Phosphatidylinositol 3-kinase: a molecule mediating BDNF-dependent spatial memory formation

Abstract

Brain-derived neurotrophic factor (BDNF) plays a critical role in synaptic plasticity such as long-term potentiation (LTP), a form of synaptic correlate of learning and memory. BDNF is also implicated in learning and memory. We have demonstrated that radial arm maze training in rats for spatial learning and memory results in a significant increase in the BDNF mRNA expression in the hippocampus. Moreover, antisense BDNF oligonucleotide treatment impaired not only acquisition, but also maintenance and/or recall of spatial memory in the maze. Although these results suggest a role of BDNF for spatial memory processes, the signal transduction mechanisms that mediate the actions of BDNF remain unknown. Here we show that phosphorylation of BDNF receptor tyrosine kinase B (TrkB), phosphatidylinositol 3-kinase (PI3-K) and Akt, a target of PI3-K, in the hippocampus increased in parallel with spatial memory formation. Moreover, an activation of translational processes was suggested in the hippocampus after the maze training. When spatial learning was inhibited by antisense BDNF oligodeoxynucleotide, the activation was diminished. Chronic treatment with PI3-K inhibitor wortmannin impaired spatial learning. Our findings suggested that activation of TrkB/PI3-K and protein synthesis signaling pathway by BDNF in the hippocampus is important for spatial memory.

Quantitative trait loci linked to thalamus and cortex gray matter volumes in BXD recombinant inbred mice

“…The results are shown in Tables 2 and 3 for the thalamus and cortex gray matter, respectively. Cortex gray matter volume was highly correlated (r ¼ 0.59, P ¼ 0.0024) with amurine thymoma viral oncogene homologue (Akt1), a protein kinase that has been shown to have an important role in neurodevelopment (Wang et al, 2003b) and working memory formation (Mizuno et al, 2003). Also, the Akt1 gene is located within the interval of the QTL we identified on chromosome 19, and its expression was also significantly QTLs that associated with anatomical traits; proximal and distal-markers within a one LOD score drop on the proximal and distal portion of QTL; Chr, the chromosome containing QTL; effect, an estimate of the magnitude of gene.…”

Wild-Type But Not FAD Mutant Presenilin-1 Prevents Neuronal Degeneration by Promoting Phosphatidylinositol 3-Kinase Neuroprotective Signaling

“…These maturation activities start at about the end of the first week in vitro and peak at the end of the second week (Dotti et al, 1988;Ichikawa et al, 1993;Lesuisse and Martin, 2002). Neuronal PI3K signaling is activated in response to a variety of stimuli including growth factors (van der Heide et al, 2006), neurotrophins (Mizuno et al, 2003), cell-cell adhesion molecules (Ditlevsen et al, 2003;Loers et al, 2005), and synaptic activity (Perkinton et al, 2002;Sutton and Chandler, 2002;Man et al, 2003). It is expected that cellcontact-dependent mechanisms of PI3K activation (Sutton and Chandler, 2002;Ditlevsen et al, 2003;Man et al, 2003;Loers et al, 2005) are mostly inactive in immature neuronal cultures and that these mechanisms become important during the maturation period when extensive cell-cell contacts are established.…”

“…PI3K/Akt signaling is of central importance for neuronal physiology. In addition to its role in neuronal survival (Brunet et al, 2001), this signaling has been implicated in dendritic morphogenesis (Jaworski et al, 2005), establishment of neuronal polarity (Jiang et al, 2005), synaptic potentiation (Opazo et al, 2003;Wang et al, 2003) and memory formation (Lin et al, 2001;Mizuno et al, 2003). Previous reports link abnormalities of this pathway with an increasing number of neurodegenerative disorders including Huntington's disease (Humbert et al, 2002), and Parkinson's disease (Chen et al, 2004;Ries et al, 2006).…”

Transient receptor potential channels as novel effectors of brain-derived neurotrophic factor signaling: Potential implications for Rett syndrome

“…Within hippocampal presynaptic terminals, MAPK/ERK-dependent phosphorylation of synapsin-I resulted in higher density of docked neurotransmitter vesicles in glutamatergic terminals, increased frequency of miniature excitatory postsynaptic currents (mEPSCs), increased paired-pulse facilitation, facilitated neurotransmitter release during high-frequency activity with consequent increases in LTP and enhancements in hippocampus-dependent learning (Kushner et al, 2005). Second, the PI3-K cascade is responsible for dendritic targeting of BDNF and TrkB mRNA (Righi et al, 2000) and has been implicated in hippocampal-dependent spatial learning (Mizuno et al, 2003). Lastly, the PLC-γ cascade also plays a critical role in hippocampal synaptic plasticity, as demonstrated by the lack of long-term potentiation (LTP) in conditional knockout mice carrying a deletion of the PLC-γ adaptor site in Trk receptors (Minichiello et al, 2002).…”