The ErbB2 tyrosine kinase functions as coreceptor for the neuregulin receptors ErbB3 and ErbB4 and can participate in signaling of EGF receptor (ErbB1), interleukin receptor gp130, and G-protein coupled receptors. ErbB2−/− mice die at midgestation because of heart malformation. Here, we report a genetic rescue of their heart development by myocardial expression of erbB2 cDNA that allows survival of the mutants to birth. In rescued erbB2 mutants, Schwann cells are lacking. Motoneurons form and can project to muscle, but nerves are poorly fasciculated and disorganized. Neuromuscular junctions form, as reflected in clustering of AChR and postsynaptic expression of the genes encoding the ␣-AChR, AChE, ⑀-AChR, and the RI subunit of the cAMP protein kinase. However, a severe loss of motoneurons on cervical and lumbar, but not on thoracic levels occurs. Our results define the roles of Schwann cells during motoneuron and synapse development, and reveal different survival requirements for distinct motoneuron populations.
Synaptic plasticity at neuronal connections has been well characterized functionally by using electrophysiological approaches, but the structural basis for this phenomenon remains controversial. We have studied the dynamic interactions between presynaptic and postsynaptic structures labeled with FM 4-64 and a membranetargeted GFP, respectively, in hippocampal slices. Under conditions of reduced neuronal activity (1 M tetrodotoxin), we observed extension of glutamate receptor-dependent processes from dendritic spines of CA1 pyramidal cells to presynaptic boutons. The formation of these spine head protrusions is blocked by ␣-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonists and by agents that reduce the release of glutamate from presynaptic terminals. Moreover, spine head protrusions form in response to exogenously applied glutamate, with clear directionality toward the glutamate electrode. Our results suggest that spontaneously released glutamate is sufficient to activate nearby spines, which can then lead to the growth of new postsynaptic processes connecting to a presynaptic site. Spines thus can compare their recent history with that of neighboring synapses and modify local connectivity accordingly.T he majority of excitatory connections in the hippocampus are made at dendritic spines, which are small protrusions (Ϸ1 m long) that extend from dendrites (1, 2). Dendritic spines can undergo significant morphological change over a timescale of seconds (3), and this motility is both actin-dependent and responsive to synaptic activity (4-7). Spine motility plays a major role in synaptogenesis (8-10) but its physiological relevance in mature spines is unknown. It has been suggested that spine motility influences the compartmentalization of electrical and calcium signals, yet in CA1 pyramidal cells the resistance of the spine neck is insufficient for electrical filtering (11), and spine dynamics will have no effect on calcium signaling because calcium diffusion through the neck is negligible (12). Recent work from our laboratory also indicates a relationship between spine motility and the ability of proteins tethered to the inner leaflet of the membrane to diffuse (13). We have further explored possible physiological roles of spine motility by investigating dynamic interactions between presynaptic and postsynaptic sites and the regulation of these dynamics by glutamate. Our results indicate that the motility of mature spines can lead to changes in synaptic connectivity. We hypothesize that when a spine has not been recently activated by glutamate released by its associated bouton, it can respond to glutamate released by a neighboring synapse. Spines thus can compare their individual recent history to the level of activity of neighboring synapses and modify hippocampal microcircuitry accordingly. MethodsTransgenic Mice. Variegated mice were generated by using standard techniques. A construct was generated where the cDNA for EGFP was fused to the membrane-anchoring domain (first 41 aa) of a...
Agrin-deficient mice die at birth because of aberrant development of the neuromuscular junctions. Here, we examined the role of agrin at brain synapses. We show that agrin is associated with excitatory but not inhibitory synapses in the cerebral cortex. Most importantly, we examined the brains of agrin-deficient mice whose perinatal death was prevented by the selective expression of agrin in motor neurons. We find that the number of presynaptic and postsynaptic specializations is strongly reduced in the cortex of 5-to 7-week-old mice. Consistent with a reduction in the number of synapses, the frequency of miniature postsynaptic currents was greatly decreased. In accordance with the synaptic localization of agrin to excitatory synapses, changes in the frequency were only detected for excitatory but not inhibitory synapses. Moreover, we find that the muscle-specific receptor tyrosine kinase MuSK, which is known to be an essential component of agrin-induced signaling at the neuromuscular junction, is also localized to a subset of excitatory synapses. Finally, some components of the mitogen-activated protein (MAP) kinase pathway, which has been shown to be activated by agrin in cultured neurons, are deregulated in agrin-deficient mice. In summary, our results provide strong evidence that agrin plays an important role in the formation and/or the maintenance of excitatory synapses in the brain, and we provide evidence that this function involves MAP kinase signaling.
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