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Introduction Schizophrenia is associated with impairments in executive functioning--particularly cognitive control. These deficits are present before illness onset (1) and are stable over the course of the illness, (2,3) showing [...], Background: The major excitatory and inhibitory neurometabolites in the brain, glutamate and y-aminobutyric acid (GABA), respectively, are related to the functional MRI signal. Disruption of resting-state functional MRI signals has been reported in psychosis spectrum disorders, but few studies have investigated the role of these metabolites in this context. Methods: We included 19 patients with first-episode psychosis and 21 healthy controls in this combined magnetic resonance spectroscopy (MRS) and resting-state functional connectivity study. All imaging was performed on a Siemens Magnetom 7 T MRI scanner. Both the MRS voxel and the seed for functional connectivity analysis were located in the dorsal anterior cingulate cortex (ACC). We used multiple regressions to test for an interaction between ACC brain connectivity, diagnosis and neurometabolites. Results: ACC brain connectivity was altered in first-episode psychosis. The relationship between ACC glutamate and ACC functional connectivity differed between patients with first-episode psychosis and healthy controls in the precuneus, retrosplenial cortex, supramarginal gyrus and angular gyrus. As well, the relationship between ACC GABA and ACC functional connectivity differed between groups in the caudate, putamen and supramarginal gyrus. Limitations: We used a small sample size. As well, although they were not chronically medicated, all participants were medicated during the study. Conclusion: We demonstrated a link between the major excitatory and inhibitory brain metabolites and resting-state functional connectivity in healthy participants, as well as an alteration in this relationship in patients with first-episode psychosis. Combining data from different imaging modalities may help our mechanistic understanding of the relationship between major neurometabolites and brain network dynamics, and shed light on the pathophysiology of first-episode psychosis.

Introduction Mood disorders, such as depression and anxiety, are closely related to bone metabolism abnormalities (1-3) and can lead to low bone mass and increased risk of fracture (4, 5). [...], Homeostasis of bone metabolism is regulated by the central nervous system, and mood disorders such as anxiety are associated with bone metabolism abnormalities, yet our understanding of the central neural circuits regulating bone metabolism is limited. Here, we demonstrate that chronic stress in crewmembers resulted in decreased bone density and elevated anxiety in an isolated habitat mimicking a space station. We then used a mouse model to demonstrate that GABAergic neural circuitry in the ventromedial hypothalamus (VMH) mediates chronic stress-induced bone loss. We show that GABAergic inputs in the dorsomedial VMH arise from a specific group of somatostatin neurons in the posterior region of the bed nucleus of the stria terminalis, which is indispensable for stress-induced bone loss and is able to trigger bone loss in the absence of stressors. In addition, the sympathetic system and glutamatergic neurons in the nucleus tractus solitarius were employed to regulate stress-induced bone loss. Our study has therefore identified the central neural mechanism by which chronic stress-induced mood disorders, such as anxiety, influence bone metabolism.

Introduction Up to 44% of patients with major depressive disorder (MDD) experience treatment-resistant depression (TRD): illness that fails to respond to multiple medication trials. (1) Among patients with MDD, those [...], Background: The therapeutic mechanism of repetitive transcranial magnetic stimulation (rTMS) for treatment-resistant depression (TRD) may involve modulation of [gamma]-aminobutyric acid (GABA) levels. We used proton magnetic resonance spectroscopy (MRS) to assess changes in GABA levels at the site of rTMS in the left dorsolateral prefrontal cortex (DLPFC). Methods: In 26 adults with TRD, we used Mescher-Garwood point-resolved spectroscopy (MEGA-PRESS) spectral-editing MRS to measure GABA in the left DLPFC before and after standard clinical treatment with rTMS. All participants but 1 were medicated, including 12 patients on GABA agonist agents. Results: Mean GABA in the DLPFC increased 10.0% (p = 0.017) post-rTMS in the overall sample. As well, GABA increased significantly in rTMS responders (n = 12; 23.6%, p = 0.015) but not in nonresponders (n = 14; 4.1%, p = not significant). Changes in GABA were not significantly affected by GABAergic agonists, but clinical response was less frequent (p = 0.005) and weaker (p = 0.035) in the 12 participants who were receiving GABA agonists concomitant with rTMS treatment. Limitations: This study had an open-label design in a popul ation receiving naturalistic treatment. Conclusion: Treatment using rTMS was associated with increases in GABA levels at the stimulation site in the left DLPFC, and the degree of GABA change was related to clinical improvement. Participants receiving concomitant treatment with a GABA agonist were less likely to respond to rTMS. These findings were consistent with earlier studies showing the effects of rTMS on GABA levels and support a GABAergic model of depression.

Introduction Transcranial magnetic stimulation (TMS) is an effective treatment for major depressive disorder (MDD), particularly in individuals resistant to first-line antidepressants. (1-3) Effect sizes of TMS from recent meta-analyses range [...], Background: GABAergic and glutamatergic neurotransmitter systems are central to the pathophysiology of depression and are potential targets of repetitive transcranial magnetic stimulation (rTMS). We assessed the effect of 10-Hz rTMS over the left dorsolateral prefrontal cortex (DLPFC) of patients with major depressive disorder on the levels of medial prefrontal cortex (MPFC) γ-aminobutyric acid (GABA) and the combined resonance of glutamate and glutamine (Glx) as assessed in vivo with proton magnetic resonance spectroscopy (¹H MRS). Methods: Currently depressed individuals between the ages of 23 and 68 years participated in a 5-week naturalistic, open-label treatment study of rTMS, with ¹H MRS measurements of MPFC GABA and Glx levels at baseline and following 5 weeks of the rTMS intervention. We applied rTMS pulses over the left DLPFC at 10 Hz and 80%-120% of motor threshold for 25 daily sessions, with each session consisting of 3000 pulses. We assessed therapeutic response using the 24-item Hamilton Rating Scale for Depression (HAMD24). The GABA and Glx levels are expressed as ratios of peak areas relative to the area of the synchronously acquired and similarly fitted unsuppressed voxel water signal (W). Results: Twenty-three currently depressed individuals (7 men) participated in the study. GABA/W in the MPFC increased 13.8% (p = 0.013) in all depressed individuals. There were no significant effects of rTMS on Glx/W. GABA/W and Glx/W were highly correlated in severely depressed patients at baseline but not after TMS. Limitations: The primary study limitations are the open-label design and the inclusion of participants currently taking stable regimens of antidepressant medications. Conclusion: These results implicate GABAergic and glutamatergic systems in the mechanism of action of rTMS for major depression, warranting further investigation in larger samples.

Body fluid homeostasis regulates the internal salt and water balance; as this balance shifts, the brain senses these changes and triggers specific goal-oriented intake behaviours (2, 3). For instance, salt-deprived [...], Thirst is the basic instinct to drink water. Previously, it was shown that neurons in several circumventricular organs of the hypothalamus are activated by thirst-inducing conditions (1). Here we identify two distinct, genetically separable neural populations in the subfornical organ that trigger or suppress thirst. We show that optogenetic activation of subfornical organ excitatory neurons, marked by the expression of the transcription factor ETV-1, evokes intense drinking behaviour, and does so even in fully water-satiated animals. The light-induced response is highly specific for water, immediate and strictly locked to the laser stimulus. In contrast, activation of a second population of subfornical organ neurons, marked by expression of the vesicular GABA transporter VGAT, drastically suppresses drinking, even in water-craving thirsty animals. These results reveal an innate brain circuit that can turn an animal's water-drinking behaviour on and off, and probably functions as a centre for thirst control in the mammalian brain.

Disorders of neuronal migration during the development of the cerebral cortex result in neuronal heterotopia, which increases the risk of epilepsy (1), (2). Neuronal heterotopia is associated with spontaneous seizures [...], Temporal lobe epilepsy (TLE) is accompanied by an abnormal location of granule cells in the dentate gyrus. Using a rat model of complex febrile seizures, which are thought to be a precipitating insult of TLE later in life, we report that aberrant migration of neonatal-generated granule cells results in granule cell ectopia that persists into adulthood. Febrile seizures induced an upregulation of GABAA receptors (GABAA-Rs) in neonatally generated granule cells, and hyperactivation of excitatory GABAA-Rs caused a reversal in the direction of granule cell migration. This abnormal migration was prevented by RNAi-mediated knockdown of the Na + K + 2Cl - cotransporter (NKCC1), which regulates the excitatory action of GABA. NKCC1 inhibition with bumetanide after febrile seizures rescued the granule cell ectopia, susceptibility to limbic seizures and development of epilepsy. Thus, this work identifies a previously unknown pathogenic role of excitatory GABAA-R signaling and highlights NKCC1 as a potential therapeutic target for preventing granule cell ectopia and the development of epilepsy after febrile seizures.

The combined-use of alcohol and energy drinks (EDs) on college campuses and in communities has become a considerable public health concern. Among college students, intercollegiate athletes have been identified as [...]

Mutations in MECP2 cause Rett syndrome as well as a variety of neuropsychiatric syndromes including autism, bipolar disorder with cognitive deficits and childhood-onset schizophrenia with intellectual disabilities (1-6). Rett syndrome [...], Mutations in the X-linked MECP2 gene, which encodes the transcriptional regulator methyl-CpG-binding protein 2 (MeCP2), cause Rett syndrome and several neurodevelopmental disorders including cognitive disorders, autism, juvenile-onset schizophrenia and encephalopathy with early lethality. Rett syndrome is characterized by apparently normal early development followed by regression, motor abnormalities, seizures and features of autism, especially stereotyped behaviours. The mechanisms mediating these features are poorly understood. Here we show that mice lacking Mecp2 from GABA (γ-aminobutyric acid)-releasing neurons recapitulate numerous Rett syndrome and autistic features, including repetitive behaviours. Loss of MeCP2 from a subset of forebrain GABAergic neurons also recapitulates many features of Rett syndrome. MeCP2-deficient GABAergic neurons show reduced inhibitory quantal size, consistent with a presynaptic reduction in glutamic acid decarboxylase 1 (Gad1) and glutamic acid decarboxylase 2 (Gad2) levels, and GABA immunoreactivity. These data demonstrate that MeCP2 is critical for normal function of GABA- releasing neurons and that subtle dysfunction of GABAergic neurons contributes to numerous neuropsychiatric phenotypes.

The pore and gate regions of voltage-gated cation channels have been often targeted with drugs acting as channel modulators. In contrast, the voltage-sensing domain (VSD) was practically not exploited for therapeutic purposes, although it is the target of various toxins. We recently designed unique diphenylamine carboxylates that are powerful Kv7.2 voltage-gated [K.sup.+] channel openers or blockers. Here we show that a unique Kv7.2 channel opener, NH29, acts as a nontoxin gating modifier. NH29 increases Kv7.2 currents, thereby producing a hyperpolarizing shift of the activation curve and slowing both activation and deactivation kinetics. In neurons, the opener depresses evoked spike discharges. NH29 dampens hippocampal glutamate and GABA release, thereby inhibiting excitatory and inhibitory postsynaptic currents. Mutagenesis and modeling data suggest that in Kv7.2, NH29 docks to the external groove formed by the interface of helices S1, S2, and S4 in a way that stabilizes the interaction between two conserved charged residues in S2 and S4, known to interact electrostatically, in the open state of Kv channels. Results indicate that NH29 may operate via a voltage-sensor trapping mechanism similar to that suggested for scorpion and sea-anemone toxins. Reflecting the promiscuous nature of the VSD, NH29 is also a potent blocker of TRPV1 channels, a feature similar to that of tarantula toxins. Our data provide a structural framework for designing unique gating-modifiers targeted to the VSD of voltage-gated cation channels and used for the treatment of hyperexcitability disorders. M-current | ion channel | KCNQ | opener doi/ 10.1073/pnas.0911294107

Slow and persistent synaptic inhibition is mediated by metabotropic [GABA.sub.B] receptors ([GABA.sub.B]RS). [GABA.sub.B]Rs are responsible for the modulation of neurotransmitter release from presynaptic terminals and for hyperpolarization at postsynaptic sites. Postsynaptic [GABA.sub.B]RS are predominantly found on dendritic spines, adjacent to excitatory synapses, but the control of their plasma membrane availability is still controversial. Here, we explore the role of glutamate receptor activation in regulating the function and surface availability of [GABA.sub.B]Rs in central neurons. We demonstrate that prolonged activation of NMDA receptors (NMDA-Rs) leads to endocytosis, a diversion from a recycling route, and subsequent lysosomal degradation of [GABA.sub.B]Rs. These sorting events are paralleled by a reduction in [GABA.sub.B]R-dependent activation of inwardly rectifying [K.sup.+] channel currents. Postendocytic sorting is critically dependent on phosphorylation of serine 783 (S783) within the [GABA.sub.B]R2 subunit, an established substrate of AMP-dependent protein kinase (AMPK). NMDA-R activation leads to a rapid increase in phosphorylation of S783, followed by a slower dephosphorylation, which results from the activity of AMPK and protein phosphatase 2A, respectively. Agonist activation of [GABA.sub.B]Rs counters the effects of NMDA. Thus, NMDA-R activation alters the phosphorylation state of S783 and acts as a molecular switch to decrease the abundance of [GABA.sub.B]RS at the neuronal plasma membrane. Such a mechanism may be of significance during synaptic plasticity or pathological conditions, such as ischemia or epilepsy, which lead to prolonged activation of glutamate receptors. endocytic | recycling | excitation-inhibition | glutamate doi/ 10.1073/pnas.1000853107

[GABA.sub.B] receptors are the G-protein-coupled receptors for GABA, the main inhibitory neurotransmitter in the brain. [GABA.sub.B] receptors are abundant on dendritic spines, where they dampen postsynaptic excitability and inhibit [Ca.sup.2+] influx through NMDA receptors when activated by spillover of GABA from neighboring GABAergic terminals. Here, we show that an excitatory signaling cascade enables spines to counteract this [GABA.sub.B]-mediated inhibition. We found that NMDA application to cultured hippocampal neurons promotes dynamin-dependent endocytosis of [GABA.sub.B] receptors. NMDA-dependent internalization of [GABA.sub.B] receptors requires activation of [Ca.sup.2+]/Calmodulin-dependent protein kinase II (CaMKII), which associates with [GABA.sub.B] receptors in vivo and phosphorylates serine 867 (S867) in the intracellular C terminus of the [GABA.sub.B1] subunit. Blockade of either CaMKII or phosphorylation of S867 renders [GABA.sub.B] receptors, refractory to NMDA-mediated internalization. Time-lapse two-photon imaging of organotypic hippocampal slices reveals that activation of NMDA receptors removes [GABA.sub.B] receptors within minutes from the surface of dendritic spines and shafts. NMDA-dependent S867 phosphorylation and internalization is predominantly detectable with the [GABA.sub.B1b] subunit isoform, which is the isoform that clusters with inhibitory effector [K.sup.+] channels in the spines. Consistent with this, NMDA receptor activation in neurons impairs the ability of [GABA.sub.B] receptors to activate [K.sup.+] channels. Thus, our data support that NMDA receptor activity endocytoses postsynaptic [GABA.sub.B] receptors through CaMKII-mediated phosphorylation of S867. This provides a means to spare NMDA receptors at individual glutamatergic synapses from reciprocal inhibition through [GABA.sub.B] receptors. [gamma]-aminobutyric acid | spines | trafficking | synaptic plasticity | GABAB doi/ 10.1073/pnas.1000909107

Author(s): Kai Liu [1]; Juhyun Kim [1]; Dong Won Kim [1]; Yi Stephanie Zhang [1]; Hechen Bao [2]; Myrto Denaxa [3]; Szu-Aun Lim [2]; Eileen Kim [4]; Chang Liu [1]; [...]

The release of [gamma]-aminobutyric acid (GABA) and ATP from rat [beta] cells was monitored using an electrophysiological assay based on overexpression [GABA.sub.A] or [P.sub.2][X.sub.2] receptor ion channels. Exocytosis of LDCVs, detected by carbon fiber amperometry of serotonin, correlated strongly (~80%) with ATP release. The increase in membrane capacitance per ATP release event was 3.4 fF, close to the expected capacitance of an individual LDCV with a diameter of 0.3 [micro]m. ATP and GABA were coreleased with serotonin with the same probability. Immunogold electron microscopy revealed that ~15% of the LDCVs contain GABA. Prespike 'pedestals,' reflecting exit of granule constituents via the fusion pore, were less frequently observed for ATP than for serotonin or GABA and the relative amplitude (amplitude of foot compared to spike) was smaller: in some cases the ATP-dependent pedestal was missing entirely. An inward tonic current, not dependent on glucose and inhibited by the [GABA.sub.A] receptor antagonist SR95531, was observed in [beta] cells in clusters of islet cells. Noise analysis indicated that it was due to the activity of individual channels with a conductance of 30 pS, the same as expected for individual [GABA.sub.A] [Cl.sup.-] channels with the ionic gradients used. We conclude that (a) LDCVs accumulate ATP and serotonin; (b) regulated release of GABA can be accounted for by exocytosis of a subset of insulin-containing LDCVs; (c) the fusion pore of LDCVs exhibits selectivity and compounds are differentially released depending on their chemical properties (including size); and (d) a glucose-independent nonvesicular form of GABA release exists in [beta] cells.

The presence of [gamma]-aminobutyric acid (GABA) in a variety of Italian cheeses that have differed in many technological traits is assessed. The analysis has provided a basis for using selected cheese-related lactobacilli to develop health-promoting dairy products enriched in GABA.

The synthesis of enantiomerically pure [beta]- substituted [gamma]-butyrolactones carried out by employing nucleophilic cyclopropane ring opening of bicyclic lactone followed by decarbethoxylation is presented. The method could be applied to synthesize an anticonvulsant drug, pregabalin (S)-3-isobutyl-[gamma]-aminobutyric acid, for the treatment of peripheral neuropathic pain.

Plants do not have a central nervous system, but researchers have found that they use some of the same signaling hormones for stress that animals do. The neurotransmitter gamma-aminobutyric acid, [...]