Transcriptome Profiling Reveals Novel Candidate Genes Related to Hippocampal Dysfunction in SREBP-1c Knockout Mice

Abstract

Lipid homeostasis is an important component of brain function, and its disturbance causes several neurological disorders, such as Huntington’s, Alzheimer’s, and Parkinson’s diseases as well as mood disorders. Sterol regulatory element-binding protein-1c (SREBP-1c) is a key modulatory molecule involved in lipid homeostasis in the central nervous system. However, little is known about the biological effects of SREBP-1c in the brain. Our previous study uncovered that mice deficient in SREBP-1c exhibit schizophrenia-like behaviors. To investigate whether there are novel molecular mechanisms involved in the neurological aberrations caused by SREBP-1c deficiency, we analyzed the transcriptomes of the hippocampus of SREBP-1c knockout (KO) mice and wild-type mice. We found seven differentially expressed genes (three up-regulated and four down-regulated genes) in the hippocampus of SREBP-1c KO mice. For further verification, we selected the three most significantly changed genes: glucagon-like peptide 2 receptors (GLP2R) involved in hippocampal neurogenesis and neuroplasticity as well as in cognitive impairments; necdin (NDN) which is related to neuronal death and neurodevelopmental disorders; and Erb-B2 receptor tyrosine kinase 4 (ERBB4) which is a receptor for schizophrenia-linked protein, neuregulin-1. The protein levels of GLP2R and NDN were considerably decreased, but the level of ERBB4 was significantly increased in the hippocampus of SREBP-1c KO mice. However, further confirmation is warranted to establish the translatability of these findings from this rodent model into human patients. We suggest that these data provide novel molecular evidence for the modulatory role of SREBP-1c in the mouse hippocampus.

SREBP-1c Deficiency Affects Hippocampal Micromorphometry and Hippocampus-Dependent Memory Ability in Mice

“…The differentially expressed genes and proteins, suggested as novel molecular candidates related to the hippocampal dysfunction of SREBP-1c KO mice in our previous study, may also provide insights into the neuroplastic alterations found in the current study [ 20 ]. Glp2r , a gene associated with neuroprotection and neurogenesis [ 43 ], and Ndn , a gene associated with neuronal differentiation and survival [ 44 , 45 ] and axonal growth [ 45 ], decrease especially in the CA3 pyramidal cell layers of SREBP-1c KO mice [ 20 ]. Although the proteins have no known direct physical or functional interactions with SREBP-1 based on a protein–protein interaction network analysis [ 20 ], their possible indirect interactions with SREBP-1c and/or other neuroplasticity-related molecules cannot be discounted.…”

“…Moreover, the remaining SREBP-1 expression present in the hippocampi of SREBP-1c-specific KO mice indirectly represents the remaining proportion of the SREBP-1a isoform in the different subregions. Furthermore, the Srebf-1a mRNA expression significantly increased in the whole hippocampal lysates of SREBP-1c KO mice [ 20 ]. Therefore, SREBP-1a might have played a role in mitigating the SREBP-1c-induced structural alterations by providing an alternative, compensatory pathway for the de novo lipid synthesis, as it shares common functions with the SREBP-1c isoform.…”

“…Glp2r , a gene associated with neuroprotection and neurogenesis [ 43 ], and Ndn , a gene associated with neuronal differentiation and survival [ 44 , 45 ] and axonal growth [ 45 ], decrease especially in the CA3 pyramidal cell layers of SREBP-1c KO mice [ 20 ]. Although the proteins have no known direct physical or functional interactions with SREBP-1 based on a protein–protein interaction network analysis [ 20 ], their possible indirect interactions with SREBP-1c and/or other neuroplasticity-related molecules cannot be discounted. Further in-depth analyses involving gene–gene and gene–environment interactions are needed to further demonstrate the extent of signaling pathway involvement.…”

“…Three- to four-month-old SREBP-1c KO mice—generous gifts from Dr. Timothy F. Osborne (Sanford Burnham Prebys Medical Discovery Institute, Orlando, FL, USA)—were maintained in a C57BL/6J strain background as previously described [ 19 , 20 ]. The animals were housed in standard cages in a specific pathogen-free facility maintained on a 12:12 h light/dark cycle at 25 °C.…”

“…Previously, we found that mice lacking SREBP-1c demonstrate schizophrenia-like behavioral symptoms [ 19 ]. Furthermore, we found that novel genes (e.g., glucagon-like peptide 2 receptor ( Glp2r ), necdin ( Ndn ), and Erb-B2 receptor tyrosine kinase 4) were significantly altered in the hippocampus of SREBP-1c knockout (KO) mice, compared with those in wild-type (WT) mice [ 20 ]. However, the mechanisms possibly underlying these abnormal behaviors and altered molecular expressions need further examination.…”