RESUMEN
A key feature of age-related hearing loss is a reduction in the expression of inhibitory neurotransmitters in the central auditory system. This loss is partially responsible for changes in central auditory processing, as inhibitory receptive fields play a critical role in shaping neural responses to sound stimuli. Vigabatrin (VGB), an antiepileptic agent that irreversibly inhibits γ-amino butyric acid (GABA) transaminase, leads to increased availability of GABA throughout the brain. This study used multi-channel electrophysiology measurements to assess the excitatory frequency response areas in old CBA mice to which VGB had been administered. We found a significant post-VGB reduction in the proportion of V-type shapes, and an increase in primary-like excitatory frequency response areas. There was also a significant increase in the mean maximum driven spike rates across the tonotopic frequency range of all treated animals, consistent with observations that GABA buildup within the central auditory system increases spike counts of neural receptive fields. This increased spiking is also seen in the rate-level functions and seems to explain the improved low-frequency thresholds.
Asunto(s)
Envejecimiento/genética , Envejecimiento/metabolismo , Percepción Auditiva/genética , Percepción Auditiva/fisiología , Nervio Coclear/metabolismo , Mesencéfalo/metabolismo , Neuronas/metabolismo , Ácido gamma-Aminobutírico/metabolismo , 4-Aminobutirato Transaminasa/antagonistas & inhibidores , 4-Aminobutirato Transaminasa/fisiología , Estimulación Acústica , Animales , Anticonvulsivantes/farmacología , Nervio Coclear/citología , Femenino , Pérdida Auditiva/etiología , Pérdida Auditiva/genética , Colículos Inferiores/metabolismo , Masculino , Ratones Endogámicos CBA , Inhibición Neural/genética , Inhibición Neural/fisiología , Presbiacusia/metabolismo , Vigabatrin/farmacologíaRESUMEN
PURPOSE OF REVIEW: There has been increased recognition of the pediatric neurotransmitter disorders. This review focuses on the clinical disorders of GABA metabolism. RECENT FINDINGS: The known clinical disorders of GABA metabolism are pyridoxine dependent epilepsy, GABA-transaminase deficiency, SSADH deficiency, and homocarnosinosis. Pyridoxine dependent epilepsy is diagnosed clinically but potentially more common presentations, with later and atypical features, widen the spectrum. No gene locus has been confirmed; the pathophysiology may involve alterations in PLP transport, binding to GAD, or other PLP-dependent pathways. SSADH deficiency is associated with developmental delay, prominent language deficits, hypotonia, ataxia, hyporeflexia, and seizures. Increased detection is reported when specific ion monitoring is used for GHB on urine organic acids. The most consistent MRI abnormality is increased signal in the globus pallidus. MR spectroscopy has demonstrated the first example of increased endogenous GABA in human brain parenchyma in this disorder. GABA-transaminase deficiency and homocarnosinosis appear to be very rare but require CSF for detection, thus allowing for the possibility that these entities, as in the other pediatric neurotransmitter disorders, are underrecognized. SUMMARY: The disorders of GABA metabolism require an increased index of clinical suspicion. Pyridoxine dependent epilepsy is a treatable condition with a potentially widening clinical spectrum, but with a prognosis dependent on early intervention. SSADH deficiency has a heterogeneous spectrum and requires careful urine organic acid testing for screening, followed by enzymatic confirmation allowing appropriate prognostic and genetic counseling.
Asunto(s)
4-Aminobutirato Transaminasa/deficiencia , Aldehído Oxidorreductasas/deficiencia , Errores Innatos del Metabolismo de los Aminoácidos/genética , Carnosina/análogos & derivados , Carnosina/metabolismo , Discapacidades del Desarrollo/genética , Epilepsia/genética , Piridoxina/fisiología , Ácido gamma-Aminobutírico/metabolismo , 4-Aminobutirato Transaminasa/fisiología , Errores Innatos del Metabolismo de los Aminoácidos/diagnóstico , Errores Innatos del Metabolismo de los Aminoácidos/fisiopatología , Encéfalo/patología , Encéfalo/fisiopatología , Niño , Discapacidades del Desarrollo/diagnóstico , Discapacidades del Desarrollo/fisiopatología , Diagnóstico Diferencial , Epilepsia/diagnóstico , Epilepsia/tratamiento farmacológico , Epilepsia/fisiopatología , Glutamato Descarboxilasa/deficiencia , Glutamato Descarboxilasa/genética , Humanos , Imagen por Resonancia Magnética , Fenotipo , Fosfato de Piridoxal/metabolismo , Succionato-Semialdehído DeshidrogenasaRESUMEN
gamma-Aminobutyrate transaminase (GABA-T), a key enzyme of the GABA shunt, converts the major inhibitory neurotransmitter, GABA, to succinic semialdehyde. Although GABA-T is a pivotal factor implicated in the pathogenesis of various neurological disorders, its function remains to be elucidated. In an effort to clarify the structural and functional roles of specific lysyl residue in human brain GABA-T, we constructed human brain GABA-T mutants, in which the lysyl residue at position 357 was mutated to various amino acids including asparagine (K357N). The purified mutant GABA-T enzymes displayed neither catalytic activity nor absorption bands at 330 and 415 nm that are characteristic of pyridoxal-5'-phosphate (PLP) covalently linked to the protein. The wild type apoenzyme reconstituted with exogenous PLP had catalytic activity, while the mutant apoenzymes did not. These results indicate that lysine 357 is essential for catalytic function, and is involved in binding PLP at the active site.
Asunto(s)
4-Aminobutirato Transaminasa/genética , 4-Aminobutirato Transaminasa/fisiología , Encéfalo/enzimología , Lisina/genética , Secuencia de Aminoácidos , Secuencia de Bases , Sitios de Unión , Catálisis , Electroforesis en Gel de Poliacrilamida , Vectores Genéticos , Humanos , Lisina/química , Datos de Secuencia Molecular , Mutagénesis Sitio-Dirigida , Mutación , Unión Proteica , Fosfato de Piridoxal/metabolismo , Proteínas Recombinantes/química , EspectrofotometríaRESUMEN
The Bacillus subtilis ycnG (gabT) and ycnH (gabD) genes were shown to encode gamma-aminobutyrate (GABA) aminotransferase and succinic semi-aldehyde dehydrogenase, respectively, and to form a GABA-inducible operon. Null mutations in gabT, gabD or the divergently transcribed ycnF (gabR) gene blocked the utilization of GABA as sole nitrogen source. GabR proved to be a transcriptional activator of the gabTD operon and a negative autoregulator. The target of GabR action was localized to an 87 bp region that includes both gabR and gabT promoters. GabR is a member of a novel but widespread family of chimeric bacterial proteins that have apparent DNA-binding and aminotransferase domains. Mutations in conserved residues of the putative aminotransferase domain abolished GabR function as a transcriptional activator, but did not affect its activity as a negative autoregulator.
Asunto(s)
4-Aminobutirato Transaminasa/fisiología , Aldehído Oxidorreductasas/fisiología , Bacillus subtilis/metabolismo , Proteínas Bacterianas/fisiología , Familia de Multigenes , Proteínas Represoras/fisiología , Transactivadores/fisiología , Ácido gamma-Aminobutírico/metabolismo , 4-Aminobutirato Transaminasa/genética , Aldehído Oxidorreductasas/genética , Secuencia de Aminoácidos , Bacillus subtilis/genética , Proteínas Bacterianas/genética , Secuencia de Bases , Mapeo Cromosómico , Cromosomas Bacterianos/genética , Clonación Molecular , Eliminación de Gen , Regulación Bacteriana de la Expresión Génica , Datos de Secuencia Molecular , Nitrógeno/metabolismo , Operón/genética , Regiones Promotoras Genéticas/genética , Proteínas Represoras/genética , Alineación de Secuencia , Homología de Secuencia de Aminoácido , Succionato-Semialdehído Deshidrogenasa , Transactivadores/genéticaRESUMEN
Neuronal dysfunction is the neurobiological basis for alcoholic behaviour, and ethanol craving seems related to hypofunction of the GABA-ergic activity. Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system (CNS). In several studies, GABA has been shown to be an important target of ethanol in the CNS, partly, as a consequence of damage to membrane-bound enzymes and receptors. GABA is involved in mediating pre- and post-synaptic inhibition of neuronal activity. It is speculated that the initial excitatory effects of ethanol may be due to inhibition of GABA-ergic activity whereas the sedative effects of the higher doses may be mediated by the activation of this inhibitory system. In the CNS, GABA is synthesised from glutamic acid by the enzyme glutamate decarboxylase (GAD) and catabolized into succinic semialdehyde by the enzyme GABA-transaminase (GABA-T), which are pyridoxal phosphate (PLP) dependent enzymes. Platelet GABA-T was characterized as being similar to central GABA-T. Inhibition of GABA-T with certain potent and selective compounds markedly increases the levels of brain GABA. Experimentally, acute ethanol treatment does not alter GABA-T activity whereas chronic treatment produces an increase in the activity, though, with some reservations since a bimodal effect has been found in chronically ethanol-treated rats. Thus, as it will be discussed below, it may be suggested that GABA-T inhibitors (e.g. vigabatrin) could have a potential role in the treatment of alcoholism and in some of the problems of ethanol withdrawal and of other drugs of abuse. Related studies on metabolism and concentrations of GABA are also promising and show a greater increase in our understanding of the aetiology and treatment of ethanol dependence and withdrawal. In general, this article also reviews both the animal and clinical observations in the field of alcoholism with regard to the GABA system.
Asunto(s)
4-Aminobutirato Transaminasa/fisiología , Alcoholismo/fisiopatología , Transmisión Sináptica/fisiología , Ácido gamma-Aminobutírico/fisiología , Alcoholismo/enzimología , Animales , Humanos , RatasAsunto(s)
Encéfalo/fisiología , Neurotransmisores/fisiología , Terminales Presinápticos/fisiología , 4-Aminobutirato Transaminasa/fisiología , Animales , Encéfalo/metabolismo , Embrión de Pollo , Dopamina/fisiología , Relación Dosis-Respuesta a Droga , Moduladores del GABA/farmacología , Humanos , N-Metilaspartato/metabolismo , N-Metilaspartato/fisiología , Neurotransmisores/metabolismo , Norepinefrina/fisiología , Terminales Presinápticos/metabolismo , Conejos , Ratas , Transmisión Sináptica/fisiología , Ácido gamma-Aminobutírico/metabolismo , Ácido gamma-Aminobutírico/fisiologíaRESUMEN
Vigabatrin (gamma-vinyl GABA, GVG) is an irreversible inhibitor of the enzyme GABA-transaminase (GABA-T) GABA-T is the enzyme responsible for the catabolism of the major inhibitory neurotransmitter gamma-aminobutyric acid (GABA) in the mammalian brain. Previously, a single administration of vigabatrin at a dose of 50 mg/kg was found to produce an anxiolytic-like effect on exploratory behaviour in rats and a decrease in the locomotor activity, 2 and 4 h after the injection and, presently, 24 h after the injection. Using an elevated plus-maze and open field tests, we investigated whether or not chronic administration of vigabatrin at the same dose (50 mg/kg/day, i.p.) for 14 and 28 days induces tolerance with regard to these effects. The anxiolytic-like effect of vigabatrin was found to persist in the elevated plus-maze test, as was the case with diazepam (5 mg/kg/day, i.p.), 24 h after the last injection. However, in the plus-maze and open field tests, the effects of vigabatrin and diazepam on the general locomotor activity were not found to be decreased.
Asunto(s)
4-Aminobutirato Transaminasa/antagonistas & inhibidores , Conducta Exploratoria/efectos de los fármacos , Ácido gamma-Aminobutírico/análogos & derivados , 4-Aminobutirato Transaminasa/fisiología , Animales , Nivel de Alerta/efectos de los fármacos , Nivel de Alerta/fisiología , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Tolerancia a Medicamentos , Conducta Exploratoria/fisiología , Inyecciones Intraperitoneales , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Inhibición Neural/efectos de los fármacos , Inhibición Neural/fisiología , Ratas , Ratas Wistar , Vigabatrin , Ácido gamma-Aminobutírico/farmacología , Ácido gamma-Aminobutírico/fisiologíaRESUMEN
The administration of GABA-transaminase inhibitors (GABA-TIs) to male rats reduces the proportion of mounts that result in intromissions. Copulatory pelvic thrusting remains normal, despite the fact that animals treated with GABA-TIs show gross deficiencies in other motor acts. In order to determine whether altered sexual behavior produced by GABA-TI could be due to deficiencies in activity of striated penile muscles, we recorded the electromyographic (EMG) activity of the ischiocavernosus (IC) muscle during copulation in male rats treated with sodium valproate. The duration of IC EMG bursts was reduced by sodium valproate in separate tests that allowed or prevented intromission. There was no effect on EMG amplitude or frequency. It is suggested that insufficient activity of the IC muscles reduces the likelihood of vaginal penetration. The actions of GABA may be localized to hypothalamic or brain stem nuclei with GABAergic projections to the spinal motoneurons controlling the IC muscles, or GABA may act directly on these neurons.
Asunto(s)
4-Aminobutirato Transaminasa/antagonistas & inhibidores , Copulación/efectos de los fármacos , Electromiografía/efectos de los fármacos , Contracción Muscular/efectos de los fármacos , Erección Peniana/efectos de los fármacos , Ácido Valproico/farmacología , 4-Aminobutirato Transaminasa/fisiología , Animales , Encéfalo/efectos de los fármacos , Encéfalo/fisiología , Copulación/fisiología , Eyaculación/efectos de los fármacos , Eyaculación/fisiología , Femenino , Inyecciones Intraperitoneales , Masculino , Contracción Muscular/fisiología , Erección Peniana/fisiología , RatasRESUMEN
The activity of gamma-aminobutyrate amino-transferase (GABA-T) and monoamine oxidase (MAO-A and -B) was measured in 42 postmortem human brains. Three brain regions (frontal cortex, cingulate cortex and hypothalamus) from 23 controls without known neurological or psychiatric disorder and from 19 suicide victims were analysed. The suicide victims were classified according to the use of violent and non-violent methods and to the presence or absence of a known history of depressive disorder. No difference was found between the series of suicide victims and the control subjects with regard to GABA-T activity. Carbon monoxide poisoning and death by drug overdose, however, were found to reduce the activity. The MAO-B activity did not differ between the groups. With MAO-A, however, a significant elevation (t = 2.01; P less than 0.05) was found in the hypothalamic region of the suicide victims. The difference seemed to be confined to the subgroup of suicides with a record of depressive disorder.
Asunto(s)
4-Aminobutirato Transaminasa/fisiología , Encéfalo/patología , Trastorno Depresivo/patología , Trastorno Depresivo/psicología , Monoaminooxidasa/fisiología , Suicidio/psicología , Adolescente , Adulto , Factores de Edad , Anciano , Trastornos de Ansiedad/patología , Trastornos de Ansiedad/psicología , Mapeo Encefálico , Intoxicación por Monóxido de Carbono/patología , Intoxicación por Monóxido de Carbono/psicología , Sobredosis de Droga/patología , Sobredosis de Droga/psicología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Preservación de Órganos , Violencia , Ácido gamma-Aminobutírico/fisiologíaRESUMEN
Elevations of brain gamma-aminobutyric acid (GABA) induced by inhibitors of GABA transaminase (GABA-T) are known to induce a number of functional effects including depression of food intake. The aim of the present study was to determine the brain GABA elevation threshold for changes in feeding and several other behaviours, in an effort to clarify whether feeding changes might be secondary to other functional deficits. To this end, various doses of the GABA-T inhibitors ethanolamine-o-sulfate (EOS) and gamma-vinyl GABA (GVG) were injected intracisternally and effects on whole brain GABA, food and water intake, open field activity, catalepsy indices, pain sensitivity, and core temperature were assessed 24 h later. Progressive increases in brain GABA levels were found to differentially affect the responses studied. At the low end of the continuum, significant decreases in feeding behaviour were associated with relatively modest increases in brain GABA (40-60%). At higher levels of GABA elevation (greater than 100%), changes in motoric functions and rectal temperature became apparent. At still higher levels (greater than 200% increases in brain GABA), significant antinociceptive effects were detected. These results support the notion that feeding decreases induced by low doses of GABA-T inhibitors may reflect a fairly specific effect on appetite mechanisms, but also indicate that with increasingly higher doses several other deficits are likely to contribute to the overall decrease in food intake.
Asunto(s)
Conducta Animal/fisiología , Encéfalo/fisiología , Conducta Alimentaria/fisiología , Ácido gamma-Aminobutírico/fisiología , 4-Aminobutirato Transaminasa/fisiología , Animales , Nivel de Alerta/fisiología , Conducta Exploratoria/fisiología , Masculino , Actividad Motora/fisiología , Nociceptores/fisiología , Ratas , Ratas Endogámicas , Tiempo de Reacción/fisiología , Receptores de GABA-A/fisiologíaAsunto(s)
Epilepsia/etiología , Ácido gamma-Aminobutírico/fisiología , 4-Aminobutirato Transaminasa/fisiología , Animales , Anticonvulsivantes/farmacología , Anticonvulsivantes/uso terapéutico , Benzodiazepinas/farmacología , Benzodiazepinas/uso terapéutico , Bicuculina/farmacología , Bicuculina/uso terapéutico , Encéfalo/metabolismo , Perros , Epilepsia/tratamiento farmacológico , Epilepsia/metabolismo , Epilepsia/fisiopatología , Humanos , Ratones , Terminaciones Nerviosas/fisiología , Pentilenotetrazol/farmacología , Pentilenotetrazol/uso terapéutico , Fenobarbital/farmacología , Fenobarbital/uso terapéutico , Fenitoína/farmacología , Fenitoína/uso terapéutico , Ratas , Receptores de GABA-A/efectos de los fármacos , Receptores de GABA-A/fisiología , Sinapsis/fisiología , Ácido Valproico/farmacología , Ácido Valproico/uso terapéutico , Ácido gamma-Aminobutírico/análogos & derivados , Ácido gamma-Aminobutírico/biosíntesis , Ácido gamma-Aminobutírico/farmacología , Ácido gamma-Aminobutírico/uso terapéuticoRESUMEN
Temporal and spatial developmental relationships between AChE and GABA-T reactivity in the sensory-motor cortex of rat were evaluated histochemically. Special attention was given to the barrels in layer IV of SmI that stain intensely for both enzymes. In the first and second postnatal weeks very low levels of diffuse GABA-T reactivity are seen in cortex, although cells and neuropil in the neostriatum are already clearly positive neonatally. There is little change until 16-18 days postnatal (dpn), when a steady increase in overall cortical reactivity for GABA-T has begun. In layer IV of SmI cortex, relatively intense foci of GABA-T staining begin to appear then, that overlap the barrel centers. GABA-T reactive non-pyramidal neurons at the periphery of these stained foci have distinctly stained processes that may enter the barrel centers. The intensity of GABA-T staining increases until 28 dpn when adult levels were reached. In contrast, AChE staining in cortex begins to appear at 2-3 dpn with prominent barrel staining seen by 6 dpn. When adult AChE reactivity levels are being achieved throughout all regions of neocortex, between 16-19 dpn, the barrel centers progressively lose demonstrable AChE-staining of their fiber plexus. Hence, the onset of GABA-T staining in the barrels during the third week postnatally coincides with the initiation of the progressive reduction in intensity of AChE staining in the same cortical zones. These observations on GABA-T correlate well with biochemical information on the time course of the maturation of the cortical GABAergic system.(ABSTRACT TRUNCATED AT 250 WORDS)