A critical role for IGF-II in memory consolidation and enhancement.
ABSTRACT We report that, in the rat, administering insulin-like growth factor II (IGF-II, also known as IGF2) significantly enhances memory retention and prevents forgetting. Inhibitory avoidance learning leads to an increase in hippocampal expression of IGF-II, which requires the transcription factor CCAAT enhancer binding protein β and is essential for memory consolidation. Furthermore, injections of recombinant IGF-II into the hippocampus after either training or memory retrieval significantly enhance memory retention and prevent forgetting. To be effective, IGF-II needs to be administered within a sensitive period of memory consolidation. IGF-II-dependent memory enhancement requires IGF-II receptors, new protein synthesis, the function of activity-regulated cytoskeletal-associated protein and glycogen-synthase kinase 3 (GSK3). Moreover, it correlates with a significant activation of synaptic GSK3β and increased expression of GluR1 (also known as GRIA1) α-amino-3-hydroxy-5-methyl-4-isoxasolepropionic acid receptor subunits. In hippocampal slices, IGF-II promotes IGF-II receptor-dependent, persistent long-term potentiation after weak synaptic stimulation. Thus, IGF-II may represent a novel target for cognitive enhancement therapies.
Full-textDOI: · Available from: Sarah Stern, Apr 11, 2014
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ABSTRACT: Clinically significant dysregulation of the insulin-like growth factor (IGF) family proteins occurs in HIV-infected individuals, but the details including whether the deficiencies in IGFs contribute to CNS dysfunction are unknown. We measured the levels of IGF1, IGF2, IGFBP1, IGFBP2, and IGF2 receptor (IGF2R) in matching plasma and cerebrospinal fluid (CSF) samples of 107 HIV+ individuals from CNS HIV Antiretroviral Therapy Effects Research (CHARTER) and analyzed their associations with demographic and disease characteristics, as well as levels of several soluble inflammatory mediators (TNFα, IL-6, IL-10, IL-17, IP-10, MCP-1, and progranulin). We also determined whether IGF1 or IGF2 deficiency is associated with HIV-associated neurocognitive disorder (HAND) and whether the levels of soluble IGF2R (an IGF scavenging receptor, which we also have found to be a cofactor for HIV infection in vitro) correlate with HIV viral load (VL). There was a positive correlation between the levels of IGF-binding proteins (IGFBPs) and those of inflammatory mediators: between plasma IGFBP1 and IL-17 (β coefficient 0.28, P = 0.009), plasma IGFBP2 and IL-6 (β coefficient 0.209, P = 0.021), CSF IGFBP1 and TNFα (β coefficient 0.394, P < 0.001), and CSF IGFBP2 and TNF-α (β coefficient 0.14, P < 0.001). As IGFBPs limit IGF availability, these results suggest that inflammation is a significant factor that modulates IGF protein expression/availability in the setting of HIV infection. However, there was no significant association between HAND and the reduced levels of plasma IGF1, IGF2, or CSF IGF1, suggesting a limited power of our study. Interestingly, plasma IGF1 was significantly reduced in subjects on non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy (ART) compared to protease inhibitor-based therapy (174.1 ± 59.8 vs. 202.8 ± 47.3 ng/ml, P = 0.008), suggesting a scenario in which ART regimen-related toxicity can contribute to HAND. Plasma IGF2R levels were positively correlated with plasma VL (β coefficient 0.37, P = 0.021) and inversely correlated with current CD4+ T cell counts (β coefficient -0.04, P = 0.021), supporting our previous findings in vitro. Together, these results strongly implicate (1) an inverse relationship between inflammation and IGF growth factor availability and the contribution of IGF deficiencies to HAND and (2) the role of IGF2R in HIV infection and as a surrogate biomarker for HIV VL.Journal of Neuroinflammation 04/2015; 12(1):72. DOI:10.1186/s12974-015-0288-6 · 4.90 Impact Factor
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ABSTRACT: Aging is generally associated with a certain cognitive decline. However, individual differences exist. While age-related memory deficits can be observed in humans and rodents in the absence of pathological conditions, some individuals maintain intact cognitive functions up to an advanced age. The mechanisms underlying learning and memory processes involve the recruitment of multiple signaling pathways and gene expression, leading to adaptative neuronal plasticity and long-lasting changes in brain circuitry. This chapter summarizes the current understanding of how these signaling cascades could be modulated by cognition-enhancing agents favouring memory formation and successful aging. It focuses on data obtained in rodents, particularly in the rat as it is the most common animal model studied in this field. First, we will discuss the role of the excitatory neurotransmitter glutamate and its receptors, downstream signaling effectors (e.g. calcium/calmodulin-dependent protein kinase II (CaMKII), protein kinase C (PKC), extracellular signal-regulated kinases (ERK), mammalian target of rapamycin (mTOR), cAMP response element-binding protein (CREB)), associated immediate early gene (e.g. Homer 1a, Arc and Zif268), and growth factors (insulin-like growth factors (IGFs) and brain-derived neurotrophic factor (BDNF)) in synaptic plasticity and memory formation. Second, the impact of the cholinergic system and related modulators on memory will be briefly reviewed. Finally, since dynorphin neuropeptides have recently been associated with memory impairments in aging, it is proposed as an attractive target to develop novel cognition-enhancing agents.Cognitive Enhancement - Handbook of Experimental Pharmacology, http://www.springer.com/us/book/9783319165219 edited by Kathleen M. Kantak, Joseph G. Wettstein, 06/2015: chapter Signaling Pathways Relevant to Cognition-Enhancing Drug Targets: pages 59-98; Springer International.
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ABSTRACT: El objetivo del presente estudio fue evaluar la correlación de los valores obtenidos de la medición del porcentaje graso del muslo (%G), del pliegue de muslo medio (PMM) y de la pierna (PMP) y, del perímetro del muslo (PM) y de la pierna (PP) y el diámetro del fémur (DF), con los parámetros obtenidos con la Tensiomiografía (TMG) en el Recto Femoral (RF) y el Gastronemio Medial (GM), de la pierna dominante, en mujeres mayores diagnosticadas de Alzheimer. La muestra, recopilada entre los años 2009 y 2011 en la Asociación Alzheimer Canarias (centro socio-sanitario diurno), involucró a 87 mujeres (77,79 ±7,34 años; 152,72 ±7,67 cm; 66,80 ±13,02 kg). Los resultados del coeficiente de Pearson y el grado de significación (p) muestran que no hay correlación entre los parámetros %G, PMP, PM y DF en RF y %G, PMP y PP en GM, con los obtenidos mediante la Tensiomiografía (TMG).Longevidad y Salud. Innovación en la actividad física., Edited by Alfonso Castillo Rodríguez, 04/2015: chapter 31: pages 804-814; Área de Cultura y Deportes de la Diputación de Málaga., ISBN: 978-84-7785-955-0