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Long-term depression (LTD) induction relies upon receptor cross-talk between group I and group II metabotropic glutamate receptors (mGluRs) in perirhinal cortex. The molecular mechanism of this mGluR interplay is not clear. Here, we show that the mGluR subtypes postulated to be involved in this mechanism are developmentally regulated and mGluR2 has a preferential role over mGluR3 in the synergistic interaction with mGluR5. We have identified a >70% reduction in basal cAMP levels following mGluR2 stimulation, which could lead to increased mGluR5 function via reduced PKA mediated phosphorylation and decreased desensitisation of mGluR5. To further investigate the roles of mGluRs in downstream intracellular signalling, we have examined the effects of mGluRs on the phosphorylation state of cAMP response element-binding protein (CREB). Both group I and group II agonists increased the phosphorylation of CREB, which indicates a cAMP- and PKA-independent signalling mechanism. These results suggest a convergence of signalling mechanisms from surface mGluRs to CREB-mediated transcription. [Copyright &y& Elsevier]

Mounting evidence suggests that the etiology of autism spectrum disorders (ASDs) is profoundly influenced by exposure to environmental factors, although the precise molecular and cellular links remain ill-defined. In this study, we examined how exposure to valproic acid (VPA) during pregnancy is associated with an increased incidence of ASD. A mouse model was established by injecting VPA at embryonic day 13, and its behavioral phenotypes including impaired social interaction, increased repetitive behaviors and decreased nociception were observed at postnatal days 21–42. VPA-treated mice showed dysregulation of synaptic structure in cortical neurons, including a reduced proportion of filopodium-type and stubby spines and increased proportions of thin and mushroom-type spines, along with a decreased spine head size. We also found that VPA-treatment led to decreased expression of phosphate and tensin homolog (PTEN) and increased levels of p -AKT protein in the hippocampus and cortex. Our data suggest that there is a correlation between VPA exposure and dysregulation of PTEN with ASD-like behavioral and neuroanatomical changes, and this may be a potential mechanism of VPA-induced ASD. [ABSTRACT FROM AUTHOR]

Evidence suggests that the stress hormones glucocorticoids (GCs) can cause cognitive deficits and neurodegeneration. Previous studies have found GCs facilitate physiological synapse weakening, termed long-term depression (LTD), though the precise mechanisms underlying this are poorly understood. Here we show that GCs activate glycogen synthase kinase-3 (GSK-3), a kinase crucial to synapse weakening signals. Critically, this ultimately leads to phosphorylation of the microtubule associated protein tau, specifically at the serine 396 residue, and this is a causal factor in the GC-mediated impairment of synaptic function. These findings reveal the link between GCs and synapse weakening signals, and the potential for stress-induced priming of neurodegeneration. This could have important implications for our understanding of how stress can lead to neurodegenerative disease. [ABSTRACT FROM AUTHOR]

This study describes a fundamental functional difference between the two main polymorphisms of the pro-form of brain-derived neurotrophic factor (proBDNF), providing an explanation as to why these forms have such different age-related neurological outcomes. Healthy young carriers of the Met66 form (present in ∼30% Caucasians) have reduced hippocampal volume and impaired hippocampal-dependent memory function, yet the same polymorphic population shows enhanced cognitive recovery after traumatic brain injury, delayed cognitive dysfunction during aging, and lower risk of late-onset Alzheimer’s disease (AD) compared to those with the more common Val66 polymorphism. To examine the differences between the protein polymorphisms in structure, kinetics of binding to proBDNF receptors and in vitro function, we generated purified cleavage-resistant human variants. Intriguingly, we found no statistical differences in those characteristics. As anticipated, exogenous application of proBDNF Val66 to rat hippocampal slices dysregulated synaptic plasticity, inhibiting long-term potentiation (LTP) and facilitating long-term depression (LTD). We subsequently observed that this occurred via the glycogen synthase kinase 3β (GSK3β) activation pathway. However, surprisingly, we found that Met66 had no such effects on either LTP or LTD. These novel findings suggest that, unlike Val66, the Met66 variant does not facilitate synapse weakening signaling, perhaps accounting for its protective effects with aging. [ABSTRACT FROM AUTHOR]

Abstract: Calcium (Ca2+) is a fundamental intracellular signalling molecule in neurons. Therefore, significant interest has been expressed in understanding how the dysregulation of Ca2+ signals might impact on neuronal function and the progression of different disease states. Many previous studies have examined the role of Ca2+ in neuronal excitotoxicity and some have started to understand how Ca2+ dysregulation might be a cause or consequence of neurodegeneration. This review will therefore focus on the significance of Ca2+ sensors, proteins that transduce Ca2+ signals, in neuronal function and dysfunction. Finally, we will assess their potential role in neurodegenerative processes, such as Alzheimer''s disease (AD), arguing that they could serve as potential therapeutic targets. [Copyright &y& Elsevier]

Abstract: The spinal synaptic plasticity is associated with a central sensitization of nociceptive input, which accounts for the generation of hyperalgesia in chronic pain. However, how group I metabotropic glutamate receptors (mGluRs) may operate spinal plasticity remains essentially unexplored. Here, we have identified spike-timing dependent synaptic plasticity in substantia gelatinosa (SG) neurons, using perforated patch-clamp recordings of SG neuron in a spinal cord slice preparation. In the presence of bicuculline and strychnine, long-term potentiation (LTP) was blocked by AP-5 and Ca2+ chelator BAPTA-AM. The group I mGluR antagonist AIDA, PLC inhibitor U-73122, and IP3 receptor blocker 2-APB shifted LTP to long-term depression (LTD) without affecting acute synaptic transmission. These findings provide a link between postsynaptic group I mGluR/PLC/IP3-gated Ca2+ store regulating the polarity of synaptic plasticity and spinal central sensitization. [Copyright &y& Elsevier]