Showing papers on "Long-term potentiation published in 2007"
TL;DR: A model in which the spontaneous membrane oscillations of neurons projecting from the striatum, in addition to the pattern of release of endogenous dopamine, bias the synapse towards preferential induction of LTP or LTD is proposed.
764 citations
TL;DR: It is concluded 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.
655 citations
TL;DR: In this paper, it was shown that Ca 2+ elevation in astrocytes transiently increased the probability of transmitter release at hippocampal area CA3-CA1 synapses, without affecting the amplitude of synaptic events.
Abstract: Astrocytes play active roles in brain physiology. They respond to neurotransmitters and modulate neuronal excitability and synaptic function. However, the influence of astrocytes on synaptic transmission and plasticity at the single synapse level is unknown. Ca 2+ elevation in astrocytes transiently increased the probability of transmitter release at hippocampal area CA3-CA1 synapses, without affecting the amplitude of synaptic events. This form of short-term plasticity was due to the release of glutamate from astrocytes, a process that depended on Ca 2+ and soluble N -ethylmaleimide–sensitive factor attachment protein receptor (SNARE) protein and that activated metabotropic glutamate receptors (mGluRs). The transient potentiation of transmitter release became persistent when the astrocytic signal was temporally coincident with postsynaptic depolarization. This persistent plasticity was mGluR-mediated but N -methyl-d-aspartate receptor–independent. These results indicate that astrocytes are actively involved in the transfer and storage of synaptic information.
617 citations
TL;DR: It is shown in mouse hippocampal pyramidal cells that LTP at individual synapses reduces the threshold for potentiation at neighbouring synapses, which supports clustered plasticity models of memory storage and could allow for the binding of behaviourally linked information on the same dendritic branch.
Abstract: Long-term potentiation (LTP) of synaptic transmission underlies aspects of learning and memory. LTP is input-specific at the level of individual synapses, but neural network models predict interactions between plasticity at nearby synapses. Here we show in mouse hippocampal pyramidal cells that LTP at individual synapses reduces the threshold for potentiation at neighbouring synapses. After input-specific LTP induction by two-photon glutamate uncaging or by synaptic stimulation, subthreshold stimuli, which by themselves were too weak to trigger LTP, caused robust LTP and spine enlargement at neighbouring spines. Furthermore, LTP induction broadened the presynaptic-postsynaptic spike interval for spike-timing-dependent LTP within a dendritic neighbourhood. The reduction in the threshold for LTP induction lasted approximately 10 min and spread over approximately 10 microm of dendrite. These local interactions between neighbouring synapses support clustered plasticity models of memory storage and could allow for the binding of behaviourally linked information on the same dendritic branch.
589 citations
TL;DR: It is demonstrated that short periods of stress exposure induce spatial reference memory deficits before affecting PFC-dependent tasks, thus suggesting that the impairment of synaptic plasticity within the hippocampus-to-PFC connection is of relevance to the stress-induced PFC dysfunction.
Abstract: Research on the detrimental effects of stress in the brain has mainly focused on the hippocampus. Because prefrontal cortex (PFC) dysfunction characterizes many stress-related disorders, we here analyzed the impact of chronic stress in rats on the integrity of the hippocampal-PFC pathway, monitored by behavioral and electrophysiological function and morphological assessment. We show that chronic stress impairs synaptic plasticity by reducing LTP induction in the hippocampal-PFC connection; in addition, it induces selective atrophy within the PFC and severely disrupts working memory and behavioral flexibility, two functions that depend on PFC integrity. We also demonstrate that short periods of stress exposure induce spatial reference memory deficits before affecting PFC-dependent tasks, thus suggesting that the impairment of synaptic plasticity within the hippocampus-to-PFC connection is of relevance to the stress-induced PFC dysfunction. These findings evidence a fundamental role of the PFC in maladaptive responses to stress and identify this area as a target for intervention in stress-related disorders.
548 citations
TL;DR: The findings implicate a role for glial Kir4.1 channel subunit in the modulation of synaptic strength and a significant loss of complex glia in passive astrocyte development.
Abstract: During neuronal activity, extracellular potassium concentration ([K+]out) becomes elevated and, if uncorrected, causes neuronal depolarization, hyperexcitability, and seizures. Clearance of K+ from the extracellular space, termed K+ spatial buffering, is considered to be an important function of astrocytes. Results from a number of studies suggest that maintenance of [K+]out by astrocytes is mediated by K+ uptake through the inward-rectifying Kir4.1 channels. To study the role of this channel in astrocyte physiology and neuronal excitability, we generated a conditional knock-out (cKO) of Kir4.1 directed to astrocytes via the human glial fibrillary acidic protein promoter gfa2. Kir4.1 cKO mice die prematurely and display severe ataxia and stress-induced seizures. Electrophysiological recordings revealed severe depolarization of both passive astrocytes and complex glia in Kir4.1 cKO hippocampal slices. Complex cell depolarization appears to be a direct consequence of Kir4.1 removal, whereas passive astrocyte depolarization seems to arise from an indirect developmental process. Furthermore, we observed a significant loss of complex glia, suggestive of a role for Kir4.1 in astrocyte development. Kir4.1 cKO passive astrocytes displayed a marked impairment of both K+ and glutamate uptake. Surprisingly, membrane and action potential properties of CA1 pyramidal neurons, as well as basal synaptic transmission in the CA1 stratum radiatum appeared unaffected, whereas spontaneous neuronal activity was reduced in the Kir4.1 cKO. However, high-frequency stimulation revealed greatly elevated posttetanic potentiation and short-term potentiation in Kir4.1 cKO hippocampus. Our findings implicate a role for glial Kir4.1 channel subunit in the modulation of synaptic strength.
518 citations
TL;DR: Results reveal a critical role for PINK1 in DA release and striatal synaptic plasticity in the nigrostriatal circuit and suggest that altered dopaminergic physiology may be a pathogenic precursor to nigrostRIatal degeneration.
Abstract: Parkinson's disease (PD) is characterized by the selective vulnerability of the nigrostriatal dopaminergic circuit. Recently, loss-of-function mutations in the PTEN-induced kinase 1 (PINK1) gene have been linked to early-onset PD. How PINK1 deficiency causes dopaminergic dysfunction and degeneration in PD patients is unknown. Here, we investigate the physiological role of PINK1 in the nigrostriatal dopaminergic circuit through the generation and multidisciplinary analysis of PINK1(-/-) mutant mice. We found that numbers of dopaminergic neurons and levels of striatal dopamine (DA) and DA receptors are unchanged in PINK1(-/-) mice. Amperometric recordings, however, revealed decreases in evoked DA release in striatal slices and reductions in the quantal size and release frequency of catecholamine in dissociated chromaffin cells. Intracellular recordings of striatal medium spiny neurons, the major dopaminergic target, showed specific impairments of corticostriatal long-term potentiation and long-term depression in PINK1(-/-) mice. Consistent with a decrease in evoked DA release, these striatal plasticity impairments could be rescued by either DA receptor agonists or agents that increase DA release, such as amphetamine or l-dopa. These results reveal a critical role for PINK1 in DA release and striatal synaptic plasticity in the nigrostriatal circuit and suggest that altered dopaminergic physiology may be a pathogenic precursor to nigrostriatal degeneration.
508 citations
TL;DR: It is shown that chronic systemic treatment of Ts65Dn mice with GABAA antagonists at non-epileptic doses causes a persistent post-drug recovery of cognition and long-term potentiation, suggesting that over-inhibition contributes to intellectual disabilities associated with Down syndrome.
Abstract: Ts65Dn mice, a model for Down syndrome, have excessive inhibition in the dentate gyrus, a condition that could compromise synaptic plasticity and mnemonic processing. We show that chronic systemic treatment of these mice with GABAA antagonists at non-epileptic doses causes a persistent post-drug recovery of cognition and long-term potentiation. These results suggest that over-inhibition contributes to intellectual disabilities associated with Down syndrome and that GABAA antagonists may be useful therapeutic agents for this disorder.
502 citations
TL;DR: Examination of the role of NE in contextual memory formation and in the synaptic delivery of GluR1-containing alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA)-type glutamate receptors during long-term potentiation (LTP), a candidate synaptic mechanism for learning, indicates that NE-driven phosphorylation of GLUR1 facilitates the synaptic deliveries of Glamorganically-containing AMPARs.
486 citations
TL;DR: Results couple activity-induced expression of Arc to expansion of the actin cytoskeleton underlying enduring LTP, identifying Arc as a key molecular effector of BDNF in synaptic plasticity.
Abstract: New gene expression is necessary for long-term potentiation (LTP) consolidation, yet roles for specific activity-induced mRNAs have not been defined. Here we probed the dynamic function of activity-induced Arc (activity-regulated cytoskeletal-associated protein)/Arg3.1 (activity-regulated gene 3.1 protein homolog) mRNA using brief, local infusions of antisense (AS) oligodeoxynucleotides at multiple time points during dentate gyrus LTP in vivo. Surprisingly, early Arc synthesis is necessary for early expression of LTP, whereas sustained synthesis is required to generate stably modified synapses. AS application 2 h after LTP induction results in a rapid and permanent reversal of LTP. This reversal is associated with rapid knockdown of upregulated Arc, dephosphorylation of actin depolymerization factor/cofilin, and loss of nascent filamentous actin (F-actin) at synaptic sites. Infusion of the F-actin stabilizing drug jasplakinolide during LTP maintenance blocks the ability of AS to reverse LTP. These results couple activity-induced expression of Arc to expansion of the actin cytoskeleton underlying enduring LTP. Furthermore, Arc synthesis is required for both the induction and consolidation of LTP elicited by local BDNF infusion, thus identifying Arc as a key molecular effector of BDNF in synaptic plasticity.
458 citations
TL;DR: It is found that acute knockdown of PSD-95 in brain slice cultures by RNAi arrests the normal development of synaptic structure and function that is driven by spontaneous activity, and data support a model in which appropriate levels of PSd-95 are required for activity-dependent synapse stabilization after initial phases of synaptic potentiation.
Abstract: The activity-dependent regulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors and the stabilization of synapses are critical to synaptic development and plasticity. One candidate molecule implicated in maturation, synaptic strengthening, and plasticity is PSD-95. Here we find that acute knockdown of PSD-95 in brain slice cultures by RNAi arrests the normal development of synaptic structure and function that is driven by spontaneous activity. Surprisingly, PSD-95 is not necessary for the induction and early expression of long-term potentiation (LTP). However, knockdown of PSD-95 leads to smaller increases in spine size after chemically induced LTP. Furthermore, although at this age spine turnover is normally low and LTP produces a transient increase, in cells with reduced PSD-95 spine turnover is high and remains increased after LTP. Taken together, our data support a model in which appropriate levels of PSD-95 are required for activity-dependent synapse stabilization after initial phases of synaptic potentiation.
TL;DR: It is shown that in eIF2alpha(+/S51A) mice, in which eif2alpha phosphorylation is reduced, the threshold for eliciting L-LTP in hippocampal slices is lowered, and memory is enhanced, and the importance of a single phosphorylated site in e IF2alpha as a key regulator of L- LTP and LTM formation is highlighted.
TL;DR: It is shown that in visual cortex the rules of this spike-timing-dependent plasticity are not rigid, but shaped by neuromodulator receptors coupled to adenylyl cyclase (AC) and phospholipase C (PLC) signaling cascades.
TL;DR: This Mini‐Review discusses how MMP‐directed cleavage of these proteins can impact the formation and function of synapses within the brain and how the development of therapeutics to attenuate MMP activity in neurodegenerative disorders may become powerful tools for future studies of synaptic formation andfunction within the developing and mature brain.
Abstract: Matrix metalloproteinases (MMPs) play critical roles in egg fertilization, embryonic development, wound repair, cancer, and inflammatory and neurologic diseases. This subfamily of metzincin peptidases can cleave extracellular matrix (ECM) and pericellular proteins that have profound effects on cell behavior. Among known MMP substrates are several proteins that play important roles in synaptogenesis, synaptic plasticity, and long-term potentiation (LTP). In this Mini-Review we discuss how MMP-directed cleavage of these proteins can impact the formation and function of synapses within the brain. Pyramidal neurons in the hippocampus, and other large neurons, are surrounded by perineuronal nets that are composed of brevican, tenascin-R, and laminin, each of which is subject to proteolytic cleavage by MMPs. Tenascin-R knockout mice show deficits in learning and memory and LTP, as do at least two MMP knockouts. Impaired LTP is also seen in brain-derived neurotrophic factor (BDNF) knockout mice, which is interesting in that pro-BDNF can be processed into mature BDNF by several MMPs and thereby regulate activation of the high-affinity BDNF receptor TrkB. At the synaptic level, MMP substrates also include ephrins, Eph receptors, and cadherins, which are also involved in synapse development and plasticity. MMPs can also process membrane-bound tumor necrosis factor-α into a potent soluble cytokine that is increasingly implicated in neuron–glial signaling, particularly in neurologic disease. Finally, we discuss how the development of therapeutics to attenuate MMP activity in neurodegenerative disorders may become powerful tools for future studies of synaptic formation and function within the developing and mature brain. © 2007 Wiley-Liss, Inc.
TL;DR: Four new lines of research comprise compelling evidence that exposures to Pb have adverse effects on the nervous system, that environmental factors increase nervous system susceptibility to P b, and that exposures in early life may cause neurodegeneration in later life.
TL;DR: In this review fundamental properties of LTP in nociceptive pathways are described and the potential functional roles are evaluated at the cellular level and at the behavioural level in experimental animals.
Abstract: Long-term potentiation (LTP) at synapses of nociceptive nerve fibres is a proposed cellular mechanism underlying some forms of hyperalgesia. In this review fundamental properties of LTP in nociceptive pathways are described. The following topics are specifically addressed: A concise definition of LTP is given and a differentiation is made between LTP and "central sensitisation". How to (and how not to) measure and how to induce LTP in pain pathways is specified. The signal transduction pathways leading to LTP at C-fibre synapses are highlighted and means of how to pre-empt and how to reverse LTP are delineated. The potential functional roles of LTP are evaluated at the cellular level and at the behavioural level in experimental animals. Finally, the impact of LTP on the perception of pain in human subjects is discussed.
TL;DR: These data provide first evidence for fear-promoting effects of TRPV1 with respect to both innate and conditioned fear and for a decisive role of this receptor in synaptic plasticity.
Abstract: The transient receptor potential vanilloid type 1 channel (TRPV1) (formerly called vanilloid receptor VR1) is known for its key role of functions in sensory nerves such as perception of inflammatory and thermal pain. Much less is known about the physiological significance of the TRPV1 expression in the brain. Here we demonstrate that TRPV1 knock-out mice (TRPV1-KO) show less anxiety-related behavior in the light-dark test and in the elevated plus maze than their wild-type littermates with no differences in locomotion. Furthermore, TRPV1-KO mice showed less freezing to a tone after auditory fear conditioning and stress sensitization. This reduction of conditioned and sensitized fear could not be explained by alterations in nociception. Also, tone perception per se was unaffected, as revealed by determination of auditory thresholds through auditory brainstem responses and distortion-product otoacoustic emissions. TRPV1-KO showed also less contextual fear if assessed 1 d or 1 month after strong conditioning protocols. These impairments in hippocampus-dependent learning were mirrored by a decrease in long-term potentiation in the Schaffer collateral-commissural pathway to CA1 hippocampal neurons. Our data provide first evidence for fear-promoting effects of TRPV1 with respect to both innate and conditioned fear and for a decisive role of this receptor in synaptic plasticity.
TL;DR: Evidence is presented that phosphorylation at the inhibitory Ser9 site on GSK‐3β is increased upon induction of long‐term potentiation (LTP) in both hippocampal subregions CA1 and the dentate gyrus (DG) in vivo, and it is found that LTP is impaired in transgenic mice conditionally overexpressing GSK•3β.
Abstract: Glycogen synthase kinase-3 (GSK-3) is a serine ⁄threonine kinase regulating diverse cellular functions including metabolism, transcription and cell survival. Numerous intracellular signalling pathways converge on GSK-3 and regulate its activity via inhibitory serine-phosphorylation. Recently, GSK-3 has been involved in learning and memory and in neurodegeneration. Here, we present evidence that implicates GSK-3 in synaptic plasticity. We show that phosphorylation at the inhibitory Ser9 site on GSK-3b is increased upon induction of long-term potentiation (LTP) in both hippocampal subregions CA1 and the dentate gyrus (DG) in vivo. The increase in inhibitory GSK-3b phosphorylation is robust and persists for at least one hour postinduction. Furthermore, we find that LTP is impaired in transgenic mice conditionally overexpressing GSK-3b. The LTP deficits can be attenuated ⁄rescued by chronic treatment with lithium, a GSK-3 inhibitor. These results suggest that the inhibition of GSK-3 facilitates the induction of LTP and this might explain some of the negative effects of GSK-3 on learning and memory. It follows that this role of GSK-3b in LTP might underlie some of the cognitive dysfunction in diseases where GSK-3 dysfunction has been implicated, including Alzheimer’s and other dementias.
TL;DR: It is demonstrated that the influence of BDNF on the actin cytoskeleton is retained into adulthood in which it serves to positively modulate the time-dependent LTP consolidation process.
Abstract: Brain-derived neurotrophic factor (BDNF) is an extremely potent, positive modulator of theta burst induced long-term potentiation (LTP) in the adult hippocampus. The present studies tested whether the neurotrophin exerts its effects by facilitating cytoskeletal changes in dendritic spines. BDNF caused no changes in phalloidin labeling of filamentous actin (F-actin) when applied alone to rat hippocampal slices but markedly enhanced the number of densely labeled spines produced by a threshold level of theta burst stimulation. Conversely, the BDNF scavenger TrkB-Fc completely blocked increases in spine F-actin produced by suprathreshold levels of theta stimulation. TrkB-Fc also blocked LTP consolidation when applied 1-2 min, but not 10 min, after theta trains. Additional experiments confirmed that p21 activated kinase and cofilin, two actin-regulatory proteins implicated in spine morphogenesis, are concentrated in spines in mature hippocampus and further showed that both undergo rapid, dose-dependent phosphorylation after infusion of BDNF. These results demonstrate that the influence of BDNF on the actin cytoskeleton is retained into adulthood in which it serves to positively modulate the time-dependent LTP consolidation process.
TL;DR: This group has shown that the induction of late-LTP requires the associative activation of heterosynaptic inputs, i.e. the synergistic activation of glutamatergic and modulatory, reinforcing inputs within specific, effective time windows.
TL;DR: Evidence is provided for activity-dependent trafficking of Kv4.2 in hippocampal spines and dendrites of hippocampal CA1 neurons and an additional mechanism for synaptic integration and plasticity through the activity- dependent regulation of K v4.
TL;DR: LTD in the hippocampus and cerebellum is probably the best characterized, although there are also other brain areas where mechanisms of LTD are well understood, and where it is thought to have a functional role.
TL;DR: Findings from studies on fear conditioning, a form of associative learning whose neural circuitry is relatively well understood, that may be particularly suited for addressing the question of changes in synaptic strength underlie learning and memory are discussed.
TL;DR: Two models are presented for how translation-dependent decay pathways such as NMD might advantageously function as critical brakes for protein synthesis in cells such as neurons that are highly dependent on spatially and temporally restricted protein expression.
TL;DR: Long-term potentiation of GABAA-mediated synaptic transmission onto dopamine neurons of the rat brain ventral tegmental area is reported, a region required for the development of drug addiction and neuroadaptations to opioid drugs might contribute to early stages of addiction.
Abstract: Excitatory brain synapses are strengthened or weakened in response to specific patterns of synaptic activation, and these changes in synaptic strength are thought to underlie persistent pathologies such as drug addiction, as well as learning. In contrast, there are few examples of synaptic plasticity of inhibitory GABA (gamma-aminobutyric acid)-releasing synapses. Here we report long-term potentiation of GABA(A)-mediated synaptic transmission (LTP(GABA)) onto dopamine neurons of the rat brain ventral tegmental area, a region required for the development of drug addiction. This novel form of LTP is heterosynaptic, requiring postsynaptic NMDA (N-methyl-d-aspartate) receptor activation at glutamate synapses, but resulting from increased GABA release at neighbouring inhibitory nerve terminals. NMDA receptor activation produces nitric oxide, a retrograde signal released from the postsynaptic dopamine neuron. Nitric oxide initiates LTP(GABA) by activating guanylate cyclase in GABA-releasing nerve terminals. Exposure to morphine both in vitro and in vivo prevents LTP(GABA). Whereas brief treatment with morphine in vitro blocks LTP(GABA) by inhibiting presynaptic glutamate release, in vivo exposure to morphine persistently interrupts signalling from nitric oxide to guanylate cyclase. These neuroadaptations to opioid drugs might contribute to early stages of addiction, and may potentially be exploited therapeutically using drugs targeting GABA(A) receptors.
TL;DR: How the remarkable plasticity of glutamatergic synapses on interneurons greatly enhances the computational capacity of the cortical microcircuit is discussed.
Abstract: Rapid memory formation relies, at least in part, on long-term potentiation (LTP) of excitatory synapses. Inhibitory interneurons of the hippocampus, which are essential for information processing, have recently been found to exhibit not one, but two forms of LTP. One form resembles LTP that occurs in pyramidal neurons, which depends on N-methyl-D-aspartate receptors and is triggered by coincident pre- and postsynaptic activity. The other depends on Ca2+ influx through glutamate receptors that preferentially open when the postsynaptic neuron is at rest. Here we review these contrasting forms of LTP and describe how they are mirrored by two forms of long-term depression. We further discuss how the remarkable plasticity of glutamatergic synapses on interneurons greatly enhances the computational capacity of the cortical microcircuit.
TL;DR: It is shown that the N-methyl-D-aspartate receptor, NMDAR, brain-derived neurotrophic factor, postsynaptic density protein 95 (PSD-95), and phosphatidylinositol 3-kinase are involved in a single pathway for synaptic potentiation.
Abstract: The N-methyl-D-aspartate receptor (NMDAR), brain-derived neurotrophic factor (BDNF), postsynaptic density protein 95 (PSD-95) and phosphatidylinositol 3-kinase (PI3K) have all been implicated in long-term potentiation. Here we show that these molecules are involved in a single pathway for synaptic potentiation. In visual cortical neurons in young rodents, the neurotrophin receptor TrkB is associated with PSD-95. When BDNF is applied to cultured visual cortical neurons, PSD-95-labeled synaptic puncta enlarge, and fluorescent recovery after photobleaching (FRAP) reveals increased delivery of green fluorescent protein-tagged PSD-95 to the dendrites. The recovery of fluorescence requires TrkB, signaling through PI3K and the serine-threonine kinase Akt, and an intact Golgi apparatus. Stimulation of NMDARs mimics the PSD-95 trafficking that is induced by BDNF but requires active BDNF and PI3K. Furthermore, local dendritic contact with a BDNF-coated microsphere induces PSD-95 FRAP throughout the dendrites of the stimulated neuron, suggesting that this mechanism induces rapid neuron-wide synaptic increases in PSD-95 and refinement whenever a few robust inputs activate the NMDAR-BDNF-PI3K pathway.
TL;DR: It is shown that phosphorylation of the GluR1 subunit on serine 845 by PKA is required for PKA-induced increases in AMPA receptor cell-surface expression because it promotes receptor insertion and decreases receptor endocytosis.
Abstract: α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors mediate the majority of excitatory synaptic transmission in the brain. Recent studies have shown that activation of PKA regulates the membrane trafficking of the AMPA receptor Glu receptor 1 (GluR1) subunit, but the role of direct phosphorylation of GluR1 in regulating receptor redistribution is not clear. Here we show that phosphorylation of the GluR1 subunit on serine 845 by PKA is required for PKA-induced increases in AMPA receptor cell-surface expression because it promotes receptor insertion and decreases receptor endocytosis. Furthermore, dephosphorylation of GluR1 serine 845 triggers NMDA-induced AMPA receptor internalization. These findings strongly suggest that dynamic changes in direct phosphorylation of GluR1 by PKA are crucial in the modulation of AMPA receptor trafficking and synaptic plasticity.
TL;DR: It is reported that conditional knockout of Cdk5 in the adult mouse brain improved performance in spatial learning tasks and enhanced hippocampal long-term potentiation and NMDA receptor (NMDAR)-mediated excitatory postsynaptic currents.
Abstract: Learning is accompanied by modulation of postsynaptic signal transduction pathways in neurons. Although the neuronal protein kinase cyclin-dependent kinase 5 (Cdk5) has been implicated in cognitive disorders, its role in learning has been obscured by the perinatal lethality of constitutive knockout mice. Here we report that conditional knockout of Cdk5 in the adult mouse brain improved performance in spatial learning tasks and enhanced hippocampal long-term potentiation and NMDA receptor (NMDAR)-mediated excitatory postsynaptic currents. Enhanced synaptic plasticity in Cdk5 knockout mice was attributed to reduced NR2B degradation, which caused elevations in total, surface and synaptic NR2B subunit levels and current through NR2B-containing NMDARs. Cdk5 facilitated the degradation of NR2B by directly interacting with both it and its protease, calpain. These findings reveal a previously unknown mechanism by which Cdk5 facilitates calpain-mediated proteolysis of NR2B and may control synaptic plasticity and learning.
TL;DR: It is proposed that theta stimulation markedly increases the probability that a spine will enter a state characterized by a large, ovoid synapse and that this morphology is important for expression and later stabilization of LTP.
Abstract: Stabilization of long-term potentiation (LTP) is commonly proposed to involve changes in synaptic morphology and reorganization of the spine cytoskeleton. Here we tested whether, as predicted from this hypothesis, induction of LTP by theta-burst stimulation activates an actin regulatory pathway and alters synapse morphology within the same dendritic spines. TBS increased severalfold the numbers of spines containing phosphorylated (p) p21-activated kinase (PAK) or its downstream target cofilin; the latter regulates actin filament assembly. The PAK/cofilin phosphoproteins were increased at 2 min but not 30 s post-TBS, peaked at 7 min, and then declined. Double immunostaining for the postsynaptic density protein PSD95 revealed that spines with high pPAK or pCofilin levels had larger synapses (+60-70%) with a more normal size frequency distribution than did neighboring spines. Based on these results and simulations of shape changes to synapse-like objects, we propose that theta stimulation markedly increases the probability that a spine will enter a state characterized by a large, ovoid synapse and that this morphology is important for expression and later stabilization of LTP.