Whereas the role of NogoA in limiting axonal fiber growth and regeneration following an injury of the mammalian central nervous system (CNS) is well known, its physiological functions in the mature uninjured CNS are less well characterized. NogoA is mainly expressed by oligodendrocytes, but also by subpopulations of neurons, in particular in plastic regions of the CNS, e.g., in the hippocampus where it is found at synaptic sites. We analyzed synaptic transmission as well as long-term synaptic plasticity (longterm potentiation, LTP) in the presence of function blocking antiNogoA or anti-Nogo receptor (NgR) antibodies and in NogoA KO mice. Whereas baseline synaptic transmission, short-term plasticity and long-term depression were not affected by either approach, long-term potentiation was significantly increased following NogoA or NgR1 neutralization. Synaptic potentiation thus seems to be restricted by NogoA. Surprisingly, synaptic weakening was not affected by interfering with NogoA signaling. Mechanistically of interest is the observation that by blockade of the GABA A receptors normal synaptic strengthening reoccurred in the absence of NogoA signaling. The present results show a unique role of NogoA expressed in the adult hippocampus in restricting physiological synaptic plasticity on a very fast time scale. NogoA could thus serve as an important negative regulator of functional and structural plasticity in mature neuronal networks.C hanges in the connectivity of neurons-synaptic plasticityregulate the fine-tuning of neuronal networks during development and during adult learning. Synaptic plasticity includes functional and structural modifications at neurons and may be the underlying mechanism for learning and memory processes (1). The storage of new information therefore might depend on ever changing neuronal networks. On the other hand, recent data indicate that the large scale organization of neuronal networks is kept remarkably stable to maintain a constant flow of information and to support long-term memory storage (reviewed in ref. 2).In the CA1 region of the hippocampus, changes in neuronal activity can lead to changes in synaptic weight. Molecular mechanisms include here changes in the number or properties of neurotransmitter receptors, retrograde messengers, structural changes at synapses, and activation of transcription/translation (3). What is less clear is whether molecular mechanisms restricting changes in synaptic weight and thus stabilizing the synapse also play a role as well. In this context it is interesting to note that preventing further potentiation of a given set of synapses in a neuronal network can be induced by a homeostatic shutdown of long-term potentiation (LTP) after intense stimulation (4). In the search for such molecular stabilizers, we investigated the protein NogoA, which has been identified as a negative regulator of structural changes in the CNS (5). NogoA prevents neurite outgrowth in the adult CNS after injury (6) and regulates the progressive restriction of plasticity dur...
Kinesin-based transport is important for synaptogenesis, neuroplasticity, and maintaining synaptic function. In an anatomical screen of neurodevelopmental mutants, we identified the exchange of a conserved residue (R561H) in the forkhead-associated domain of the kinesin-3 family member Unc-104/KIF1A as the genetic cause for defects in synaptic terminal- and dendrite morphogenesis. Previous structure-based analysis suggested that the corresponding residue in KIF1A might be involved in stabilizing the activated state of kinesin-3 dimers. Herein we provide the first in vivo evidence for the functional importance of R561. The R561H allele (unc-104bris) is not embryonic lethal, which allowed us to investigate consequences of disturbed Unc-104 function on postembryonic synapse development and larval behavior. We demonstrate that Unc-104 regulates the reliable apposition of active zones and postsynaptic densities, possibly by controlling site-specific delivery of its cargo. Next, we identified a role for Unc-104 in restraining neuromuscular junction growth and coordinating dendrite branch morphogenesis, suggesting that Unc-104 is also involved in dendritic transport. Mutations in KIF1A/unc-104 have been associated with hereditary spastic paraplegia and hereditary sensory and autonomic neuropathy type 2. However, we did not observe synapse retraction or dystonic posterior paralysis. Overall, our study demonstrates the specificity of defects caused by selective impairments of distinct molecular motors and highlights the critical importance of Unc-104 for the maturation of neuronal structures during embryonic development, larval synaptic terminal outgrowth, and dendrite morphogenesis.
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