Mice Deficient in Collapsin Response Mediator Protein-1 Exhibit Impaired Long-Term Potentiation and Impaired Spatial Learning and Memory

Abstract

Collapsing response mediator protein-1 (CRMP-1) was initially identified in brain and has been implicated in plexin-dependent neuronal function. The high amino acid sequence identity among the five CRMPs has hindered determination of the functions of each individual CRMP. We generated viable and fertile CRMP-1 knock-out (CRMP-1 Ϫ / Ϫ ) mice with no evidence of gross abnormality in the major organs. CRMP-1 Ϫ / Ϫ mice exhibited intense microtubule-associated protein 2 (MAP2) staining in the proximal portion of the dendrites, but reduced and disorganized MAP2 staining in the distal dendrites of hippocampal CA1 pyramidal cells. Immunoreactivity to GAP-43 (growth-associated protein-43) and PSD95 (postsynaptic density-95) (a postsynaptic membrane adherent cytoskeletal protein) was also decreased in the CA1 region of the knock-out mice. These changes were consistent with the mutant mice showing a reduction in long-term potentiation (LTP) in the CA1 region and impaired performance in hippocampal-dependent spatial learning and memory tests. CRMP-1 Ϫ / Ϫ mice showed a normal synapsin I labeling pattern in CA1 and normal paired-pulse facilitation. These findings provide the first evidence suggesting that CRMP-1 may be involved in proper neurite outgrowth in the adult hippocampus and that loss of CRMP-1 may affect LTP maintenance and spatial learning and memory.

Regulation of Spine Development by Semaphorin3A through Cyclin-Dependent Kinase 5 Phosphorylation of Collapsin Response Mediator Protein 1

“…As the mean spine area of crmp1 Ϫ/Ϫ layer V neurons stained by the Golgi-impregnation method was smaller than that of crmp1 ϩ/Ϫ (see Results), CRMP1 may play a role in establishing stable synapses. This idea of CRMP1 as a regulator of synaptic transmission is consistent with a recent observation that crmp1 Ϫ/Ϫ mice show impaired long-term potentiation, learning, and memory (Su et al, 2007). Several lines of evidence suggest that Cdk5 plays an essential role in modulating synaptic transmission (Cheung et al, 2006).…”

Systematic interaction network filtering identifies CRMP1 as a novel suppressor of huntingtin misfolding and neurotoxicity

“…This supports previous observations that CRMP1 is predominantly expressed in neurons (Bretin et al 2005), suggesting that abnormal dysregulation of the protein in HD brains might contribute to the neurodegenerative disease phenotype. A potential importance of CRMP1 for neuronal function under physiological conditions is also supported by gene knockdown studies in mice, indicating that CRMP1 function is critical for learning and memory (Su et al 2007). Thus, for further more detailed experimental investigations, we focused our efforts on the protein CRMP1, which likely is a neuron-specific modulator of mutant HTT misfolding and aggregation in brains of HD patients.…”

“…CRMP1 is a cytoplasmic phosphoprotein that is predominantly expressed in neurons (Goshima et al 1995). Previous studies revealed that mice lacking CRMP1 show impairment of learning and memory (Su et al 2007), suggesting that a reduction of CRMP1 levels in HD brains might contribute to the disease phenotype (Paulsen et al 2013). This view is also supported by studies in cell model systems, indicating that reduced levels of CRMP1 promote death of spinal cord neurons (Kurnellas et al 2010).…”

Dock3 Stimulates Axonal Outgrowth via GSK-3β-Mediated Microtubule Assembly

“…Previous studies have reported that cytoskeletal regulation is also involved in synaptogenesis. For example, activation of GSK-3␤ and loss of CRMP-1 inhibits LTP with synapseassociated impairments (Zhou and Snider, 2005;Su et al, 2007, Yamashita et al, 2007. In addition, Rac1 regulates dendritic spine density and shape in rat and mouse pyramidal neurons (Nakayama et al, 2000;Tashiro and Yuste, 2004).…”