CPG15

One of the first CPGs selected for full scale characterization was cpg15. cpg15 is a downstream target of the classic synaptic-plasticity signaling cascade, involving the NMDA receptor, MAPK, CaMK, and CREB (Fujino et al., MCN 2003) and its developmental expression is spatially and temporally correlated with synapse formation and activity-dependent plasticity (Corriveau et al., J. Neurosci. 1999; Lee & Nedivi, J. Neurosci. 2002; Harwell et al. J. Neurobiol., 2005). cpg15 encodes a small highly conserved protein that is attached to the extracellular membrane through a GPI anchor. CPG15 overexpression enhances dendritic and axonal elaboration in a non-cell-autonomous manner, as well as synapse formation and maturation (Nedivi et al., Science 1998; Cantallops, Haas & Cline, Nat. Neurosci. 2000). Similar to other growth factors, CPG15 plays a dual role in the nervous system, acting as a survival factor for cortical progenitors and later as a growth and differentiation factor (Putz, Harwell & Nedivi, Nat. Neurosci. 2005).

We have generated a knockout mouse for cpg15 (cpg15 KO). We find that in the cpg15 KO, there is a developmental delay in axonal and dendritic arborization and formation of excitatory synapses. In the dentate gyrus of the hippocampus as many as 30% of spines initially lack synapses. Chronic in vivo imaging of cortical pyramidal neurons through a cranial window shows that while dendritic spine dynamics in cpg15 KO mice are comparable to controls, fewer of the dynamic events in these mice are stabilized, and thus favor persistent spine loss (Fujino et al., Genes & Dev. 2011). These results suggest that the in vivo developmental deficits in the cpg15 KO mouse derive from lack of a synaptic stabilization signal, perhaps supplied in an activity-dependent manner. While adult circuits appear structurally normal, they are functionally suboptimal, leading to poor performance in learning tasks. These findings suggest a potential molecular mechanism for selective synapse stabilization and establish a role for CPG15 in efficient circuit formation and function. We are currently examining visual system development in the full and conditional cpg15 KO mice, and using a number of different approaches to screen for CPG15 receptors.

We find that in the cpg15 knockout mouse (cpg15 KO) there is abnormal postnatal development of excitatory connectivity in the hippocampus (Fujino et al., Genes & Dev. 2011), as well as visual cortex (Picard et al., J. Neurosci. 2014). In the dentate gyrus of the hippocampus as many as 30% of spines initially lack synapses. Chronic in vivo imaging of cortical pyramidal neurons through a cranial window shows that while dendritic spine dynamics in cpg15 KO mice are comparable to controls, fewer of the dynamic events in these mice are stabilized, and thus favor persistent spine loss (Fujino et al., Genes & Dev. 2011). These results suggest that the in vivo developmental deficits in the cpg15 KO mouse derive from lack of a synaptic stabilization signal. My project makes use of new in vivo synaptic labeling methods and multi-color two-photon microscopy to examine how CPG15 regulates synapse stabilization in vivo and explores whether CPG15 could link experience driven neuronal activity and new synapse stabilization.