (>100um), proline has been shown to activate N-methyl-D-aspartate (NMDA) receptors, alpha amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors, and strychnine-sensitive glycine receptors (Cohen and Nadler, 1997;Takemoto, 2005).…”

Section: Introductionmentioning

confidence: 99%

Glutamate-related gene expression changes with age in the mouse auditory midbrain

et al. 2007

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Glutamate is the main excitatory neurotransmitter in both the peripheral and central auditory systems. Changes of glutamate and glutamate-related genes with age may be an important factor in the pathogenesis of age-related hearing loss -presbycusis. In this study, changes in glutamate-related mRNA gene expression in the CBA mouse inferior colliculus with age and hearing loss were examined and correlations were sought between these changes and functional hearing measures, such as the auditory brainstem response (ABR) and distortion product otoacoustic emissions (DPOAEs). Gene expression of 68 glutamate-related genes was investigated using both genechip microarray and real-time PCR (qPCR) molecular techniques for four different age/hearing loss CBA mouse subject groups. Two genes showed consistent differences between groups for both the genechip and qPCR. Pyrroline-5-carboxylate synthetase enzyme (Pycs) showed down-regulation with age and a highaffinity glutamate transporter (Slc1a3) showed up-regulation with age and hearing loss. Since Pycs plays a role in converting glutamate to proline, its deficiency in old age may lead to both glutamate increases and proline deficiencies in the auditory midbrain, playing a role in the subsequent inducement of glutamate toxicity and loss of proline neuroprotective effects. The up-regulation of Slc1a3 gene expression may reflect a cellular compensatory mechanism to protect against age-related glutamate or calcium excitoxicity.

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Proline-induced potentiation of glutamate transmission

Cited by 84 publications

References 45 publications

Hyperprolinemia is a risk factor for schizoaffective disorder

Hyperprolinemia is a risk factor for schizoaffective disorder

Estudos traducionais de neuropsiquiatria e esquizofrenia: modelos animais genéticos e de neurodesenvolvimento

Glutamate-related gene expression changes with age in the mouse auditory midbrain

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