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Research Notes: Gamma-aminobutyric Acid (GABA)Int Rev Neurobiol. 2006. Prader-Willi syndrome (PWS) is the result of a lack of expression of genes on the paternally derived chromosome 15q11-q13 and can be considered as a hypothalamic disorder. Its behavioral phenotype is characterized by ritualistic, stereotyped, and compulsive behaviors as well as motor abnormalities. After adolescence, recurrent affective psychoses are relatively frequent, especially in patients with uniparental disomy. These psychotic states have a subacute onset with complete recovery and comprise an increase of psychomotor symptoms that show resemblance with catatonia. Some evidence has emerged that gamma-aminobutyric acid (GABA) dysfunctionality is involved in both PWS and catatonia. Treatment of these atypical psychoses should preferably include GABA mimetic compounds like lorazepam, valproic acid, and possibly topiramate. J Neuropsychiatry Clin Neurosci. 1997 Winter. Plasma gamma-aminobutyric acid (GABA) levels were measured in 14 subjects with Prader-Willi syndrome, 9 subjects with Angelman syndrome, and matched control subjects. Mean levels in both patient groups were 2 to 3 times higher than in nonretarded moderately obese or retarded nonobese control subjects. Levels in each patient group differed significantly from both control groups. Neither the two patient groups nor the two control groups differed. GABA levels seemed unrelated to genetic status (chromosome 15 deletion or disomy). These preliminary findings of elevated plasma GABA levels possibly represent a compensatory increase in presynaptic GABA release in response to hyposensitivity of a subset of GABA receptors and could produce increased postsynaptic activation of other normal GABA receptor subtypes, resulting in complex alterations of GABAergic function throughout the brain. Wiad Lek. 2003. Pathogenesis of hepatic encephalopathy has not been fully revealed and there are many factors which may affect its development. Ammonia and changes in GABA-ergic neurotransmission seem to be the most essential of these factors. Hepatic encephalopathy is frequently, though not always, accompanied by elevated blood ammonia level. Due to the changes in permeability of blood-brain barrier the ammonia level in the brain also increases which results in both stimulating and inhibitory neurotransmission disturbances. Ammonia also affects abnormal interaction of metabolic neurones and astrocytes as well as glutamine-serotonin balance. Another essential factor affecting hepatic encephalopathy development are disturbances in GABA-ergic neurotransmission connected with GABAA receptor complex. When the liver is damaged GABA-ergic neurotransmission increases due to a higher GABA level, natural benzodiazepine receptor agonists as well as neurosteroids synthesised in astrocytes. Many studies point to the fact that ammonia and GABA-ergic neurotransmission disturbances interrelate with each other. There is a concept saying that both these factors cause hepatic encephalopathy. Ammonia may indirectly increase GABA-ergic neurotransmission and also inhibit the function of the central nervous system by synergistic activity with benzodiazepine receptor ligands. So far it is not known whether GABA-ergic neurotransmission is affected by ammonia only or by other factors as well. Metab Brain Dis. 2002 Dec. There appears to be a consensus that hepatic encephalopathy (HE) is a metabolic encephalopathy with a multifactorial pathogenesis. One of the factors considered to be important in the pathogenesis of HE is ammonia. However, the mechanisms by which ammonia contributes to the manifestations of HE remain poorly defined. Ammonia could be more definitively implicated in the pathogenesis of HE if its effects can be shown to lead to an enhancement of inhibitory neurotransmission. In this context the effects of ammonia on the GABA (gamma-aminobutyric acid) neurotransmitter system may be relevant. Ammonia, at the modestly increased concentrations that commonly occur in precoma HE (0.15 mM-0.75 mM), has been shown to increase GABA-induced chloride current in cultured neurons, probably by modifying the affinity of the GABA(A) receptor for GABA. Comparable ammonia concentrations also enhanced synergistically the binding of a GABA agonist and a benzodiazepine (BZ) agonist to the GABA(A) receptor complex, phenomena which would enhance the neuroinhibitory effects of these ligands. Also, GABA increased the potency of ammonia-induced enhancement of the binding of a BZ agonist to the GABA(A) receptor complex, and brain levels of BZ agonists are elevated in liver failure. In addition, ammonia has been shown to inhibit astrocytic uptake of GABA by 30%-50%, an effect which would increase the synaptic availability of GABA at GABA(A) receptors. Furthermore, increased ammonia concentrations upregulate the peripheral-type benzodiazepine receptor in the outer membrane of astroglial mitochondria, thereby enhancing astrocytic mitochondrial synthesis and release of neurosteroids. Some neurosteroids, for example tetrahydroprogesterone (THP) and tetrahydrodeoxycorticosterone (THDOC), are potent agonists of the GABA(A) receptor complex, on which there are specific binding sites for neurosteroids, that are distinct from those for BZs and barbiturates. Tetrahydroprogesterone and tetrahydrodeoxycorticosterone levels were found to be increased in a mouse model of acute liver failure, and, when THP or THDOC was injected into normal mice, sedation and Alzheimer type II astrocytic changes in the cortex, striatum, and hypothalmus were induced. Each of these direct or indirect effects of ammonia on the GABA neurotransmitter system has the potential of increasing inhibitory neurotransmission, and, hence, contributing to the manifestations of HE. Metab Brain Dis. 1998 Dec. The ammonia and GABAergic neurotransmission hypotheses of the pathogenesis of hepatic encephalopathy (HE) have appeared to be unrelated and perhaps mutually exclusive. Observations in animal models of fulminant hepatic failure, that are consistent with increased GABAergic inhibitory neurotransmission contributing to the manifestations of HE, include: (i) abnormal visual evoked potential waveforms that resemble those induced by GABA(A)/benzodiazepine (BZ) receptor complex agonists; (ii) GABA(A)/BZ receptor complex antagonist-induced ameliorations of encephalopathy; (iii) increased resistance to drugs which decrease GABAergic tone; and (iv) hypersensitivity of CNS neurons to depression by GABA(A)/BZ receptor complex agonists. Mechanisms of increased GABAergic tone in HE may include the following: (i) increased brain concentrations of natural BZs; and (ii) increased GABA concentrations in synaptic clefts, possibly due to increased blood-brain-barrier permeability to GABA and a decrease in GABA(B) receptor density. Both neuroelectrophysiological and behavioral data indicate that ammonia concentrations in the range 0.75-2 mM induce increased excitatory neurotransmission. In contrast, recently, ammonia concentrations in the range 0.15-0.75 mM, i.e. concentrations that commonly occur in plasma in precoma HE, have been shown: (i) to increase GABA-induced chloride current in cultured neurons; and (ii) to enhance synergistically the binding of GABA(A)/BZ receptor agonists. In addition, increased ammonia concentrations enhance synthesis of neurosteroids in astrocytes, and some neurosteroids potently augment GABAergic neurotransmission. Thus, the modestly elevated concentrations of ammonia, that commonly occur in liver failure, may contribute to the manifestations of HE by enhancing GABAergic inhibitory neurotransmission. This concept appears to unify the ammonia and GABAergic neurotransmission hypotheses. |