Term Synaptic Plasticity Research Articles

Increased Activity of Src Homology 2 Domain Containing Phosphotyrosine Phosphatase 2 (Shp2) Regulates Activity-dependent AMPA Receptor Trafficking

Long term synaptic plasticity, such as long term potentiation (LTP), has been widely accepted as a cellular mechanism underlying memory. Recently, it has been unraveled that Shp2 plays a role in synaptic plasticity and memory in Drosophila and mice, revealing significant and conserved effects of Shp2 in cognitive function. However, the exact mechanism underlying this function of Shp2 in synaptic plasticity and memory still remains elusive. Here, we examine the regulation of Shp2 in hippocampal LTP and contextual fear conditioning. We find that Shp2 is rapidly recruited into spines after LTP induction. Furthermore, the phosphorylation level of Shp2 at Tyr-542 is elevated after LTP stimuli either in cultured hippocampal neurons or acute slices. Notably, contextual fear conditioning also regulates the phosphorylation level of Shp2 at Tyr-542, suggesting fine-tuned regulation of Shp2 in LTP and memory formation. By using a Shp2-specific inhibitor and adeno-associated virus-Cre mediated Shp2 knock-out in cultured neurons, we provide evidence that the phosphatase activity of Shp2 is critical for activity-dependent AMPA receptor surface trafficking. Collectively, our results have revealed a regulatory mechanism of Shp2 underlying LTP and memory, broadening our understanding of Shp2 in cognitive function.

LAMP5 Fine-Tunes GABAergic Synaptic Transmission in Defined Circuits of the Mouse Brain.

LAMP5 is member of the LAMP family of membrane proteins. In contrast to the canonical members of this protein family, LAMP1 and LAMP2, which show widespread expression in many tissues, LAMP 5 is brain specific in mice. In C. elegans, the LAMP5 ortholog UNC-46 has been suggested to act a trafficking chaperone, essential for the correct targeting of the nematode vesicular GABA-transporter UNC-47. We show here that in the mouse brain LAMP5 is expressed in subpopulations of GABAergic forebrain neurons in the striato-nigral system and the olfactory bulb. The protein was present at synaptic terminals, overlapping with the mammalian vesicular GABA-transporter VGAT. In LAMP5-deficient mice localization of the transporter was unaffected arguing against a conserved role in VGAT trafficking. Electrophysiological analyses in mutants showed alterations in short term synaptic plasticity suggesting that LAMP5 is involved in controlling the dynamics of evoked GABAergic transmission. At the behavioral level, LAMP5 mutant mice showed decreased anxiety and deficits in olfactory discrimination. Altogether, this work implicates LAMP5 function in GABAergic neurotransmission in defined neuronal subpopulations.

The Role of Astrocytic Aquaporin-4 in Synaptic Plasticity and Learning and Memory.

Aquaporin-4 (AQP4) is the predominant water channel expressed by astrocytes in the central nervous system (CNS). AQP4 is widely expressed throughout the brain, especially at the blood-brain barrier where AQP4 is highly polarized to astrocytic foot processes in contact with blood vessels. The bidirectional water transport function of AQP4 suggests its role in cerebral water balance in the CNS. The regulation of AQP4 has been extensively investigated in various neuropathological conditions such as cerebral edema, epilepsy, and ischemia, however, the functional role of AQP4 in synaptic plasticity, learning, and memory is only beginning to be elucidated. In this review, we explore the current literature on AQP4 and its influence on long term potentiation (LTP) and long term depression (LTD) in the hippocampus as well as the potential relationship between AQP4 and in learning and memory. We begin by discussing recent in vitro and in vivo studies using AQP4-null and wild-type mice, in particular, the impairment of LTP and LTD observed in the hippocampus. Early evidence using AQP4-null mice have suggested that impaired LTP and LTD is brain-derived neurotrophic factor dependent. Others have indicated a possible link between defective LTP and the downregulation of glutamate transporter-1 which is rescued by chronic treatment of β-lactam antibiotic ceftriaxone. Furthermore, behavioral studies may shed some light into the functional role of AQP4 in learning and memory. AQP4-null mice performances utilizing Morris water maze, object placement tests, and contextual fear conditioning proposed a specific role of AQP4 in memory consolidation. All together, these studies highlight the potential influence AQP4 may have on long term synaptic plasticity and memory.

Re-innervation of Learning with Neuronal Plasticity: the Neuromuscular Junction as a Model

Re-innervation of Learning with Neuronal Plasticity: the Neuromuscular Junction as a Model

Role of Liver X Receptor in AD Pathophysiology.

Alzheimer's disease (AD) is the major cause of dementia worldwide. The pharmacological activation of nuclear receptors (Liver X receptors: LXRs or Retinoid X receptors: RXR) has been shown to induce overexpression of the ATP-Binding Cassette A1 (ABCA1) and Apolipoprotein E (ApoE), changes that are associated with improvement in cognition and reduction of amyloid beta pathology in amyloidogenic AD mouse models (i.e. APP, PS1: 2tg-AD). Here we investigated whether treatment with a specific LXR agonist has a measurable impact on the cognitive impairment in an amyloid and Tau AD mouse model (3xTg-AD: 12-months-old; three months treatment). The data suggests that the LXR agonist GW3965 is associated with increased expression of ApoE and ABCA1 in the hippocampus and cerebral cortex without a detectable reduction of the amyloid load. We also report that most cells overexpressing ApoE (86±12%) are neurons localized in the granular cell layer of the hippocampus and entorhinal cortex. In the GW3965 treated 3xTg-AD mice we also observed reduction in astrogliosis and increased number of stem and proliferating cells in the subgranular zone of the dentate gyrus. Additionally, we show that GW3965 rescued hippocampus long term synaptic plasticity, which had been disrupted by oligomeric amyloid beta peptides. The effect of GW3965 on synaptic function was protein synthesis dependent. Our findings identify alternative functional/molecular mechanisms by which LXR agonists may exert their potential benefits as a therapeutic strategy against AD.

SYNAPTIC PLASTICITY IN THE SOMATOSENSORY CORTEX

The term synaptic plasticity implies modification in the strength or efficacy of synaptic transmission between pre-existing synapses. Long-term changes in synaptic efficacy have been widely proposed as the cellular mechanism of the learning and memory machineries of the brain. However both the induction and expression mechanisms of synaptic plasticity processes remain elusive and more diverse than formerly though. In this review we show the principal mechanisms of experience-dependent plasticity in the somatosensory barrel cortex. The somatosensory barrel cortex is composed of local circuits interconnected by vertical and horizontal projections. Sensory information from the whiskers is transmitted through the brain stem and thalamus to layer 4 neurons in the barrel cortex. Sensory responses are relayed from layer 4 to layer 2/3 and then to layer 5 and layer 6. At the same time, there is feedback from layer 5 to layer 2/3 and layer 6 to layer 4. This vertical organization is linked horizontally by strong projections between barrels. Distinct synaptic and intrinsic properties of these neurons are involved in different sensory plasticity responses observed in the barrel cortex.

Short-term plasticity and modulation of synaptic transmission at mammalian inhibitory cholinergic olivocochlear synapses.

The organ of Corti, the mammalian sensory epithelium of the inner ear, has two types of mechanoreceptor cells, inner hair cells (IHCs) and outer hair cells (OHCs). In this sensory epithelium, vibrations produced by sound waves are transformed into electrical signals. When depolarized by incoming sounds, IHCs release glutamate and activate auditory nerve fibers innervating them and OHCs, by virtue of their electromotile property, increase the amplification and fine tuning of sound signals. The medial olivocochlear (MOC) system, an efferent feedback system, inhibits OHC activity and thereby reduces the sensitivity and sharp tuning of cochlear afferent fibers. During neonatal development, IHCs fire Ca2+ action potentials which evoke glutamate release promoting activity in the immature auditory system in the absence of sensory stimuli. During this period, MOC fibers also innervate IHCs and are thought to modulate their firing rate. Both the MOC-OHC and the MOC-IHC synapses are cholinergic, fast and inhibitory and mediated by the α9α10 nicotinic cholinergic receptor (nAChR) coupled to the activation of calcium-activated potassium channels that hyperpolarize the hair cells. In this review we discuss the biophysical, functional and molecular data which demonstrate that at the synapses between MOC efferent fibers and cochlear hair cells, modulation of transmitter release as well as short term synaptic plasticity mechanisms, operating both at the presynaptic terminal and at the postsynaptic hair-cell, determine the efficacy of these synapses and shape the hair cell response pattern.

Apolipoprotein E4 impairs in vivo hippocampal long-term synaptic plasticity by reducing the phosphorylation of CaMKIIα and CREB.

Inheritance of the apolipoprotein E genotype ε4 (APOE4) is a powerful risk factor for most cases of late-onset Alzheimer's disease (AD). However, the effects of ApoE4 on the long-term synaptic plasticity and its underlying mechanism have not clearly investigated. In the present study, we examined the effects of ApoE4 on the hippocampal late-phase long-term potentiation (L-LTP) and investigated its probable molecular mechanisms by using in vivo field potential recording, immunohistochemistry, and western blotting. The results showed that: (1) intra-hippocampal injection of 0.2 μg ApoE4, but not ApoE2, before high frequency stimulations (HFSs) attenuated the induction of hippocampal L-LTP in the CA1 region, while injection of the same concentration of ApoE4 after HFSs, even at a higher concentration (2 μg), did not affect the long term synaptic plasticity; (2) ApoE4 injection did not affect the paired pulse facilitation in the hippocampal CA1 region; (3) ApoE4 injection before, not after, HFSs significantly decreased the levels of phosphorylated Ca2+/calmodulin-dependent protein kinase IIα (p-CaMKIIα) and phosphorylated cAMP response element-binding protein (p-CREB) in the hippocampus. These results demonstrated for the first time that ApoE4 could impair hippocampal L-LTP by reducing p-CaMKIIα and p-CREB, suggesting that the ApoE4-induced suppression of hippocampal long-term synaptic plasticity may contribute to the cognitive impairments in genetic AD; and both CaMKIIα and CREB are important intracellular targets of the neurotoxic ApoE4.

Autaptic Connections and Synaptic Depression Constrain and Promote Gamma Oscillations

Computational models of gamma oscillations have helped increase our understanding of the mechanisms that shape these 40–80 Hz cortical rhythms. Evidence suggests that interneurons known as basket cells are responsible for the generation of gamma oscillations. However, current models of gamma oscillations lack the dynamic short term synaptic plasticity seen at basket cell-basket cell synapses as well as the large autaptic synapses basket cells are known to express. Hence, I sought to extend the Wang-Buzsáki model of gamma oscillations to include these features. I found that autapses increased the synchrony of basket cell membrane potentials across the network during neocortical gamma oscillations as well as allowed the network to oscillate over a broader range of depolarizing drive. I also found that including realistic synaptic depression filtered the output of the network. Depression restricted the network to oscillate in the 60–80 Hz range rather than the 40–120 Hz range seen in the standard model. This work shows the importance of including accurate synapses in any future model of gamma oscillations.

Increased Voluntary Ethanol Consumption and Changes in Hippocampal Synaptic Plasticity in Isolated C57BL/6J Mice

Social isolation (SI) is a notable model of prolonged mild stress, characterized by multiple neurochemical and behavioral alterations, that appears particularly suitable for studying different aspects of the interplay between stress and ethanol (EtOH) consumption in order to characterize potential molecular mechanisms, including changes in the function of inhibitory GABAergic synapses, underlying such interaction. In C57BL/6J mice, SI is associated with an altered hippocampal concentration of the neuroactive steroids 3α-hydroxy-5α-pregnan-20-one (3α-5α-THP), an increased expression of the α4 and δ subunit of γ-aminobutyric acid type A receptors (GABAARs) in the dentate gyrus (DG), and a parallel enhancement of the stimulatory action of 4,5,6,7-tetrahydroisoxazolo[5,4-c] pyridin-3-ol (THIP) on GABAergic tonic currents recorded in voltage-clamped DG granule cells (DGGCs). In addition, SI in C57BL/6J mice determines an increase in voluntary EtOH consumption and EtOH preference when compared to group-housed (GH) control animals. Furthermore, in hippocampal slices of SI mice we also observed a marked reduction of both cellular excitability and long term potentiation (LTP) in pyramidal neurons of the CA1 hippocampal sub-region, effects that were prevented by the long term treatment of SI mice with the neuroactive steroid precursor progesterone. In this article, we summarize some of our recent findings on the effects of SI in C57BL/6J mice on voluntary EtOH intake, regulation of GABAARs gene expression and function and hippocampal long term synaptic plasticity.

Defining the molecular targets of cerebellar PKG by quantitative (phospho)proteomics in a knock-out mouse model

Background The NO/cGMP/PKG pathway plays a crucial role in the induction of cerebellar long term depression (LTD), synaptic plasticity, and motor learning. Previous studies showed that Purkinje cell specific PKG I knock-out mice exhibit strongly reduced LTD and deficits in adaptation of the vestibular ocular reflex [1]. To better understand the molecular mechanisms of PKG I and its involvement in LTD and motor learning, we combined the use of a mouse model deficient for PKG I expression with an LC-MS/MS based in-depth proteomics and phosphoproteomics analysis directly in cerebellum tissue.

P.2.006 Effects of serotonin (5-HT)1B receptor ligands on amphetamine-seeking behaviour in rats

RMTg onto DA cells was reduced, and RMTg neurons showed a reduced spontaneous activity in sP rats. In vitro electrophysiology experiments showed that depolarization-induced suppression of inhibition (DSI), a form of endocannabinoid-mediated short term synaptic plasticity expressed by inhibitory synapses from RMTg onto VTA DA neurons, is larger in sP rats. This phenomenon is selectively mediated by the endocannabinoid 2-arachidonoylglycerol (2-AG), which activates presynaptic type 1-cannabinoid (CB1) receptors. The larger DSI in sP rats reflects a difference in the rate 2-AG is degraded, and not in CB1 number and/or function. Given that sP rats are vulnerable phenotypes, and that they express larger DSI, our results suggest that differences in regulation of 2-AG signaling might control specific sources of vulnerability.

Ca2+-independent Activation of Ca2+/Calmodulin-dependent Protein Kinase II Bound to the C-terminal Domain of CaV2.1 Calcium Channels

Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) forms a major component of the postsynaptic density where its functions in synaptic plasticity are well established, but its presynaptic actions are poorly defined. Here we show that CaMKII binds directly to the C-terminal domain of Ca(V)2.1 channels. Binding is enhanced by autophosphorylation, and the kinase-channel signaling complex persists after dephosphorylation and removal of the Ca(2+)/CaM stimulus. Autophosphorylated CaMKII can bind the Ca(V)2.1 channel and synapsin-1 simultaneously. CaMKII binding to Ca(V)2.1 channels induces Ca(2+)-independent activity of the kinase, which phosphorylates the enzyme itself as well as the neuronal substrate synapsin-1. Facilitation and inactivation of Ca(V)2.1 channels by binding of Ca(2+)/CaM mediates short term synaptic plasticity in transfected superior cervical ganglion neurons, and these regulatory effects are prevented by a competing peptide and the endogenous brain inhibitor CaMKIIN, which blocks binding of CaMKII to Ca(V)2.1 channels. These results define the functional properties of a signaling complex of CaMKII and Ca(V)2.1 channels in which both binding partners are persistently activated by their association, and they further suggest that this complex is important in presynaptic terminals in regulating protein phosphorylation and short term synaptic plasticity.

Differentiation in the protein synthesis-dependency of persistent synaptic plasticity in mossy fiber and associational/commissural CA3 synapses in vivo

Long-term potentiation (LTP) and long-term depression (LTD) are two mechanisms involved in the long-term storage of information in hippocampal synapses. In the hippocampal CA1 region, the late phases of LTP and LTD are protein-synthesis dependent. In the dentate gyrus, late-LTP but not LTD requires protein synthesis. The protein synthesis-dependency of persistent plasticity at CA3 synapses has not yet been characterized. Here, the roles of protein transcription and translation at mossy fiber (mf) and associational/commissural (AC)- synapses were studied in freely behaving rats. In control animals, low-frequency stimulation (LFS) evoked robust LTD (>24 h), whereas high-frequency stimulation (HFS) elicited robust LTP (>24 h) at both mf-CA3 and AC-CA3 synapses. Translation inhibitors prevented early and late phases of LTP and LTD at mf-CA3 synapses. In contrast, at AC–CA3 synapses, translation inhibitors prevented intermediate/late-LTP and late-LTD only. Transcription effects were also synapse-specific: whereas transcription inhibitors inhibited late-LTP and late-LTD (>3 h) at mf-CA3 synapses, at AC–CA3 synapses, protein transcription affected early-LTP and late-LTD. These results show that the AC-CA3 and mf-CA3 synapses display different properties in terms of their protein synthesis dependency, suggesting different roles in the processing of short- and long term synaptic plasticity.

Optogenetic field potential recording in cortical slices

We introduce a method that uses optogenetic stimulation to evoke field potentials in brain slices prepared from transgenic mice expressing channelrhodopsin-2-YFP. Cortical slices in a recording chamber were stimulated with a 473nm blue laser via either a laser scanning photostimulation setup or by direct guidance of a fiber optic. Field potentials evoked by either of the two optogenetic stimulation methods had stable amplitude, consistent waveform, and similar components as events evoked with a conventional stimulating electrode. The amplitude of evoked excitatory postsynaptic potentials increased with increasing laser intensity or pulse duration. We further demonstrated that optogenetic stimulation can be used for the induction and monitoring of long-term depression. We conclude that this technique allows for efficient and reliable activation of field potentials in brain slice preparation, and will be useful for studying short and long term synaptic plasticity.

Balancing Arc Synthesis, mRNA Decay, and Proteasomal Degradation: MAXIMAL PROTEIN EXPRESSION TRIGGERED BY RAPID EYE MOVEMENT SLEEP-LIKE BURSTS OF MUSCARINIC CHOLINERGIC RECEPTOR STIMULATION

Cholinergic signaling induces Arc/Arg3.1, an immediate early gene crucial for synaptic plasticity. However, the molecular mechanisms that dictate Arc mRNA and protein dynamics during and after cholinergic epochs are little understood. Using human SH-SY5Y neuroblastoma cells, we show that muscarinic cholinergic receptor (mAchR) stimulation triggers Arc synthesis, whereas translation-dependent RNA decay and proteasomal degradation strictly limit the amount and duration of Arc expression. Chronic application of the mAchR agonist, carbachol (Cch), induces Arc transcription via ERK signaling and release of calcium from IP(3)-sensitive stores. Arc translation requires ERK activation, but not changes in intracellular calcium. Proteasomal degradation of Arc (half-life ∼37 min) was enhanced by thapsigargin, an inhibitor of the endoplasmic calcium-ATPase pump. Similar mechanisms of Arc protein regulation were observed in cultured rat hippocampal slices. Functionally, we studied the impact of cholinergic epoch duration and temporal pattern on Arc protein expression. Acute Cch treatment (as short as 2 min) induces transient, moderate Arc expression, whereas continuous treatment of more than 30 min induces maximal expression, followed by rapid decline. Cholinergic activity associated with rapid eye movement sleep may function to facilitate long term synaptic plasticity and memory. Employing a paradigm designed to mimic intermittent rapid eye movement sleep epochs, we show that application of Cch in a series of short bursts generates persistent and maximal Arc protein expression. The results demonstrate dynamic, multifaceted control of Arc synthesis during mAchR signaling, and implicate cholinergic epoch duration and repetition as critical determinants of Arc expression and function in synaptic plasticity and behavior.

Enriching the environment to disinhibit the brain and improve cognition

Enriching the environment to disinhibit the brain and improve cognition

Circadian Oscillations within the Hippocampus Support Memory Formation and Persistence

The ability to sustain memories over long periods of time, sometimes even a lifetime, is one of the most remarkable properties of the brain. Much knowledge has been gained over the past few decades regarding the molecular correlates of memory formation. Once a memory is forged, however, the molecular events that provide permanence are as of yet unclear. Studies in multiple organisms have revealed that circadian rhythmicity is important for the formation, stability, and recall of memories (Gerstner et al., 2009).The neuronal events that provide this link need to be explored further. This article will discuss the findings related to the circadian regulation of memory-dependent processes in the hippocampus. Specifically, the circadian-controlled mitogen-activated protein kinase (MAPK) and cAMP signal transduction pathway plays critical roles in the consolidation of hippocampus-dependent memory. A series of studies have revealed the circadian oscillation of this pathway within the hippocampus, an activity that is absent in memory-deficient, transgenic mice lacking Ca2+-stimulated adenylyl cyclases. Interference with these oscillations proceeding the cellular memory consolidation period impairs the persistence of hippocampus-dependent memory. These data suggest that the persistence of long-term memories may depend upon reactivation of this signal transduction pathway in the hippocampus during the circadian cycle. New data reveals the dependence of hippocampal oscillation in MAPK activity on the suprachiasmatic nucleus, again underscoring the importance of this region in maintaining the circadian physiology of memory. Finally, the downstream ramification of these oscillations in terms of gene expression and epigenetics should be considered, as emerging evidence is pointing strongly to a circadian link between epigenetics and long-term synaptic plasticity.

Molecular Determinants of CaV2.1 Channel Regulation by Calcium-binding Protein-1

Presynaptic Ca(V)2.1 channels, which conduct P/Q-type Ca(2+) currents, initiate synaptic transmission at most synapses in the central nervous system. Regulation of Ca(V)2.1 channels by CaM contributes significantly to short term facilitation and rapid depression of synaptic transmission. Short term synaptic plasticity is diverse in form and function at different synapses, yet CaM is ubiquitously expressed. Differential regulation of Ca(V)2.1 channels by CaM-like Ca(2+) sensor (CaS) proteins differentially affects short term synaptic facilitation and rapid synaptic depression in transfected sympathetic neuron synapses. Here, we define the molecular determinants for differential regulation of Ca(V)2.1 channels by the CaS protein calcium-binding protein-1 (CaBP1) by analysis of chimeras in which the unique structural domains of CaBP1 are inserted into CaM. Our results show that the N-terminal domain, including its myristoylation site, and the second EF-hand, which is inactive in Ca(2+) binding, are the key molecular determinants of differential regulation of Ca(V)2.1 channels by CaBP1. These findings give insight into the molecular code by which CaS proteins differentially regulate Ca(V)2.1 channel function and provide diversity of form and function of short term synaptic plasticity.

Input-rate modulation of gamma oscillations is sensitive to network topology, delays and short-term plasticity

Simulated networks of excitatory and inhibitory neurons have previously been shown to reproduce critical features of experimental data regarding neural coding in V1, such as a positive relationship between thalamic input spike rate and the power of gamma frequency oscillations. This effect, referred to as modulated gamma power, could represent a neural code in V1 for stimulus characteristics that affect thalamic spike rate such as contrast or intensity. The simulated network's assumptions included homogeneous random connectivity, equal synaptic delays after spike arrival, and constant synaptic efficacies. Plausible alternative assumptions include small world connectivity, a wide distribution of axonal propagation delays, and short term synaptic plasticity, and here we assess the individual impact of each of these on the model's success in reproducing modulated gamma power. First, we developed several alternative algorithms for simulating directed networks with clustered connectivity and balanced excitation and inhibition. We found that modulated gamma power was absent in all small-world networks that had a relatively low abundance of reciprocal connectivity, which suggests that such motifs are present in V1 cortical networks at levels at least equal to those found in random networks. We also found in a different network type that the balance of excitation and inhibition could be destroyed when the network was in the small-world regime. Given all neurons had identical in-degrees, this result suggests that balance relies on motif distributions as well as mean connectivity. Second, altering the distribution of axonal delays had little effect, but increasing the mean delay led to a secondary gamma modulation at harmonics of the main peak, and since this is not observed experimentally, it suggests a mean delay in V1 networks less than 2ms. Finally, we compared two types of excitatory synaptic plasticity, and found that modulated beta power emerged in addition to gamma power for one type, in the presence of short term depression in interneurons.This article is part of a Special Issue entitled “Neural Coding”.