Astrocytes convert network excitation to tonic inhibition of neurons

<p>Abstract</p> <p>Background</p> <p>Glutamate and γ-aminobutyric acid (GABA) transporters play important roles in balancing excitatory and inhibitory signals in the brain. Increasing evidence suggest that they may act concertedly to regulate extracellular levels of the neurotransmitters.</p> <p>Results</p> <p>Here we present evidence that glutamate uptake-induced release of GABA from astrocytes has a direct impact on the excitability of pyramidal neurons in the hippocampus. We demonstrate that GABA, synthesized from the polyamine putrescine, is released from astrocytes by the reverse action of glial GABA transporter (GAT) subtypes GAT-2 or GAT-3. GABA release can be prevented by blocking glutamate uptake with the non-transportable inhibitor DHK, confirming that it is the glutamate transporter activity that triggers the reversal of GABA transporters, conceivably by elevating the intracellular Na⁺concentration in astrocytes. The released GABA significantly contributes to the tonic inhibition of neurons in a network activity-dependent manner. Blockade of the Glu/GABA exchange mechanism increases the duration of seizure-like events in the low-[Mg²⁺] <it>in vitro </it>model of epilepsy. Under <it>in vivo </it>conditions the increased GABA release modulates the power of gamma range oscillation in the CA1 region, suggesting that the Glu/GABA exchange mechanism is also functioning in the intact hippocampus under physiological conditions.</p> <p>Conclusions</p> <p>The results suggest the existence of a novel molecular mechanism by which astrocytes transform glutamat<it>ergic </it>excitation into GABA<it>ergic </it>inhibition providing an adjustable, <it>in situ </it>negative feedback on the excitability of neurons.</p

The domain-variant indirect association between electrophysiological response to reward and ADHD presentations is moderated by dopaminergic polymorphisms

Background: Understanding the etiopathogenesis of attention-deficit/hyperactivity disorder (ADHD) may necessitate decomposition of the heterogeneous clinical phenotype into more homogeneous intermediate phenotypes. Reinforcement sensitivity is a promising candidate, but the exact nature of the ADHD-reward relation – including how, for whom, and to which ADHD dimensions atypicalities in reward processing are relevant – is equivocal. Methods: Aims were to examine, in a carefully phenotyped sample of adolescents (N = 305; Mage = 15.30 years, SD = 1.07; 39.7% girls), whether functional dopaminergic polymorphisms implicated in both reward processing and ADHD (1) are differentially associated with event-related potentials (ERPs) of reward anticipation at distinct levels of ADHD risk (nno risk = 174, nat-risk = 131, ndiagnosed = 83); and (2) moderate the indirect effect of dispositional affectivity on the association between ERPs and ADHD domains. Results: In adolescents at-risk for or with ADHD, carrying a hypodopaminergic allele was associated with enhanced ERPs of attention allocation to cue and attenuated ERPs of anticipatory attention to feedback. No associations were observed in adolescents not at-risk for or without ADHD. Controlling for age and sex, both the negative indirect effect of positive affectivity (PA) on the association between ERPs and inattention and the positive indirect effect of PA on the association between ERPs and hyperactivity/impulsivity were supported only for those with high activity dopamine transporter (DAT) alleles. Conclusions: Reward and affective processing are promising intermediate phenotypes relevant to disentangling ADHD developmental pathways. Consistent with developmental multifinality, through the successive effects of reward anticipation and positive affectivity, functional dopaminergic variants may confer protection against inattention or risk for hyperactivity/impulsivity