No abstract

Binding of the neurotrophin brain-derived neurotrophic factor (BDNF) to the TrkB receptor is a major survival mechanism during embryonic development. In the aged brain, however, BDNF levels are low, suggesting that if TrkB is to play a role in survival at this stage additional mechanisms must have developed. We here show that TrkB activity is most robust in the hippocampus of 21-d-old BDNF-knockout mice as well as in old, wild-type, and BDNF heterozygous animals. Moreover, robust TrkB activity is evident in old but not young hippocampal neurons differentiating in vitro in the absence of any exogenous neurotrophin and also in neurons from BDNF ؊/؊ embryos. Age-associated increase in TrkB activity correlated with a mild yet progressive loss of cholesterol. This, in turn, correlated with increased expression of the cholesterol catabolic enzyme cholesterol 24-hydroxylase. Direct cause-effect, cholesterol loss-high TrkB activity was demonstrated by pharmacological means and by manipulating the levels of cholesterol 24-hydroxylase. Because reduced levels of cholesterol and increased expression of choleseterol-24-hydroxylase were also observed in the hippocampus of aged mice, changes in cellular cholesterol content may be used to modulate receptor activity strength in vivo, autonomously or as a way to complement the natural decay of neurotrophin production. INTRODUCTIONDuring development, neurotrophins are mandatory for the survival, differentiation, and growth of different neuronal populations (Reichardt, 2006). In the mature nervous system, neurotrophins are important for the modulation of neuronal connectivity and activity-dependent plasticity (Conover and Yancopoulos, 1997;Blum and Konnerth, 2005). Neurotrophins bind and activate receptor tyrosine kinases (RTKs), in turn leading to multiple intracellular signaling pathways, most notoriously those involving mitogen-activated protein kinases and phosphatidylinositol 3-kinase (PI3K) (Kaplan and Miller, 2000;Reichardt, 2006). In the hippocampus, a region of the brain critically involved in certain types of learning and memory, the most prominently expressed neurotrophin receptor is TrkB (Tokuyama et al., 1998), whose cognate ligand is BDNF (brain-derived neurotrophic factor). In agreement with a role in memory-associated processes, loss-of-function studies of both TrkB and BDNF result in changes in affective and cognitive states in mammals and humans (Minichiello et al., 1999;Pozzo-Miller et al., 1999;Xu et al., 2000;Egan et al., 2003;Yeo et al., 2004). Although there is no doubt that BDNF is the main modulator of TrkB activity, a number of evidences indicate that certain roles mediated by the activation of TrkB may occur independently from BDNF. For instance, TrkB conditional knockout mice present clear defects in pre-and postsynaptic morphogenesis in the hippocampus (Luikart et al., 2005), yet this is not the case in BDNF conditional knockout mice (Gorski et al., 2003;Hill et al., 2005). The last observations are in turn consistent with the lack of an overt effect on...

Cognitive and motor performances decline during aging. Although it is clear that such signs reflect synaptic compromise, the underlying mechanisms have not been defined. We found that the levels and activity of the synaptic plasticity modulators phosphatidylinositol-(4,5)-bisphosphate (PI(4,5)P₂) and phospholipase Cγ (PLCγ) were substantially reduced in hippocampal synaptic membranes from old mice. In addition, these membranes contained reduced levels of the PI(4,5)P₂-clustering molecule myristoylated alanine-rich C kinase substrate (MARCKS). Consistent with a cause-effect relationship, raising MARCKS levels in the brain of old mice led to increased synaptic membrane clustering of PI(4,5)P₂ and to PLCγ activation. MARCKS overexpression in the hippocampus of old mice or intraventricular perfusion of MARCKS peptide resulted in enhanced long-term potentiation and improved memory. These results reveal one of the mechanisms involved in brain dysfunction during aging.