Reduced Cortical γ-Aminobutyric Acid Levels in Depressed Patients Determined by Proton Magnetic Resonance Spectroscopy
ABSTRACT Several lines of emerging evidence suggest that dysfunction of gamma-aminobutyric acid (GABA) systems is associated with major depression. However, investigation of this hypothesis is limited by difficulty obtaining noninvasive in vivo measures of brain GABA levels. In this study we used in vivo proton magnetic resonance spectroscopy to investigate the hypothesis that abnormalities in the GABA neurotransmitter system are associated with the neurobiologic processes of depression.
The GABA levels were measured in the occipital cortex of medication-free depressed patients meeting DSM-IV criteria (n = 14) and healthy control subjects with no history of mental illness (n = 18) using a localized difference editing proton magnetic resonance spectroscopy protocol. An analysis of covariance was employed to examine the effects of depression, sex, and age.
The depressed patients demonstrated a highly significant (52%) reduction in occipital cortex GABA levels compared with the group of healthy subjects. While there were significant age and sex effects, there was no interaction of diagnosis with either age or sex.
This study provides the first evidence of abnormally low cortical GABA concentrations in the brains of depressed patients.
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- "The contribution of altered GABA levels may still have influenced our data. However, GABA concentration in general is much lower than combined Glx (Sanacora et al., 1999). Also, Glx signal is mostly dominated by glutamate (Auer et al., 2000). "
ABSTRACT: An excitatory-inhibitory neurotransmitter dysbalance has been suggested in pathogenesis of panic disorder. The neuropeptide S (NPS) system has been implicated in modulating GABA and glutamate neurotransmission in animal models and to genetically drive altered fear circuit function and an increased risk of panic disorder in humans. Probing a multi-level imaging genetic risk model of panic, in the present magnetic resonance spectroscopy (MRS) study brain glutamate+glutamine (Glx) levels in the bilateral anterior cingulate cortex (ACC) during a pharmacological cholecystokinin tetrapeptide (CCK-4) panic challenge were assessed depending on the functional neuropeptide S receptor gene (NPSR1) rs324981 A/T variant in a final sample of 35 healthy male subjects. The subjective panic response (Panic Symptom Scale; PSS) as well as cortisol and ACTH levels were ascertained throughout the experiment. CCK-4 injection was followed by a strong panic response. A significant time×genotype interaction was detected (p=.008), with significantly lower ACC Glx/Cr levels in T allele carriers as compared to AA homozygotes 5min after injection (p=.003). CCK-4 induced significant HPA axis stimulation, but no effect of genotype was discerned. The present pilot data suggests NPSR1 gene variation to modulate Glx levels in the ACC during acute states of stress and anxiety, with blunted, i.e. possibly maladaptive ACC glutamatergic reactivity in T risk allele carriers. Our results underline the notion of a genetically driven rapid and dynamic response mechanism in the neural regulation of human anxiety and further strengthen the emerging role of the NPS system in anxiety. Copyright © 2015. Published by Elsevier B.V.European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 07/2015; DOI:10.1016/j.euroneuro.2015.07.011 · 5.40 Impact Factor
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- "ed hippocampal GAD65 of the mice . ( A ) Western blotting analysis of GAD65 , GAT1 , GABA A Rα5 , and GABA A Rβ2 / 3 ; ( B ) Gray intensity comparison . N = 8 / group ; * p < 0 . 05 . neurological dysfunction . For instance , excessively increased excitatory Glu but reduced inhibitory GABA is closely associated with pathophysiology of depression ( Sanacora et al . , 1999 ) . Drugs facilitating glutamatergic transmission may enhance memory ( Staubli et al . , 1994 ) . Similar effect can be obtained by antag - onizing GABA transmission ( Kim et al . , 2014 ) . Nevertheless , a disrupted balance between excitatory and inhibitory neurotrans - mitter systems is central to the pathogenesis of a variety of neu"
ABSTRACT: Farnesoid X receptor (FXR) is a nuclear hormone receptor involved in bile acid synthesis and homeostasis. Dysfunction of FXR is involved in cholestasis and atherosclerosis. FXR is prevalent in liver, gallbladder, and intestine, but it is not yet clear whether it modulates neurobehavior. In the current study, we tested the hypothesis that mouse FXR deficiency affects a specific subset of neurotransmitters and results in an unique behavioral phenotype. The FXR knockout mice showed less depressive-like and anxiety-related behavior, but increased motor activity. They had impaired memory and reduced motor coordination. There were changes of glutamatergic, GABAergic, serotoninergic, and norepinephrinergic neurotransmission in either hippocampus or cerebellum. FXR deletion decreased the amount of the GABA synthesis enzyme GAD65 in hippocampus but increased GABA transporter GAT1 in cerebral cortex. FXR deletion increased serum concentrations of many bile acids, including taurodehydrocholic acid, taurocholic acid, deoxycholic acid (DCA), glycocholic acid (GCA), tauro-α-muricholic acid, tauro-ω-muricholic acid, and hyodeoxycholic acid (HDCA). There were also changes in brain concentrations of taurocholic acid, taurodehydrocholic acid, tauro-ω-muricholic acid, tauro-β-muricholic acid, deoxycholic acid, and lithocholic acid (LCA). Taken together, the results from studies with FXR knockout mice suggest that FXR contributes to the homeostasis of multiple neurotransmitter systems in different brain regions and modulates neurobehavior. The effect appears to be at least partially mediated by bile acids that are known to cross the blood-brain barrier (BBB) inducing potential neurotoxicity.Frontiers in Behavioral Neuroscience 03/2015; 9:70. DOI:10.3389/fnbeh.2015.00070 · 4.16 Impact Factor
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- "Changes in GABA-glutamate balance may also be involved in these particular disorders. Depressed patients exhibit increased glutamate (Sanacora et al., 2004) and decreased GABA (Sanacora et al., 1999; Hasler et al., 2007) cortical content, although the latter might differ according to depression subtypes (Sanacora et al., 2004). The decrease in brain GABA content may (Honig et al., 1988) or may not (Sanacora et al., 1999; Sanacora et al., 2004) correlate with depression scores. "
ABSTRACT: In patients suffering from stress-related pathologies and depression, frontal cortex GABA and glutamate contents are reported to decrease and increase, respectively. This suggests that the GABA and/or glutamate content may participate in pathological phenotype expression. Whether differences in frontal cortex GABA and glutamate contents would be associated with specific behavioral and neurobiological patterns remains unclear, especially in the event of exposure to moderate stress. We hypothesized that an increase in prefrontal cortex GABA/glutamate ratio would be associated with a blunted prefrontal cortex activation, an enhanced hypothalamo-pituitary-adrenocortical (HPA) axis activation and changes in behavior. Rats being restrained for 1-h were then tested in an open-field test in order to assess their behavior while under stress, and were sacrificed immediately afterward. The GABA/glutamate ratio was assessed by (1)H high-resolution magic angle spinning magnetic resonance spectroscopy ((1)H-HRMAS-MRS). The neurobiological response was evaluated through prefrontal cortex mRNA expression and plasma corticosterone levels. The stressed rats were distributed into two subgroups according to their high (H-G/g) or low (L-G/g) GABA/glutamate ratio. Compared to the L-G/g rats, the H-G/g rats exhibited a decrease in c-fos, Arc, Npas4, Nr4a2 mRNA expression suggesting blunted prefrontal cortex activation. They also showed a more pronounced stress with an enhanced rise in corticosterone, alanine aminotransferase (ALAT), aspartate aminotransferase (ASAT), creatine kinase (CK) and lactate dehydrogenase (LDH) levels, as well as behavioral disturbances with decreased locomotion speed. These changes were independent from prefrontal cortex energetic status as mTOR and adenosine monophosphate-activated protein kinase (AMPK) pathway activities were similar in both subpopulations. The differences in GABA/glutamate ratio in the frontal cortex observed in the stressed animals may participate in shaping individual differences in psychophysiological reactions. Copyright © 2014. Published by Elsevier Ltd.Neuroscience 11/2014; 285. DOI:10.1016/j.neuroscience.2014.10.058 · 3.33 Impact Factor