No abstract

Synaptic inputs on dendrites are nonlinearly converted to action potential outputs, yet the spatiotemporal patterns of dendritic activation remain to be elucidated at single-synapse resolution. In rodents, we optically imaged synaptic activities from hundreds of dendritic spines in hippocampal and neocortical pyramidal neurons ex vivo and in vivo. Adjacent spines were frequently synchronized in spontaneously active networks, thereby forming dendritic foci that received locally convergent inputs from presynaptic cell assemblies. This precise subcellular geometry manifested itself during N-methyl-D-aspartate receptor-dependent circuit remodeling. Thus, clustered synaptic plasticity is innately programmed to compartmentalize correlated inputs along dendrites and may reify nonlinear synaptic integration.

Forkhead box O (Foxo) transcription factors induce muscle atrophy by upregulating the muscle-specific E3 ubiquitin ligases MuRF-1 and atrogin-1/MAFbx, but other than Akt, the upstream regulators of Foxos during muscle atrophy are largely unknown. To examine the involvement of the dystrophin glycoprotein complex (DGC) in regulation of Foxo activities and muscle atrophy, we analyzed the expression of DGC members during tail suspension, a model of unloading-induced muscle atrophy. Among several DGC members, only neuronal NOS (nNOS) quickly dislocated from the sarcolemma to the cytoplasm during tail suspension. Electron paramagnetic resonance spectrometry revealed production of NO in atrophying muscle. nNOS-null mice showed much milder muscle atrophy after tail suspension than did wild-type mice. Importantly, nuclear accumulation of dephosphorylated Foxo3a was not evident in nNOS-null muscle, and neither MuRF-1 nor atrogin-1/ MAFbx were upregulated during tail suspension. Furthermore, an nNOS-specific inhibitor, 7-nitroindazole, significantly prevented suspension-induced muscle atrophy. The NF-κB pathway was activated in both wildtype and nNOS-null muscle during tail suspension. We also show that nNOS was involved in the mechanism of denervation-induced atrophy. We conclude that nNOS/NO mediates muscle atrophy via regulation of Foxo transcription factors and is a new therapeutic target for disuse-induced muscle atrophy.

Brain-derived neurotrophic factor (BDNF) is one of neurotrophins involved in the development and maintenance of both the peripheral nervous system and CNS. Although the expression of BDNF and its receptor TrkB still occurs in the adult stage, their physiological role in the mature CNS is not fully understood. In the present study we examined in detail the possibility that BDNF modulates synaptic neurotransmissions by using patch-clamp technique in rat hippocampal CA1 region. BDNF (20 -100 ng/ml) did not show any appreciable effect on evoked EPSCs, but it markedly reduced both evoked and spontaneous IPSCs within 5 min, and the reduction persisted while BDNF was present. BDNF also attenuated GABA A receptor-mediated response to applied GABA. However, BDNF failed to attenuate IPSCs when the postsynaptic pyramidal neuron was loaded intracellularly with 200 nM K252a, an alkaloid that inhibits the kinase activity of Trk receptor family, through the patch pipette. Intracellular application of 200 nM K252b, a weaker inhibitor of Trk-type kinase, did not affect the inhibition. The attenuating effect also was prevented by postsynaptic injection of U73122 (5 M), a broad-spectrum PLC inhibitor, and by strong chelation of intracellular Ca 2ϩ with 10 mM BAPTA. These data suggest that BDNF modulates GABA A synaptic responses by postsynaptic activation of Trk-type receptor and subsequent Ca 2ϩ mobilization in the CNS.Key words: BDNF; GABA A receptor; disinhibition; plasticity; LTP; hippocampus Brain-derived neurotrophic factor (BDNF) is one of the neurotrophins involved in the development and maintenance of both the peripheral nervous system and CNS. During brain development neurotrophins and their receptors display distinct stage-and tissue-specific patterns of expression (Ernfors et al., 1990a;Phillips et al., 1990;Merlio et al., 1992). BDNF mRNA is observed in the embryonic stage and is still present in the postnatal and adult stages (Ernfors et al., 1990b;Maisonpierre et al., 1990; Freidman et al., 1991). In the adult stage its expression level is modulated dramatically by neuronal activity (Falkenberg et al., 1992;Patterson et al., 1992;Rocamora et al., 1992;Bengzon et al., 1993;Kokaia et al., 1993). Moreover, expression of TrkB, a functional BDNF receptor, not only increases during embryonic development but also continues to increase until several weeks after birth in the hippocampus (Masana et al., 1993;Ringstedt et al., 1993). These observations suggest that in the adult CNS dynamic change in BDNF level still can trigger neuronal plasticity via activation of TrkB. Indeed, neurotrophins are secreted by neurons in both a constitutive and an activity-dependent manner Thoenen, 1995, 1996;Griesbeck et al., 1995;Thoenen, 1995;Goodmann et al., 1996). Additionally, BDNF induces long-lasting enhancement of synaptic transmission (Kang and Schuman, 1995) and facilitates the induction of long-term potentiation (LTP) in the hippocampus (Figurov et al., 1996); however, the site and mechanism of action of BDNF remain unclear, becau...

Neuroligin (NLG), a postsynaptic adhesion molecule, is involved in the formation of synapses by binding to a cognate presynaptic ligand, neurexin. Here we report that neuroligin-1 (NLG1) undergoes ectodomain shedding at the juxtamembrane stalk region to generate a secreted form of NLG1 and a membrane-tethered C-terminal fragment (CTF) in adult rat brains in vivo as well as in neuronal cultures. Pharmacological and genetic studies identified ADAM10 as the major protease responsible for NLG1 shedding, the latter being augmented by synaptic NMDA receptor activation or interaction with soluble neurexin ligands. NLG1-CTF was subsequently cleaved by presenilin/γ-secretase. Secretion of soluble NLG1 was significantly upregulated under a prolonged epileptic seizure condition, and inhibition of NLG1 shedding led to an increase in numbers of dendritic spines in neuronal cultures. Collectively, neuronal activity-dependent proteolytic processing of NLG1 may negatively regulate the remodeling of spines at excitatory synapses.