Changiz Taghibiglou

LTP Inhibits LTD in the Hippocampus via Regulation of GSK3β

Glycogen synthase kinase-3 (GSK3) has been implicated in major neurological disorders, but its role in normal neuronal function is largely unknown. Here we show that GSK3beta mediates an interaction between two major forms of synaptic plasticity in the brain, N-methyl-D-aspartate (NMDA) receptor-dependent long-term potentiation (LTP) and NMDA receptor-dependent long-term depression (LTD). In rat hippocampal slices, GSK3beta inhibitors block the induction of LTD. Furthermore, the activity of GSK3beta is enhanced during LTD via activation of PP1. Conversely, following the induction of LTP, there is inhibition of GSK3beta activity. This regulation of GSK3beta during LTP involves activation of NMDA receptors and the PI3K-Akt pathway and disrupts the ability of synapses to undergo LTD for up to 1 hr. We conclude that the regulation of GSK3beta activity provides a powerful mechanism to preserve information encoded during LTP from erasure by subsequent LTD, perhaps thereby permitting the initial consolidation of learnt information.

Activation of PI3-kinase is required for AMPA receptor insertion during LTP of mEPSCs in cultured hippocampal neurons.

Hippocampal CA1 homosynaptic long-term potentiation (LTP) is expressed specifically at activated synapses. Increased insertion of postsynaptic alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid receptors (AMPARs) appears to be crucial for CA1 LTP. However, the mechanism underlying AMPAR insertion during LTP remains largely unknown. We now report that phosphatidylinositol 3-kinase (PI3K) is complexed with AMPARs at synapses and activated by selective stimulation of synaptic N-methyl-D-aspartate (NMDA) receptors. Activation of the AMPAR-associated PI3K is required for the increased cell surface expression of AMPARs and LTP. Thus, our results strongly suggest that the AMPAR-PI3K complex may constitute a critical molecular signal responsible for AMPAR insertion at activated CA1 synapses during LTP, and consequently, this lipid kinase may serve to determine the polarity of NMDA receptor-dependent synaptic plasticity.

Mechanisms of hepatic very low-density lipoprotein overproduction in insulin resistance.

An important complication of insulin-resistant states, such as obesity and type 2 diabetes, is an atherogenic dyslipidemia profile characterized by hypertriglyceridemia, low plasma high-density lipoproteins (HDL) cholesterol and a small, dense low-density lipoprotein (LDL) particle profile. The physiological basis of this metabolic dyslipidemia appears to be hepatic overproduction of apoB-containing very low-density lipoprotein (VLDL) particles. This has focused attention on the mechanisms that regulate VLDL secretion in insulin-resistant states. Recent studies in animal models of insulin resistance, particularly the fructose-fed hamster, have enhanced our understanding of these mechanisms, and certain key factors have recently been identified that play important roles in hepatic insulin resistance and dysregulation of the VLDL secretory process. This review focuses on these recent developments as well as on the hypothesis that an interaction between enhanced flux of free fatty acids from peripheral tissues to liver, chronic up-regulation of de novo lipogenesis by hyperinsulinemia and attenuated insulin signaling in the liver may be critical to the VLDL overproduction state observed in insulin resistance. It should be noted that the focus of this review is on molecular mechanisms of the hypertriglyceridemic state associated with insulin resistance and not that observed in association with insulin deficiency (e.g., in streptozotocin-treated animals), which appears to have a different etiology and is related to a catabolic defect rather than secretory overproduction of triglyceride-rich lipoproteins.

Tyrosine phosphorylation of GluR2 is required for insulin‐stimulated AMPA receptor endocytosis and LTD

The α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionic acid (AMPA) subtype of glutamate receptors is subject to functionally distinct constitutive and regulated clathrin‐dependent endocytosis, contributing to various forms of synaptic plasticity. In HEK293 cells transiently expressing GluR1 or GluR2 mutants containing domain deletions or point mutations in their intracellular carboxyl termini (CT), we found that deletion of the first 10 amino acids (834–843) selectively reduced the rate of constitutive AMPA receptor endocytosis, whereas truncation of the last 15 amino acids of the GluR2 CT, or point mutation of the tyrosine residues in this region, only eliminated the regulated (insulin‐stimulated) endocytosis. Moreover, in hippocampal slices, both insulin treatment and low‐frequency stimulation (LFS) specifically stimulated tyrosine phosphorylation of the GluR2 subunits of native AMPA receptors, and the enhanced phosphorylation appears necessary for both insulin‐ and LFS‐induced long‐term depression of AMPA receptor‐mediated excitatory postsynaptic currents. Thus, our results demonstrate that constitutive and regulated AMPA receptor endocytosis requires different sequences within GluR CTs and tyrosine phosphorylation of GluR2 CT is required for the regulated AMPA receptor endocytosis and hence the expression of certain forms of synaptic plasticity.

The role of GSK-3 in synaptic plasticity.

Glycogen synthase kinase‐3 (GSK‐3), an important component of the glycogen metabolism pathway, is highly expressed in the CNS. It has been implicated in major neurological disorders including Alzheimers disease, schizophrenia and bipolar disorders. Despite its central role in these conditions it was not known until recently whether GSK‐3 has neuronal‐specific functions under normal conditions. However recent work has shown that GSK‐3 is involved in the regulation of, and cross‐talk between, two major forms of synaptic plasticity, N‐methyl‐D‐aspartate receptor (NMDAR)‐dependent long‐term potentiation (LTP) and NMDAR‐dependent long‐term depression (LTD). The present article summarizes this recent work and discusses its potential relevance to the treatment of neurological disorders.

A biochemical and functional characterization of diet-induced brain insulin resistance

While considerable research has examined diminished insulin responses within peripheral tissues, comparatively little has been done to examine the effects of this metabolic disruption upon the CNS. The present study employed biochemical and electrophysiological assays of acutely prepared brain slices to determine whether neural insulin resistance is a component of the metabolic syndrome observed within the fructose‐fed (FF) hamster. The tyrosine phosphorylation levels of the insulin receptor (IR) and insulin receptor substrate 1 (IRS‐1) in response to insulin were significantly reduced within FF hamsters. Also, insulin‐mediated phosphorylation of both residues necessary for activation of the serine‐threonine kinase Akt/PKB, a key effector of insulin signaling, was markedly decreased. Elevated levels of the protein tyrosine phosphatase 1B, which dephosphorylates the IR and IRS‐1, were also observed within the cerebral cortex and hippocampus of FF hamsters. Examination of whether a nutritionally induced compromise of neural insulin signaling altered synaptic function revealed a significant attenuation of insulin‐induced long‐term depression, but no effect upon either paired‐pulse facilitation or electrically induced long‐term potentiation. Collectively, our results demonstrate, for the first time, that nutritionally induced insulin resistance significantly affects the neural insulin signaling pathway, and suggest that brain insulin resistance may contribute to cognitive impairment.

A pivotal role of GSK-3 in synaptic plasticity.

Glycogen synthase kinase-3 (GSK-3) has many cellular functions. Recent evidence suggests that it plays a key role in certain types of synaptic plasticity, in particular a form of long-term depression (LTD) that is induced by the synaptic activation of N-methyl-D-aspartate receptors (NMDARs). In the present article we summarize what is currently known concerning the roles of GSK-3 in synaptic plasticity at both glutamatergic and GABAergic synapses. We summarize its role in cognition and speculate on how alterations in the synaptic functioning of GSK-3 may be a major factor in certain neurodegenerative disorders.

Role of NMDA receptor–dependent activation of SREBP1 in excitotoxic and ischemic neuronal injuries

Excitotoxic neuronal damage caused by overactivation of N-methyl-D-aspartate glutamate receptors (NMDARs) is thought to be a principal cause of neuronal loss after stroke and brain trauma. Here we report that activation of sterol regulatory element binding protein-1 (SREBP-1) transcription factor in affected neurons is an essential step in NMDAR-mediated excitotoxic neuronal death in both in vitro and in vivo models of stroke. The NMDAR-mediated activation of SREBP-1 is a result of increased insulin-induced gene-1 (Insig-1) degradation, which can be inhibited with an Insig-1–derived interference peptide (Indip) that we have developed. Using a focal ischemia model of stroke, we show that systemic administration of Indip not only prevents SREBP-1 activation but also substantially reduces neuronal damage and improves behavioral outcome. Our study suggests that agents that reduce SREBP-1 activation such as Indip may represent a new class of neuroprotective therapeutics against stroke.

Cell-penetrating Peptides as a Novel Transdermal Drug Delivery System

In the last decade, almost one‐third of the newly discovered drugs approved by the US FDA were biomolecules and biologics. Effective delivery of therapeutic biomolecules to their target is a challenging issue. Innovations in drug delivery systems have improved the efficiency of many of new biopharmaceuticals. Designing of novel transdermal delivery systems has been one of the most important pharmaceutical innovations, which offers a number of advantages. The cell‐penetrating peptides have been increasingly used to mediate delivery of bimolecular cargoes such as small molecules, small interfering RNA nucleotides, drug‐loaded nanoparticles, proteins, and peptides, both in vitro and in vivo, without using any receptors and without causing any significant membrane damage. Among several different drug delivery routes, application of cell‐penetrating peptides in the topical and transdermal delivery systems has recently garnered tremendous attention in both cosmeceutical and pharmaceutical research and industries. In this review, we discuss history of cell‐penetrating peptides, cell‐penetrating peptide/cargo complex formation, and their mechanisms of cell and skin transduction.

Novel Central Nervous System Drug Delivery Systems

For decades, biomedical and pharmaceutical researchers have worked to devise new and more effective therapeutics to treat diseases affecting the central nervous system. The blood–brain barrier effectively protects the brain, but poses a profound challenge to drug delivery across this barrier. Many traditional drugs cannot cross the blood–brain barrier in appreciable concentrations, with less than 1% of most drugs reaching the central nervous system, leading to a lack of available treatments for many central nervous system diseases, such as stroke, neurodegenerative disorders, and brain tumors. Due to the ineffective nature of most treatments for central nervous system disorders, the development of novel drug delivery systems is an area of great interest and active research. Multiple novel strategies show promise for effective central nervous system drug delivery, giving potential for more effective and safer therapies in the future. This review outlines several novel drug delivery techniques, including intranasal drug delivery, nanoparticles, drug modifications, convection‐enhanced infusion, and ultrasound‐mediated drug delivery. It also assesses possible clinical applications, limitations, and examples of current clinical and preclinical research for each of these drug delivery approaches. Improved central nervous system drug delivery is extremely important and will allow for improved treatment of central nervous system diseases, causing improved therapies for those who are affected by central nervous system diseases.