IGFBP2 Plays an Essential Role in Cognitive Development during Early Life

Abstract

Identifying the mechanisms underlying cognitive development in early life is a critical objective. The expression of insulin‐like growth factor binding protein 2 (IGFBP2) in the hippocampus increases during neonatal development and is associated with learning and memory, but a causal connection has not been established. Here, it is reported that neurons and astrocytes expressing IGFBP2 are distributed throughout the hippocampus. IGFBP2 enhances excitatory inputs onto CA1 pyramidal neurons, facilitating intrinsic excitability and spike transmission, and regulates plasticity at excitatory synapses in a cell‐type specific manner. It facilitates long‐term potentiation (LTP) by enhancing N‐methyl‐d‐aspartate (NMDA) receptor‐dependent excitatory postsynaptic current (EPSC), and enhances neurite proliferation and elongation. Knockout of igfbp2 reduces the numbers of pyramidal cells and interneurons, impairs LTP and cognitive performance, and reduces tonic excitation of pyramidal neurons that are all rescued by IGFBP2. The results provide insight into the requirement for IGFBP2 in cognition in early life.

IGFBP-2 Signaling in the Brain: From Brain Development to Higher Order Brain Functions

“…In another study, prolonged hypoxia led to enhanced expression of IGFBP-2 with extensive neuronal loss in the ligated hemisphere as compared to the control hemisphere. Therefore, hypoxia leads to alterations in IGFBP-2 expression (41, 64). Different patterns of IGFBP-2 expression associated with different degrees of injury suggest that IGFBP-2 may contribute to neuronal rescue and/or brain repair processes [Figure 3; (65)].…”

“…For IGFBPs binding to IGF-IR, a single detergent molecule contacts residues known to be critical (111). Proteolytic degradation of IGFBP-2 near cell surface receptors has lower affinity for IGFs and thus by competing with IGFs, HBD of IGFBP-2 may bind with that detergent molecule in IGF-IR to initiate downstream signaling via autophosphorylation of the receptor (41). Moreover, the presence or absence of sialic acid residue in the IGF-IR may be another factor for interaction with IGFBP-2.…”

“…It has been reported that IGFBP-2 can be cleaved proteolytically, and the smaller fragments that contain HBD still possess the biological activity necessary to bind with extracellular matrix proteins (ECM) and to bind with low affinity to IGF-l (39, 40). Khan et al (41) showed that the HBD domain of IGFBP-2 independently activates glutamate receptors that translate into enhanced information processing in the hippocampus in a cell type-specific manner, which is crucial for cognitive development at early life in rodents. In addition, IGFBP-2 binding to cell surface proteoglycan in rat olfactory bulb is solely mediated by HBD and not by RGD peptides (39).…”

“…Via the HBD domain, IGFBP-2 can bind to different glycosaminoglycans: chondroitin-4 and−6 sulfate, keratan sulfate, aggrecan, heparin, vitronectin, laminin, collagens, and fibronectin, a probable mechanism for IGFBP-2 to bind with ECM proteins prior to complex formation with IGF-I/II (25, 39, 48, 49), suggesting IGFs-independent functions of IGFBP-2 mediated by the HBD domain. Interestingly, proteolytic degradation of IGFBP-2 can occur on the neuronal surface (39), may be the probable mechanism by which the HBD may directly bind with IGF-IR or other receptors (AMPAR, NMDAR, GABAR) on neurons (41, 50). IGFBP-2 also exerts its functions within cells since it has been detected within the nucleus, nuclear surface, and cytoplasm (51).…”

Identification of potential core genes in atrial fibrillation based on bioinformatics analysis

“…For example : colorectal cancer(14), hepatocellular carcinoma(15), bladder cancer (16), breast cancer (17), etc. In addition,a study suggests that increased expression of IGFBP2 in the hippocampus during neonatal development is associated with learning and memory, which provides insights into the cognitive needs of IGFBP2 in early life (18). In the eld of cardiovascular disease, Han et al found that microRNA-873 alleviated myocardial damage in gestational diabetic rats by upregulated IGFBP2 (19).However, there are limited studies on the relationship between IGFBP2 and atrial brillation.…”