[Show abstract][Hide abstract] ABSTRACT: How do microglia regulate synaptic function? In this issue of Neuron, Zhang et al. (2014) describe a novel form of long-term depression of AMPA receptor-mediated synaptic transmission in the hippocampus involving the activation of microglia.
[Show abstract][Hide abstract] ABSTRACT: N-methyl-d-aspartate receptor (NMDAR)-dependent long-term potentiation (LTP) is extensively studied since it is believed to use the same molecular mechanisms that are required for many forms of learning and memory. Unfortunately, many controversies exist, not least the seemingly simple issue concerning the locus of expression of LTP. Here, we review our recent work and some of the extensive literature on this topic and present new data that collectively suggest that LTP can be explained, during its first few hours, by the coexistence of at least three mechanistically distinct processes that are all triggered by the synaptic activation of NMDARs.
Philosophical Transactions of The Royal Society B Biological Sciences 01/2014; 369(1633):20130131. · 6.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We summarize the reviews and research papers submitted by speakers at a discussion meeting on Synaptic Plasticity in Health and Disease held at the Royal Society, London on 2-3 December 2013, and a subsequent satellite meeting convened at the Royal Society/Kavli Centre at Chicheley Hall on 4-5 December 2013. Together, these contributions give an overview of current research and controversies in a vibrant branch of neuroscience with important implications for the understanding of many forms of learning and memory, and a wide spectrum of neurological and cognitive disorders.
Philosophical Transactions of The Royal Society B Biological Sciences 01/2014; 369(1633):20130129. · 6.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In this review, we focus on the role of the Shank family of proteins in autism. In recent years, autism research has been flourishing. With genetic, molecular, imaging and electrophysiological studies being supported by behavioural studies using animal models, there is real hope that we may soon understand the fundamental pathology of autism. There is also genuine potential to develop a molecular-level pharmacological treatment that may be able to deal with the most severe symptoms of autism, and clinical trials are already underway. The Shank family of proteins has been strongly implicated as a contributing factor in autism in certain individuals and sits at the core of the alleged autistic pathway. Here, we analyse studies that relate Shank to autism and discuss what light this sheds on the possible causes of autism.
Philosophical Transactions of The Royal Society B Biological Sciences 01/2014; 369(1633):20130143. · 6.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The microtubule-associated protein tau is a principal component of neurofibrillary tangles, and has been identified as a key molecule in Alzheimer's disease and other tauopathies. However, it is unknown how a protein that is primarily located in axons is involved in a disease that is believed to have a synaptic origin. To investigate a possible synaptic function of tau, we studied synaptic plasticity in the hippocampus and found a selective deficit in long-term depression (LTD) in tau knockout mice in vivo and in vitro, an effect that was replicated by RNAi knockdown of tau in vitro. We found that the induction of LTD is associated with the glycogen synthase kinase-3-mediated phosphorylation of tau. These observations demonstrate that tau has a critical physiological function in LTD.
Philosophical Transactions of The Royal Society B Biological Sciences 01/2014; 369(1633):20130144. · 6.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The neuroendocrine response to episodes of acute stress is crucial for survival whereas the prolonged response to chronic stress can be detrimental. Learning and memory are particularly susceptible to stress with cognitive deficits being well characterized consequences of chronic stress. Although there is good evidence that acute stress can enhance cognitive performance, the mechanism(s) for this are unclear. We find that hippocampal slices, either prepared from rats following 30 min restraint stress or directly exposed to glucocorticoids, exhibit an N-methyl-d-aspartic acid receptor-independent form of long-term potentiation. We demonstrate that the mechanism involves an NMDA receptor and PKA-dependent insertion of Ca(2+)-permeable AMPA receptors into synapses. These then trigger the additional NMDA receptor-independent form of LTP during high frequency stimulation.
[Show abstract][Hide abstract] ABSTRACT: The insular cortex (IC) is known to play important roles in higher brain functions such as memory and pain. Activity-dependent long-term depression (LTD) is a major form of synaptic plasticity related to memory and chronic pain. Previous studies of LTD have mainly focused on the hippocampus, and no study in the IC has been reported. In this study, using a 64-channel recording system, we show for the first time that repetitive low-frequency stimulation (LFS) can elicit frequency-dependent LTD of glutamate receptor-mediated excitatory synaptic transmission in both superficial and deep layers of the IC of adult mice. The induction of LTD in the IC required activation of the N-methyl-d-aspartate (NMDA) receptor, metabotropic glutamate receptor (mGluR)5, and L-type voltage-gated calcium channel. Protein phosphatase 1/2A and endocannabinoid signaling are also critical for the induction of LTD. In contrast, inhibiting protein kinase C, protein kinase A, protein kinase Mζ or calcium/calmodulin-dependent protein kinase II did not affect LFS-evoked LTD in the IC. Bath application of the group I mGluR agonist (RS)-3,5-dihydroxyphenylglycine produced another form of LTD in the IC, which was NMDA receptor-independent and could not be occluded by LFS-induced LTD. Our studies have characterised the basic mechanisms of LTD in the IC at the network level, and suggest that two different forms of LTD may co-exist in the same population of IC synapses.
European Journal of Neuroscience 08/2013; · 3.75 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Inhibition of Arp2/3-mediated actin polymerization by PICK1 is a central mechanism to AMPA receptor (AMPAR) internalization and long-term depression (LTD), although the signaling pathways that modulate this process in response to NMDA receptor (NMDAR) activation are unknown. Here, we define a function for the GTPase Arf1 in this process. We show that Arf1-GTP binds PICK1 to limit PICK1-mediated inhibition of Arp2/3 activity. Expression of mutant Arf1 that does not bind PICK1 leads to reduced surface levels of GluA2-containing AMPARs and smaller spines in hippocampal neurons, which occludes subsequent NMDA-induced AMPAR internalization and spine shrinkage. In organotypic slices, NMDAR-dependent LTD of AMPAR excitatory postsynaptic currents is abolished in neurons expressing mutant Arf1. Furthermore, NMDAR stimulation downregulates Arf1 activation and binding to PICK1 via the Arf-GAP GIT1. This study defines Arf1 as a critical regulator of actin dynamics and synaptic function via modulation of PICK1.
[Show abstract][Hide abstract] ABSTRACT: The insular cortex (IC) is widely believed to be an important forebrain structure involved in cognitive and sensory processes such as memory and pain. However, little work has been performed at the cellular level to investigate the synaptic basis of IC-related brain functions. To bridge the gap, the present study was designed to characterize the basic synaptic mechanisms for insular long-term potentiation (LTP). Using a 64-channel recording system, we found that an enduring form of late-phase LTP (L-LTP) could be reliably recorded for at least 3 h in different layers of the IC slices following theta burst stimulation. The induction of insular LTP is protein synthesis-dependent and requires activation of both GluN2A and GluN2B subunits of the NMDA receptor, L-type voltage-gated calcium channels, and metabotropic glutamate receptor 1. The paired-pulse facilitation ratio was unaffected by insular L-LTP induction, and expression of insular L-LTP requires the recruitment of postsynaptic calcium-permeable AMPA receptors. Our results provide the first in vitro report of long-term multi-channel recordings of L-LTP in the IC from adult mice, and suggest its potential important roles in insular-related memory and chronic pain.
Journal of Neurophysiology 05/2013; · 3.30 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Metabotropic glutamate (mGlu) receptors are implicated in many neurological and psychiatric diseases and are the targets of therapeutic agents currently in clinical development. Their activation has diverse effects in the central nervous system (CNS) that includes an involvement in synaptic plasticity. We previously reported that the brief exposure of hippocampal slices to dihydroxyphenylglycine (DHPG) can result in a long-term depression (LTD) of excitatory synaptic transmission. Surprisingly, this LTD could be fully reversed by mGlu receptor antagonists in a manner that was itself fully reversible upon washout of the antagonist. Here, 15 years after the discovery of DHPG-LTD and its reversible reversibility, we summarise these initial findings. We then present new data on DHPG-LTD, which demonstrates that evoked epileptiform activity triggered by activation of group I mGlu receptors can also be reversibly reversed by mGlu receptor antagonists. Furthermore, we show that the phenomenon of reversible reversibility is not specific to group I mGlu receptors. We report that activation of group II mGlu receptors in the temporo-ammonic pathway (TAP) and mossy fibre pathway within the hippocampus and in the cortical input to neurons of the lateral amygdala induces an LTD that is reversed by LY341495, a group II mGlu receptor antagonist. We also show that activation of group III mGlu8 receptors induces an LTD at lateral perforant path inputs to the dentate gyrus and that this LTD is reversed by MDCPG, an mGlu8 receptor antagonist. In conclusion, we have shown that activation of representative members of each of the three groups of mGlu receptors can induce forms of LTD than can be reversed by antagonists, and that in each case washout of the antagonist is associated with the re-establishment of the LTD.
[Show abstract][Hide abstract] ABSTRACT: Postsynaptic Ca2+ transients triggered by neurotransmission at excitatory synapses are a key signaling step for the induction of synaptic plasticity and are typically recorded in tissue slices using two-photon fluorescence imaging with Ca2+-sensitive dyes. The signals generated are small with very low peak signal/noise ratios (pSNRs) that make detailed analysis problematic. Here, we implement a wavelet-based de-noising algorithm (PURE-LET) to enhance signal/noise ratio for Ca2+ fluorescence transients evoked by single synaptic events under physiological conditions. Using simulated Ca2+ transients with defined noise levels, we analyzed the ability of the PURE-LET algorithm to retrieve the underlying signal. Fitting single Ca2+ transients with an exponential rise and decay model revealed a distortion of trise but improved accuracy and reliability of tdecay and peak amplitude after PURE-LET de-noising compared to raw signals. The PURE-LET de-noising algorithm also provided a ~30-dB gain in pSNR compared to ~16-dB pSNR gain after an optimized binomial filter. The higher pSNR provided by PURE-LET de-noising increased discrimination accuracy between successes and failures of synaptic transmission as measured by the occurrence of synaptic Ca2+ transients by ~20% relative to an optimized binomial filter. Furthermore, in comparison to binomial filter, no optimization of PURE-LET de-noising was required for reducing arbitrary bias. In conclusion, the de-noising of fluorescent Ca2+ transients using PURE-LET enhances detection and characterization of Ca2+ responses at central excitatory synapses.
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVE:
The concept of inflammation-induced sensitization is emerging in the field of perinatal brain injury, stroke, Alzheimer disease, and multiple sclerosis. However, mechanisms underpinning this process remain unidentified.
We combined in vivo systemic lipopolysaccharide-induced or interleukin (IL)-1β-induced sensitization of neonatal and adult rodent cortical neurons to excitotoxic neurodegeneration with in vitro IL-1β sensitization of human and rodent neurons to excitotoxic neurodegeneration. Within these inflammation-induced sensitization models, we assessed metabotropic glutamate receptors (mGluR) signaling and regulation.
We demonstrate for the first time that group I mGluRs mediate inflammation-induced sensitization to neuronal excitotoxicity in neonatal and adult neurons across species. Inflammation-induced G protein-coupled receptor kinase 2 (GRK2) downregulation and genetic deletion of GRK2 mimicked the sensitizing effect of inflammation on excitotoxic neurodegeneration. Thus, we identify GRK2 as a potential molecular link between inflammation and mGluR-mediated sensitization.
Collectively, our findings indicate that inflammation-induced sensitization is universal across species and ages and that group I mGluRs and GRK2 represent new avenues for neuroprotection in perinatal and adult neurological disorders.
Annals of Neurology 02/2013; · 11.19 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A consensus has famously yet to emerge on the locus and mechanisms underlying the expression of the canonical NMDA receptor-dependent form of LTP. An objective assessment of the evidence leads us to conclude that both presynaptic and postsynaptic expression mechanisms contribute to this type of synaptic plasticity.
[Show abstract][Hide abstract] ABSTRACT: Key points• N‐Methyl‐d‐aspartate receptor (NMDAR)‐dependent potentiation of synaptic transmission is widely accepted as a cellular model of learning and memory. • It is most often studied in the CA1 area of rat hippocampal slices where it comprises a decremental and a sustained phase, which are commonly referred to as short‐term potentiation (STP) and long‐term potentiation (LTP), respectively. • In this study we show for the first time that STP and LTP are triggered by the activation of different classes of NMDARs and that STP itself comprises two pharmacologically and kinetically distinct components. • We suggest that the mechanistic separation of STP and LTP is likely to have important functional implications in that these two forms of synaptic plasticity can subserve unique physiological functions in a behaving animal. Abstract Potentiation at synapses between CA3 and the CA1 pyramidal neurons comprises both transient and sustained phases, commonly referred to as short‐term potentiation (STP or transient LTP) and long‐term potentiation (LTP), respectively. Here, we utilized four subtype‐selective N‐methyl‐d‐aspartate receptor (NMDAR) antagonists to investigate whether the induction of STP and LTP is dependent on the activation of different NMDAR subtypes. We find that the induction of LTP involves the activation of NMDARs containing both the GluN2A and the GluN2B subunits. Surprisingly, however, we find that STP can be separated into two components, the major form of which involves activation of NMDARs containing both GluN2B and GluN2D subunits. These data demonstrate that synaptic potentiation at CA1 synapses is more complex than is commonly thought, an observation that has major implications for understanding the role of NMDARs in cognition.
The Journal of Physiology 01/2013; 591(4). · 4.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Long-term potentiation (LTP), a cellular model of learning and memory, is generally regarded as a unitary phenomenon that alters the strength of synaptic transmission by increasing the postsynaptic response to the release of a quantum of neurotransmitter. LTP, at CA3-CA1 synapses in the hippocampus, contains a stimulation-labile phase of short-term potentiation (STP, or transient LTP, t-LTP) that decays into stable LTP. By studying the responses of populations of neurons to brief bursts of high-frequency afferent stimulation before and after the induction of LTP, we found that synaptic responses during bursts are potentiated equally during LTP but not during STP. We show that STP modulates the frequency response of synaptic transmission whereas LTP preserves the fidelity. Thus, STP and LTP have different functional consequences for the transfer of synaptic information.
[Show abstract][Hide abstract] ABSTRACT: JAK-STAT is an efficient and highly regulated system mainly dedicated to the regulation of gene expression. Primarily identified as functioning in hematopoietic cells, its role has been found critical in all cell types, including neurons. This review will focus on JAK-STAT functions in the mature central nervous system. Our recent research suggests the intriguing possibility of a non-nuclear role of STAT3 during synaptic plasticity. Dysregulation of the JAK-STAT pathway in inflammation, cancer and neurodegenerative diseases positions it at the heart of most brain disorders, highlighting the importance to understand how it can influence the fate and functions of brain cells.
[Show abstract][Hide abstract] ABSTRACT: Theta oscillations (4-12 Hz) in neuronal networks are known to predispose the synapses involved to plastic changes and may underlie their association with learning behaviors. The lowered threshold for synaptic plasticity during theta oscillations is thought to be due to decreased GABAergic inhibition. Interneuronal kainate receptors (KARs) regulate GABAergic transmission and are implicated in theta activity; however, the physiological significance of this regulation is unknown. In rat hippocampus, we show that during theta activity, there is excitatory postsynaptic drive to CA1 interneurons mediated by KARs. This promotes feedforward inhibition of pyramidal neurons, raising the threshold for induction of theta-burst long-term potentiation. These results identify a novel mechanism whereby the activation of postsynaptic KARs in CA1 interneurons gate changes in synaptic efficacy to a physiologically relevant patterned stimulation.
Journal of Neuroscience 12/2012; 32(50):18215-26. · 6.91 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Since its characterisation in 2001, the mGlu8-selective agonist DCPG has been widely used to explore the potential functional role of this group III mGlu receptor within the central nervous system. This research has implicated mGlu8 receptors in a number of disease states and conditions such as epilepsy and anxiety, suggesting that mGlu8-selective ligands may hold important therapeutic potential. However, there is evidence that DCPG exerts off-target effects at higher concentrations, limiting its use as an mGlu8-selective agonist. Here, we have used field recordings in rat hippocampal slices to investigate the effects of DCPG in the lateral perforant path (LPP), a pathway known to express high levels of mGlu8. We show that DCPG does inhibit excitatory transmission in this pathway, but produces a biphasic concentration-response curve suggesting activation of two distinct receptor types. The putative mGlu8-selective antagonist MDCPG antagonises the high, but not the low, potency component of this concentration-response curve. In addition, higher concentrations of DCPG also depress excitatory transmission in the medial perforant path (MPP), a pathway expressing very low levels of mGlu8 receptors. Experiments in slices from mice lacking mGlu8 receptors indicate that concentrations of DCPG > 1 μM produce large non-selective effects in both the LPP and MPP. Further experiments in slices from mGlu2, 4 and 7 knock-out mice, as well as in an mGlu2-deficient substrain of Wistar rat, reveal that these non-selective effects are mediated primarily by mGlu2 receptors. Taken together, our results confirm the mGlu8-selectivity of DCPG at submicromolar concentrations, but suggest that care must be taken when employing higher concentrations of the agonist, which may additionally activate mGlu2 receptors, especially at synapses where their expression is high. MDCPG may be a useful tool in determining whether observable DCPG effects are attributable to mGlu8, versus mGlu2, receptor activation.