Reduction of glial glutamate transporters in the parietal cortex and hippocampus of the EL mouse

There is extensive experimental evidence indicating a crucial role for glutamate in epileptogenesis and epileptic activity. The glial glutamate transporters GLT1 and GLAST are proposed to account for the majority of extracellular glutamate re-uptake. In the present study, polyclonal antibodies specific to GLT1 and GLAST were generated and characterized, revealing distribution patterns for the two transporters confirming those previously reported. In situ hybridization and immunoblotting were then used to compare levels of these two transporters in the parietal cortex and hippocampus of unstimulated and stimulated EL mice with DDY control mice. Additionally, HPLC determined tissue glutamate concentrations in the same regions of these animals. These experiments revealed reductions in GLT1 mRNA and protein in the parietal cortex of unstimulated and stimulated EL mice compared with DDY controls, accompanied by an increase in tissue glutamate concentration in the stimulated EL mice group. GLT1 mRNA was also reduced in the CA3 hippocampal subfield of both unstimulated and stimulated EL mice. GLAST protein was reduced in the hippocampus of the stimulated EL mice group, while no changes in GLAST mRNA or protein were detected in the parietal cortex of EL mice when compared with DDY controls. The glial glutamate transporter down-regulation reported here may play a role in seizure initiation, spread and maintenance in the EL mouse.     

Representational geometry of perceptual decisions in the monkey parietal cortex

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Cell-type-specific recruitment of GABAergic interneurons in the primary somatosensory cortex by long-range inputs

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Disrupting the experience of control in the human brain: pre-supplementary motor area contributes to the sense of agency

The feeling of controlling events through one''s actions is fundamental to human experience, but its neural basis remains unclear. This ‘sense of agency’ (SoA) can be measured quantitatively as a temporal linkage between voluntary actions and their external effects. We investigated the brain areas underlying this aspect of action awareness by using theta-burst stimulation to locally and reversibly disrupt human brain function. Disruption of the pre-supplementary motor area (pre-SMA), a key structure for preparation and initiation of a voluntary action, was shown to reduce the temporal linkage between a voluntary key-press action and a subsequent electrocutaneous stimulus. In contrast, disruption of the sensorimotor cortex, which processes signals more directly related to action execution and sensory feedback, had no significant effect. Our results provide the first direct evidence of a pre-SMA contribution to SoA.     

Involvement of GABA and cholinergic receptors in the nucleus accumbens on feedback control of somatodendritic dopamine release in the ventral tegmental area

The objectives of the present study were to examine the involvement of GABA and cholinergic receptors within the nucleus accumbens (ACB) on feedback regulation of somatodendritic dopamine (DA) release in the ventral tegmental area (VTA). Adult male Wistar rats were implanted with ipsilateral dual guide cannulae for in vivo microdialysis studies. Activation of the feedback system was accomplished by perfusion of the ACB with the DA uptake inhibitor GBR 12909 (GBR; 100 microm). To assess the involvement of GABA and cholinergic receptors in regulating this feedback system, antagonists (100 microm) for GABAA (bicuculline, BIC), GABAB (phaclofen, PHAC), muscarinic (scopolamine, SCOP), and nicotinic (mecamylamine, MEC) receptors were perfused through the probe in the ACB while measuring extracellular DA levels in the ACB and VTA. Local perfusion of the ACB with GBR significantly increased (500% of baseline) the extracellular levels of DA in the ACB and produced a concomitant decrease (50% of baseline) in the extracellular DA levels in the VTA. Perfusion of the ACB with BIC or PHAC alone produced a 200-400% increase in the extracellular levels of DA in the ACB but neither antagonist altered the levels of DA in the VTA. Co-perfusion of either GABA receptor antagonist with GBR further increased the extracellular levels of DA in the ACB to 700-800% of baseline. However, coperfusion with BIC completely prevented the reduction in the extracellular levels of DA in the VTA produced by GBR alone, whereas PHAC partially prevented the reduction. Local perfusion of the ACB with either MEC or SCOP alone had little effect on the extracellular levels of DA in the ACB or VTA. Co-perfusion of either cholinergic receptor antagonist with GBR markedly reduced the extracellular levels of DA in the ACB and prevented the effects of GBR on reducing DA levels in the VTA. Overall, the results of this study suggest that terminal DA release in the ACB is under tonic GABA inhibition mediated by GABAA (and possibly GABAB) receptors, and tonic cholinergic excitation mediated by both muscarinic and nicotinic receptors. Activation of GABAA (and possibly GABAB) receptors within the ACB may be involved in the feedback inhibition of VTA DA neurons. Cholinergic interneurons may influence the negative feedback system by regulating terminal DA release within the ACB.     

Stimulation of 5-hydroxytryptamine (5-HT(2C) ) receptors in the ventrotegmental area inhibits stress-induced but not basal dopamine release in the rat prefrontal cortex

The present study investigated whether 5-HT(2C) receptors in the ventrotegmental area and prefrontal cortex regulate basal and stimulus-evoked dopamine release in the prefrontal cortex. Using the in vivo microdialysis technique in conscious rats, we studied the effect of a selective 5-HT(2C) receptor agonist, Ro60-0175, on basal and immobilization stress-induced dopamine release in the prefrontal cortex. Ro60-0175 intraperitoneally (2.5 mg/kg) and into the ventrotegmental area (10 microg/0.5 microL) completely antagonized the effect of stress on extracellular dopamine without altering basal levels. Infusion of 10 microm Ro60-0175 through the cortical probe had no significant effect on basal and stress-induced dopamine release. SB242084 (10 mg/kg), a selective antagonist of 5-HT(2C) receptors, significantly increased basal extracellular dopamine and completely prevented the effect of intraperitoneal and intraventrotegmental Ro60-0175 on the stress-induced rise of extracellular dopamine, but had no effect itself in stressed rats. The results show that Ro60-0175 suppresses cortical dopamine release induced by immobilization stress through the stimulation of 5-HT(2C) receptors in the ventrotegmental area. While confirming that endogenous 5-HT acting on 5-HT(2C) receptors tonically inhibit basal dopamine release in the prefrontal cortex, the present findings suggest that the stimulation of 5-HT(2C) receptors with an exogenous agonist preferentially inhibit stimulated release.