Deletion of olfactomedin 2 induces changes in the AMPA receptor complex and impairs visual, olfactory, and motor functions in mice

Abstract

Olfactomedin 2 (Olfm2) is a secretory glycoprotein belonging to the family of olfactomedin domain-containing proteins. A previous study has shown that a mutation in OLFM2 is associated with primary open angle glaucoma in Japanese patients. In the present study, we generated Olfm2 deficient mice by replacing the Olfm2 gene with the LacZ gene. Loss of Olfm2 resulted in no gross abnormalities. However, Olfm2 null mice showed reduced exploration, locomotion, olfactory sensitivity, abnormal motor coordination, and anxiety related behavior. The pattern of the Olfm2 gene expression was studied in the brain and eye using β-galactosidase staining. In the brain, Olfm2 was mainly expressed in the olfactory bulb, cortex, piriform cortex, olfactory trabeculae, inferior and superior colliculus. In the eye expression was detected mainly in retinal ganglion cells. In Olfm2 null mice, the amplitude of the first negative wave in the visual evoked potential test was significantly reduced as compared with wild-type littermates. Olfm2, similar to Olfm1, interacted with the GluR2 subunit of the AMPAR complexes and Olfm2 co-segregated with the AMPA receptor subunit GluR2 and other synaptic proteins in the synaptosomal membrane fraction upon biochemical fractionation of adult mice cortex and retina. Immunoprecipitation from the synaptosomal membrane fraction of Olfm2 null mouse brain cortex using the GluR2 antibody showed reduced levels of several components of the AMPAR complex in the immunoprecipitates including Olfm1, PSD95 and CNIH2. These results suggest that heterodimers of Olfm1 and Olfm2 interact with AMPAR more efficiently than Olfm2 homodimers and that Olfm2 plays a role in the organization of the AMPA receptor complexes.

Olfactomedin-1 Has a V-shaped Disulfide-linked Tetrameric Structure

“…Olfm2 has been shown to have a similar role in AMPA receptor binding or regulation ( 11 ). Gliomedin is also known to be involved in sodium channel clustering and maintenance ( 40 , 41 ).…”

“…The four Olfm paralogs and myocilin are oligomerized through coiled-coil domains, whereas gliomedin is oligomerized through a collagen-like domain. Oligomerization of these molecules is important for function ( 10 ), and Olfm1 can form complexes with Olfm2 and Olfm3 ( 11 , 12 ). However, it is not clear how Olfm1 or the paralog (Olfm2, -3, and -4) oligomers are structurally arranged.…”

AMPA receptors and their minions: auxiliary proteins in AMPA receptor trafficking

“…Regarding plasticity, both Noelin-1 and 2 have also been shown by independent studies to interact directly with AMPARs [ 10 , 392 – 395 ]. Noelin-1 interacts with additional AMPAR auxiliary subunits, such as TARP γ8 and neuritin; in addition, Noelin-1, 2, and 3 are able to form heterodimers and have a similar expression pattern, suggesting the possible coexistence of multiple Noelin isoforms within a given AMPAR complex [ 394 , 395 ] (Fig. 6 ).…”

Forebrain excitatory neuron-specific SENP2 knockout mouse displays hyperactivity, impaired learning and memory, and anxiolytic-like behavior

“…The 17 genes associated with anxiolytic-like effect on behavior, including that APOE [23], TSPO [24], UCP2 [25], MT1 [26], MT2 [27], AIM2 [28], CNR2 [29], LCN2 [30], DLK1 [31], CNTF [32], MYD88 [33], HDC [34], ALOX5 [35], TLR4 [36], ROCK1 [37], MOV10 [38], DDC [39]. The 9 genes associated with anxiety-like effect on behavior, including that LAMP5 [40], KALRN [41], CRHR1 [42], CCK [43], SNAP25 [44], OLFM2 [45], FAAH [46], IQSEC2 [47], EMX1 [48]. These data suggest that either the anxiolytic-like effects gene up-regulated or anxiety-like effects gene down-regulated could be a reduced level of anxiety.…”