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Insulin receptors are highly enriched at neuronal synapses, but whose function remains unclear. Here we present evidence that brief incubations of rat hippocampal slices with insulin resulted in an increased protein expression of dendritic scaffolding protein postsynaptic density-95 (PSD-95) in area CA1. This insulin-induced increase in the PSD-95 protein expression was inhibited by the tyrosine kinase inhibitor, AG1024, phosphatidylinositol 3-kinase (PI3K) inhibitors, LY294002 and wortmannin, translational inhibitors, anisomycin and rapamycin, but not by LY303511 (an inactive analogue of LY294002), and transcriptional inhibitor, actinomycin D, suggesting that insulin regulates the translation of PSD-95 by activating the receptor tyrosine kinase-PI3K-mammalian target of rapamycin (mTOR) signaling pathway. A similar insulin-induced increase in the PSD-95 protein expression was detected after stimulation of the synaptic fractions isolated from the hippocampal neurons. Furthermore, insulin treatment did not affect the PSD-95 mRNA levels. In agreement, insulin rapidly induced the phosphorylation of 3-phosphoinositidedependent protein kinase-1 (PDK1), protein kinase B (Akt), and mTOR, effects that were prevented by the AG1024 and LY294002. We also show that insulin stimulated the phosphorylation of 4E-binding protein 1 (4E-BP1) and p70S6 kinase (p70S6K) in a mTOR-dependent manner. Finally, we demonstrate the constitutive expression of PSD-95 mRNA in the synaptic fractions isolated from hippocampal neurons. Taken together, these findings suggest that activation of the PI3K-Akt-mTOR signaling pathway is essential for the insulin-induced up-regulation of local PSD-95 protein synthesis in neuronal dendrites and indicate a new molecular mechanism that may contribute to the modulation of synaptic function by insulin in hippocampal area CA1.Insulin and its receptor are widely dispersed throughout the brain with the highest density located in the olfactory bulb, cerebral cortex, hypothalamus, and hippocampus, where they are thought to subserve a number of functions including regulation of glucose metabolism, food intake and body weight, fertility and reproduction, learning, memory, and attention (1-4). Brain insulin receptors are present in particularly high concentrations in neurons, and in much lower levels in glia (5). Although the mRNA of insulin receptors is largely localized in neuronal somata, abundant insulin receptors are found in both cell bodies and synapses (5-7). However, very little is known about the functional significance of synaptic insulin receptors in the neurons. Recently, several studies have drawn links between insulin signaling and intracellular trafficking and plasma membrane expression of ion channels and neurotransmitter receptors at the central nervous system synapses. For example, it has been shown that insulin rapidly recruits functional GABA A receptors to postsynaptic domains in hippocampal neurons, resulting in a long-lasting enhancement of GABA A receptor-mediated synaptic transmission (8). ...

Recent work has demonstrated that brief application of insulin to hippocampal slices can induce a novel form of long-term depression (insulin-LTD) in the CA1 region of the hippocampus; however, the molecular details of how insulin triggers LTD remain unclear. Using electrophysiological and biochemical approaches in the hippocampal slices, we show here that insulin-LTD (i) is specific to 3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor-but not NMDA receptormediated synaptic transmission; (ii) is induced and expressed postsynaptically but does not require the activation of ionotropic and metabotropic glutamate receptors; (iii) requires a concomitant Ca 2+ influx through L-type voltage-activated Ca 2+ channels (VACCs) and the release of Ca 2+ from intracellular stores; (iv) requires the series of protein kinases, including protein tyrosine kinase (PTK), phosphatidylinositol 3-kinase (PI3K), and protein kinase C (PKC); (v) is mechanistically distinct from low-frequency stimulation-induced LTD (LFS-LTD) and independent on protein phosphatase 1/2 A (PP1/2 A) and PP2B activation; (vi) is dependent on a rapamycin-sensitive local translation of dendritic mRNA, and (vii) is associated with a persistent decrease in the surface expression of GluR2 subunit. These results suggest that a PI3K/PKC-dependent insulin signaling, which controls postsynaptic surface AMPA receptor numbers through PP-independent endocytosis, may be a major expression mechanism of insulin-LTD in hippocampal CA1 neurons. Keywords: endocytosis, insulin, long-term depression (LTD), phosphatidylinositol 3-kinase (PI3K), protein kinase C (PKC). Long-term depression (LTD) is a persistent, use-dependent decrease of synaptic efficacy that, together with converse process, long-term potentiation (LTP), has been considered to be crucial for information storage in the brain and refinement of neuronal circuitry during development (Siegelbaum and Kandel 1991). In the hippocampus, LTD is divided into three categories: homosynaptic, heterosynaptic and associative LTD (Linden and Connor 1995). The best-characterized form of homosynaptic LTD is induced in CA1 region of the hippocampus by prolonged low-frequency synaptic stimulation (LFS) via a NMDA receptor-dependent rise in postsynaptic [Ca 2+ ] i and the activation of a protein phosphatase cascade (Bear and Abraham 1996). Recent work has shown that a mechanistically distinct type of LTD can also be induced in CA1 region by other types of synaptic stimulation or brief pharmacological treatments. For example, pairedpulse stimulation repeated at 1 Hz for 15 min or a direct application of the selective group I metabotropic glutamate receptor (mGluR) agonist (S)-3,5-dihydroxyphenylglycine (DHPG), can induce a robust mGluR-dependent form of LTD that is independent of NMDA receptor activation but requires a local translation of dendritic mRNA

Currently there are no therapies for treating Alzheimer's disease (AD) that can effectively halt disease progression. Existing drugs such as acetylcholinesterase inhibitors or NMDA receptor antagonists offers only symptomatic benefit. More recently, transplantation of neural stem cells (NSCs) to treat neurodegenerative diseases, including AD, has been investigated as a new therapeutic approach. Transplanted cells have the potential to replace damaged neural circuitry and secrete neurotrophic factors to counter symptomatic deterioration or to alter lesion protein levels. However, since there are animal models that can recapitulate AD in its entirety, it is challenging to precisely characterize the positive effects of transplanting NSCs. In the present review, we discuss the types of mouse modeling system that are available and the effect in each model after human-derived NSC (hNSC) or murine-derived NSC (mNSC) transplantation. Taken together, results from studies involving NSC transplantation in AD models indicate that this strategy could serve as a new therapeutic approach.