Until now, the only well documented, fast excitatory neurotransmitter in the brain has been glutamate. Although there is evidence for adenosine 5'-triphosphate (ATP) acting as a transmitter in the peripheral nervous system, suggestions for such a role in the central nervous system have so far not been supported by any direct evidence. Here we report the recording of evoked and miniature synaptic currents in the rat medial habenula. The fast rise time of the currents showed that they were mediated by a ligand-activated ion channel rather than a second messenger system, thus limiting the known transmitter candidates. Evidence was found for the presence on the cells of glutamate, gamma-aminobutyric acid, acetylcholine and ATP receptors, but not for 5-hydroxytryptamine (5HT3) or glycine receptors. The evoked currents were unaffected by blockers of glutamate, gamma-aminobutyric acid or acetylcholine receptors but were blocked by the ATP receptor-blocker, suramin and the desensitizing ATP receptor-agonist alpha,beta-methylene-ATP. Our evidence identifies for the first time synaptic currents in the brain, mediated directly by ATP receptors.

Hansen et al. review recent structural data that have provided insight into the function and allosteric modulation of NMDA receptors.

The balance between excitatory and inhibitory synapses is crucial for normal brain function. Wnt proteins stimulate synapse formation by increasing synaptic assembly. However, it is unclear whether Wnt signaling differentially regulates the formation of excitatory and inhibitory synapses. Here, we demonstrate that Wnt7a preferentially stimulates excitatory synapse formation and function. In hippocampal neurons, Wnt7a increases the number of excitatory synapses, whereas inhibitory synapses are unaffected. Wnt7a or postsynaptic expression of Dishevelled-1 (Dvl1), a core Wnt signaling component, increases the frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs), but not miniature inhibitory postsynaptic currents (mIPSCs). Wnt7a increases the density and maturity of dendritic spines, whereas Wnt7a-Dvl1-deficient mice exhibit defects in spine morphogenesis and mossy fiber-CA3 synaptic transmission in the hippocampus. Using a postsynaptic reporter for Ca 2+ /Calmodulin-dependent protein kinase II (CaMKII) activity, we demonstrate that Wnt7a rapidly activates CaMKII in spines. Importantly, CaMKII inhibition abolishes the effects of Wnt7a on spine growth and excitatory synaptic strength. These data indicate that Wnt7a signaling is critical to regulate spine growth and synaptic strength through the local activation of CaMKII at dendritic spines. Therefore, aberrant Wnt7a signaling may contribute to neurological disorders in which excitatory signaling is disrupted.Wnt7a | Dvl1 mutant | plasticity T he formation of functional neuronal circuits requires the assembly of different types of synapses with great specificity. The development of an appropriate balance of glutamatergic excitatory and GABAergic inhibitory synapses (E/I ratio) is essential for proper circuit function (1, 2) because an imbalance in the E/I ratio can result in neurological disorders (3-5). Some synaptogenic factors regulate both excitatory and inhibitory synapses (6, 7), whereas other synaptic organizers are more specific (8-10). However, the precise mechanisms by which synaptic organizing signals regulate excitatory and inhibitory synapses remain poorly understood.In the central nervous system, most excitatory inputs are located on dendritic spines, postsynaptic protrusions that function as domains where synaptic activity is regulated in a compartmentalized manner (11-13). Several intracellular molecules have been implicated in the formation and maturation of dendritic spines (14-16), but the mechanisms by which extracellular factors signal through intracellular regulators to promote spine development and maturation remain poorly characterized.Wnt secreted proteins are synaptic organizers that stimulate the formation of central and peripheral synapses (17-19) by promoting presynaptic assembly (20) and the clustering of postsynaptic components (19,(21)(22)(23)(24). In cultured neurons, Wnt5a regulates postsynaptic development of both GABAergic and glutamatergic synapses (24,25). However, it is unclear whether other Wnts play a...

SUMMARY1. Single channel recording techniques were used to study the ion channel openings resulting from activation of N-methyl-D-aspartate (NMDA) receptors by the agonist glutamate. Patches were from cells acutely dissociated from adult rat hippocampus (CAI). Channel activity was studied at low glutamate concentrations (20-100 nM) with 1 puM-glycine, in the absence of extracellular divalent cations. A. J. GIBB AND D. COLQUHOUN supports the idea that the NMDA receptor channel gating has the properties of a discrete Markov process.7. The long duration of NMDA receptor channel clusters suggests that they contribute to the slow time course of the NMDA receptor-mediated synaptic current.

Recent studies have shown that RIC-3, originally identified inCaenorhabditis elegans as the protein encoded by the gene resistance to inhibitors of cholinesterase (ric-3), can enhance functional expression of ␣7 nicotinic acetylcholine receptors (nAChRs). In the present study, the influence of C. elegans and human RIC-3 upon multiple homomeric (␣7, ␣8, and ␣9) and heteromeric (␣3␤2, ␣3␤4, ␣4␤2, ␣4␤4, and ␣9␣10) nAChR subtypes has been examined in transfected mammalian cells by radioligand binding and functional characterization. Coexpression of RIC-3 facilitates a dramatic enhancement of the ability of ␣7 (and the closely related ␣8 subunit) to generate functional nAChRs in otherwise nonpermissive mammalian cells. In contrast, coexpression of RIC-3 did not facilitate functional expression of either homomeric ␣9 or heteromeric ␣9␣10 nAChRs in mammalian cell lines. It is noteworthy that whereas RIC-3 has been reported to cause a marked functional inhibition of heteromeric nAChRs such as ␣3␤4 and ␣4␤2 expressed in Xenopus laevis oocytes, RIC-3 significantly enhances levels of functional expression of these and other (␣3␤2 and ␣4␤4) heteromeric nAChRs when expressed in mammalian cell lines. In addition, the interaction of multiple nAChR subunits (␣3, ␣4, ␣7, ␤2, and ␤4) with RIC-3 has been demonstrated by coimmunoprecipitation from metabolically labeled transfected cells. It is significant that coimmunoprecipitation experiments have provided evidence that RIC-3 associates with unassembled nAChR subunits, a finding that is consistent with previous suggestions that RIC-3 may act by enhancing the maturation (subunit folding and assembly) of nAChRs. We conclude that RIC-3 is an nAChR-associated protein that can enhance functional expression of multiple nAChR subtypes in transfected mammalian cells.