The intracellular domain of Nfasc186-NrCAM is then used to anchor AnkyrinG and other components of the AIS complex through interactions similar to those used to assemble nodes of Ranvier (Rasband, 2010 and Sherman and Brophy, 2005). Hence, according to this model, loss of Nfasc186 will lead to instability of sodium channels and concomitant delocalization of their associated AnkyrinG and NrCAM. Our model does not rule out the possibility that AnkryinG is also required for maintenance of the AIS by stabilizing Nfasc186, similar to its role at nodes

of Ranvier (Dzhashiashvili et al., 2007). From the current study, it was not possible to differentiate the sequence of AIS component disassembly

following Nfasc186 click here loss. Similarly, two different studies check details on the AIS of cultured neurons have found that the simultaneous accumulation of Nav channels, AnkyrinG, βIV-Spectrin, NrCAM, and Neurofascin did not permit a differential analysis of the assembly of individual AIS components (Boiko et al., 2007 and Hedstrom et al., 2008). An intriguing consequence of inactivating the Nfasc gene in adult neurons was the longer persistence of Nfasc186 at nodes of Ranvier in contrast to the AIS. This suggests that Nfasc186 has a shorter half-life at the AIS compared to nodes. According to the model we propose above, this difference would be expected if others the major difference between the mature AIS and nodes of Ranvier is the rate of turnover of their

constituent molecules. This is consistent with the emerging view that plasticity of the AIS may play a role in modulating the electrical properties of neurons ( Grubb and Burrone, 2010a and Grubb and Burrone, 2010b). The enhanced sensitivity of the AIS to hypoperfusion-induced hypoxia ( Schafer et al., 2009) may also reflect the fact that the AIS is inherently less stable than related structures, such as nodes. The fundamental role we propose for Nfasc186 in anchoring new proteins may represent an important target in regulating normal AIS function. The formation of pinceau synapses between basket cell axons and the AIS of Purkinje cells in the cerebellum has been shown to be disrupted either in the absence of AnkyrinG or by using a dominant-negative form of Nfasc186 (Ango et al., 2004). Here, we have shown that the intact AIS is also essential for maintenance of pinceau synapses. However, the persistence of apparently intact pinceau synapses for some time after AIS disruption indicates a role for other proteins in contributing to the stabilization of these structures. The perineuronal nets formed by the extracellular matrix are possible candidates (Celio et al., 1998 and Rasband, 2010).