, 2002). A likely mechanism for presynaptic recruitment requiring the intracellular region of PTPσ (Figures 4D and 4E) is binding of the second phosphatase domain (D2) to α-liprins (Pulido et al., 1995). α-Liprins directly interact with

CASK, RIMs, and ERC/ELKS/CAST and are important for presynaptic differentiation in Drosophila and Caenorhabditis elegans ( Stryker and Johnson, 2007). The mechanism linking TrkCTK- and TrkCTK+ to glutamatergic postsynaptic proteins is not yet known but presumably occurs via the shared extracellular, transmembrane, and 75-aa membrane-proximal intracellular region. TrkCTK- (NC2) could further recruit the scaffold protein tamalin to activate Arf6-Rac signaling ( Esteban et al., 2006) and TrkCTK+ could recruit and activate PLCγ, Shc, and Frs2 leading to Ras and PI3-kinase ( Huang and Reichardt, 2003). The existence of eight alternatively spliced TrkC variants Akt tumor possessing different intracellular regions and a common extracellular region may contribute to diversity of glutamatergic postsynaptic composition. We show here that TrkC is required in cortical neurons in vivo for development of dendritic spines, a function that does not require TrkC kinase activity (Figures 8A–8D). These data indicate a noncatalytic function of TrkC in morphological excitatory synaptogenesis in vivo. Linkage Selleckchem Veliparib of NTRK3 to panic

disorder ( Armengol et al., 2002), obsessive-compulsive disorder Cediranib (AZD2171) ( Alonso et al., 2008), and childhood-onset mood disorders ( Feng et al., 2008) in patients supports the importance of TrkC for cognitive function.

Deletion of all TrkC isoforms in mice (NTRK3−/−) results in earlier postnatal lethality by several weeks compared with deletion of only the kinase-active isoforms (NTRK3TK−/−) ( Klein et al., 1994 and Tessarollo et al., 1997). The earlier lethality with additional loss of the noncatalytic isoforms may be in part because of a defect in synaptogenesis. Brain-specific transgenic overexpression of TrkC increases anxiety-related behaviors and markedly increases hippocampal CA1 field EPSPs in vivo after classical conditioning or LTP induction ( Dierssen et al., 2006 and Sahun et al., 2007). Such outcomes are consistent with enhanced glutamatergic synapse development, at the expense of inhibitory GABAergic synapses, upon TrkC overexpression. However, these global genetic manipulations clearly have multiple consequences. The in vivo knockdown of TrkC performed here also did not specifically assess the role of TrkC interaction with PTPσ. A more specific TrkC knockin will be needed to precisely define the role of its interaction with PTPσ in vivo without altering NT-3 and kinase-mediated functions. Consistent with the proposed dual function of PTPσ, Ptprs−/− mice also show multiple defects, including increased lethality, ataxia, and neuroendocrine dysplasia, as well as altered hippocampal and cortical development ( Elchebly et al., 1999, Meathrel et al.