Olfactomedin-3 Enhances Seizure Activity by Interacting With AMPA Receptors in Epilepsy Models

Abstract

Background: OLFM3 (olfactomedin-3) is a member of the olfactomedin domain family, which has been found to stimulate the formation and adhesion of tight cell connections and to regulate cytoskeleton formation and cell migration. Differences in the gene coding for OLFM3 have been found between patients with epilepsy and controls. However, the exact role of OLFM3 in epilepsy has not been thoroughly investigated. Methods: Biochemical methods were used to assess OLFM3 expression and localization in the cortex of patients with temporal lobe epilepsy and in the hippocampus and cortex of epileptic mice. Electrophysiological recordings were used to measure the role of OLFM3 in regulating hippocampal excitability in a model of magnesium-free-induced seizure in vitro. Behavioral experiments were performed in a pentylenetetrazol (PTZ)-induced seizure model, and electroencephalograms (EEGs) were recorded in the chronic phase of the kainic acid (KA)-induced epilepsy model in vivo. OLFM3 and its interaction with AMPAR (α-amino-3-hydroxy-5-methyl-4isoxazole-propionic acid receptor) subunits were analyzed by co-immunoprecipitation. Results: The expression of OLFM3 was increased in the cortex of patients with temporal lobe epilepsy and in the hippocampus and cortex of epileptic mice compared with controls. Interestingly, lentivirus-mediated overexpression of OLFM3 in the hippocampus increased the susceptibility of mice to PTZ-induced seizures, and OLFM3 knockdown had the opposite effect. OLFM3 affected AMPAR currents in a brain-slice model of epileptiform activity induced by Mg2+-free medium. We found that OLFM3 co-immunoprecipitation with GluA1 and GluA2. Furthermore, downregulation or overexpression of OLFM3 in the hippocampus affected the membrane expression of GluA1 and GluA2 in epileptic mice. Conclusion: These findings reveal that OLFM3 may enhance seizure activity by interacting with GluA1 and GluA2, potentially indicating a molecular mechanism for new therapeutic strategies.

Identification and Analysis of ZIC-Related Genes in Cerebellum of Autism Spectrum Disorders

“… 36 The olfactomedin structural domain family protein OLFM3, which is present in neurons, promotes the formation of tight junctions. 37 An increased risk of ASD is associated with disruption of the tight junctions, one of the vital components of the blood–brain barrier (BBB). 38 SLC27A4, with the highest AUC value among the genes negatively associated with ZIC1, is a member of the fatty acid transport family of proteins involved in the translocation of fatty acids across the BBB.…”

Bioinformatics analyses of significant genes, related pathways and candidate prognostic biomarkers in Alzheimer’s disease

“…Li et al [62], Kowalczyk et al [63] and Sun et al [64] revealed that the expression of ADCYAP1, NPAS4, NPSR1, HTR2C, GABRB2, ALOX12B, ADRB3, EGR3, HSPA1A and IL3RA are associated with progression of schizophrenia, but these genes might be novel target for AD. GABRA6 [65], GABRA1 [66], GABRG2 [67], SLC4A10 [68], HCN1 [69], GABRA4 [70], KCNC2 [71], SCN2A [72], SYN2 [73], FGF12 [74], SCN8A [75], OLFM3 [76], PLCB1 [77], KCNQ5 [78], TUBB2A [79], SIK1 [80], ABCC2 [81], SLC6A12 [82] and COL6A2 [83] have been reported to be closely related to the occurrence and development of epilepsy, but these genes might be novel target for AD. Previous investigation demonstrates that RGS4 [84] [92], NRN1 [93], SYT1 [94], GRIN2B [95], AVP (arginine vasopressin) [96], VSNL1 [97], HTR2A [98], PAK3 [99] [108], IGF1 [109], PLK2 [110], CBLN4 [111], CAP2 [112], SV2B [113], CAMK4 [114], INA (internexin neuronal intermediate filament protein alpha) [115] KIF5A [179] are associated with amyotrophic lateral sclerosis, but these genes might be novel target for AD.…”

“…Matsuzaki et al [55], Shepard et al [56], Lennertz et al [57], Klemettilä et al [58], Ullah et al [59], Kim et al [60], Sasayama et al [61], Li et al [62], Kowalczyk et al [63] and Sun et al [64] revealed that the expression of ADCYAP1, NPAS4, NPSR1, HTR2C, GABRB2, ALOX12B, ADRB3, EGR3, HSPA1A and IL3RA are associated with progression of schizophrenia, but these genes might be novel target for AD. GABRA6 [65], GABRA1 [66], GABRG2 [67], SLC4A10 [68], HCN1 [69], GABRA4 [70], KCNC2 [71], SCN2A [72], SYN2 [73], FGF12 [74], SCN8A [75], OLFM3 [76], PLCB1 [77], KCNQ5 [78], TUBB2A [79], SIK1 [80], ABCC2 [81], SLC6A12 [82] and COL6A2 [83] have been reported to be closely related to the occurrence and development of epilepsy, but these genes might be novel target for AD. Previous investigation demonstrates that RGS4 [84], CXCL11 [85], EGR1 [86], CALB1 [87], BDNF (brain derived neurotrophic factor) [88], TERT (telomerase reverse transcriptase) [89], NEFL (neurofilament light) [90], SNAP25 [91], RPH3A [92], NRN1 [93], SYT1 [94], GRIN2B [95], AVP (arginine vasopressin) [96], VSNL1 [97], HTR2A [98], PAK3 [99], STXBP5L [100], HCRTR2 [101], SYP (synaptophysin) [102], SYT10 [103], PRKCE (protein kinase C epsilon) [104], NRG1 [105], KISS1 [106], NRXN3 [107], RAB3A [108], IGF1 [109], PLK2 [110], CBLN4 [111], CAP2 [112], SV2B [113], CAMK4 [114], INA (internexin neuronal intermediate filament protein alpha) [115], GAP43 [116], TTR (transthyretin) [117], CXCR2 [118], IL1R2 [119], CXCR4 [120], CCR2 [121], MYOCD (myocardin) [122], S100A12 […”

“…Matsuzaki et al [54], Shepard et al [55], Lennertz et al [56], Klemettilä et al [57], Ullah et al [58], Kim et al [59], Sasayama et al [60], Li et al [61], Kowalczyk et al [62] and Sun et al [63] revealed that the expression of ADCYAP1, NPAS4, NPSR1, HTR2C, GABRB2, ALOX12B, ADRB3, EGR3, HSPA1A and IL3RA are associated with progression of schizophrenia, but these genes might be novel target for AD. GABRA6 [64], GABRA1 [65], GABRG2 [66], SLC4A10 [67], HCN1 [68], GABRA4 [69], KCNC2 [70], SCN2A [71], SYN2 [72], FGF12 [73], SCN8A [74], OLFM3 [75], PLCB1 [76], KCNQ5 [77], TUBB2A [78], SIK1 [79], ABCC2 [80], SLC6A12 [81] and COL6A2 [82] have been reported to be closely related to the occurrence and development of epilepsy, but these genes might be novel target for AD. Previous investigation demonstrates that RGS4 [83], CXCL11 [84], EGR1 [85], CALB1 [86], BDNF (brain derived neurotrophic factor) [87], TERT (telomerase reverse transcriptase) [88], NEFL (neurofilament light) [89], SNAP25 [90], RPH3A [91], NRN1 [92], SYT1 [93], GRIN2B [94], AVP (arginine vasopressin) [95], VSNL1 [96], HTR2A…”