Article

Basal GABA regulates GABA(B)R conformation and release probability at single hippocampal synapses.

Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Neuron (Impact Factor: 15.77). 07/2010; 67(2):253-67. DOI: 10.1016/j.neuron.2010.06.022
Source: PubMed

ABSTRACT Presynaptic GABA(B) receptor (GABA(B)R) heterodimers are composed of GB(1a)/GB(2) subunits and critically influence synaptic and cognitive functions. Here, we explored local GABA(B)R activation by integrating optical tools for monitoring receptor conformation and synaptic vesicle release at individual presynaptic boutons of hippocampal neurons. Utilizing fluorescence resonance energy transfer (FRET) spectroscopy, we detected a wide range of FRET values for CFP/YFP-tagged GB(1a)/GB(2) receptors that negatively correlated with release probabilities at single synapses. High FRET of GABA(B)Rs associated with low release probability. Notably, pharmacological manipulations that either reduced or increased basal receptor activation decreased intersynapse variability of GB(1a)/GB(2) receptor conformation. Despite variability along axons, presynaptic GABA(B)R tone was dendrite specific, having a greater impact on synapses at highly innervated proximal branches. Prolonged neuronal inactivity reduced basal receptor activation, leading to homeostatic augmentation of release probability. Our findings suggest that local variations in basal GABA concentration are a major determinant of GB(1a)/GB(2) conformational variability, which contributes to heterogeneity of neurotransmitter release at hippocampal synapses.

0 Bookmarks
 · 
84 Views
  • Neurobiology of Learning and Memory 01/2014; · 3.33 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: GABAB receptor is present at pre- and post-synaptic sites and participates in many brain functions including cognition, reward and anxiety. Although a lot of research has shown that activation or blockade of GABAB receptor may produce different even opposing effects on long-term potentiation (LTP) and cognitive functions, there is little information available concerning the effect of GABAB receptor on behavioral LTP, a learning-induced LTP model. Herein, we firstly examined the effects of 2-OH saclofen, a GABAB receptor antagonist, on the induction of behavioral LTP and Y-maze learning performance. In addition, GABAB receptor has been reported to be present on cholinergic terminals and to regulate the ACh release. Therefore, we also investigated the effects of 2-OH saclofen on the impairments in behavioral LTP and cognitive function induced by scopolamine, an acetylcholine receptor antagonist. We found that intrahippocampal application of 2-OH saclofen could significantly enhance the population spike (PS) amplitude with a dose-response relationship, and 20 μM 2-OH saclofen evidently facilitated the formation of behavioral LTP in the perforant pathway to the dentate gyrus (PP-DG) and led to an obvious improvement in maze learning performance. Furthermore, intrahippocampal 20 μM 2-OH saclofen administration could markedly reverse the scopolamine-induced impairments in the behavioral LTP and maze performance. Our data demonstrate that blockade of GABAB receptor displays a facilitatory role in the induction of behavioral LTP and maze learning task, and the antagonist of GABAB receptor seems to exert the potentially therapeutic value in the cognitive defect induced by cholinergic dysfunction.
    Neurobiology of Learning and Memory 04/2014; · 3.33 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Accumulation of amyloid-β peptides (Aβ), the proteolytic products of the amyloid precursor protein (APP), induces a variety of synaptic dysfunctions ranging from hyperactivity to depression that are thought to cause cognitive decline in Alzheimer's disease. While depression of synaptic transmission has been extensively studied, the mechanisms underlying synaptic hyperactivity remain unknown. Here, we show that Aβ40 monomers and dimers augment release probability through local fine-tuning of APP-APP interactions at excitatory hippocampal boutons. Aβ40 binds to the APP, increases the APP homodimer fraction at the plasma membrane, and promotes APP-APP interactions. The APP activation induces structural rearrangements in the APP/Gi/o-protein complex, boosting presynaptic calcium flux and vesicle release. The APP growth-factor-like domain (GFLD) mediates APP-APP conformational changes and presynaptic enhancement. Thus, the APP homodimer constitutes a presynaptic receptor that transduces signal from Aβ40 to glutamate release. Excessive APP activation may initiate a positive feedback loop, contributing to hippocampal hyperactivity in Alzheimer's disease.
    Cell reports. 05/2014;

Full-text

Download
15 Downloads
Available from
May 22, 2014