Bidirectional Plasticity Research Articles

Selective loss of bi-directional synaptic plasticity in the direct and indirect striatal output pathways accompanies generation of parkinsonism and l-DOPA induced dyskinesia in mouse models

Parkinsonian symptoms arise due to over-activity of the indirect striatal output pathway, and under-activity of the direct striatal output pathway. l-DOPA-induced dyskinesia (LID) is caused when the opposite circuitry problems are established, with the indirect pathway becoming underactive, and the direct pathway becoming over-active. Here, we define synaptic plasticity abnormalities in these pathways associated with parkinsonism, symptomatic benefits of l-DOPA, and LID. We applied spike-timing dependent plasticity protocols to cortico-striatal synapses in slices from 6-OHDA-lesioned mouse models of parkinsonism and LID, generated in BAC transgenic mice with eGFP targeting the direct or indirect output pathways, with and without l-DOPA present. In naïve mice, bidirectional synaptic plasticity, i.e. LTP and LTD, was induced, resulting in an EPSP amplitude change of approximately 50% in each direction in both striatal output pathways, as shown previously. In parkinsonism and dyskinesia, both pathways exhibited unidirectional plasticity, irrespective of stimulation paradigm. In parkinsonian animals, the indirect pathway only exhibited LTP (LTP protocol: 143.5±14.6%; LTD protocol 177.7±22.3% of baseline), whereas the direct pathway only showed LTD (LTP protocol: 74.3±4.0% and LTD protocol: 63.3±8.7%). A symptomatic dose of l-DOPA restored bidirectional plasticity on both pathways to levels comparable to naïve animals (Indirect pathway: LTP protocol: 124.4±22.0% and LTD protocol: 52.1±18.5% of baseline. Direct pathway: LTP protocol: 140.7±7.3% and LTD protocol: 58.4±6.0% of baseline). In dyskinesia, in the presence of l-DOPA, the indirect pathway exhibited only LTD (LTP protocol: 68.9±21.3% and LTD protocol 52.0±14.2% of baseline), whereas in the direct pathway, only LTP could be induced (LTP protocol: 156.6±13.2% and LTD protocol 166.7±15.8% of baseline). We conclude that normal motor control requires bidirectional plasticity of both striatal outputs, which underlies the symptomatic benefits of l-DOPA. Switching from bidirectional to unidirectional plasticity drives global changes in striatal pathway excitability, and underpins parkinsonism and dyskinesia.

GluN2B-containing NMDA receptors blockade rescues bidirectional synaptic plasticity in the bed nucleus of the stria terminalis of cocaine self-administering rats.

Drugs of abuse have detrimental effects on homeostatic synaptic plasticity in the motivational brain network. Bidirectional plasticity at excitatory synapses helps keep neural circuits within a functional range to allow for behavioral flexibility. Therefore, impaired bidirectional plasticity of excitatory synapses may contribute to the behavioral hallmarks of addiction, yet this relationship remains unclear. Here we tracked excitatory synaptic strength in the oval bed nucleus of the stria terminalis (ovBNST) using whole-cell voltage-clamp recordings in brain slices from rats self-administering sucrose or cocaine. In the cocaine group, we measured both a persistent increase in AMPA to NMDA ratio (A:N) and slow decay time of NMDA currents throughout the self-administration period and after withdrawal from cocaine. In contrast, the sucrose group exhibited an early increase in A:N ratios (acquisition) that returned toward baseline values with continued self-administration (maintenance) and after withdrawal. The sucrose rats also displayed a decrease in NMDA current decay time with continued self-administration (maintenance), which normalized after withdrawal. Cocaine self-administering rats exhibited impairment in NMDA-dependent long-term depression (LTD) that could be rescued by GluN2B-containing NMDA receptor blockade. Sucrose self-administering rats demonstrated no impairment in NMDA-dependent LTD. During the maintenance period of self-administration, in vivo (daily intraperitoneally for 5 days) pharmacologic blockade of GluN2B-containing NMDA receptors did not reduce lever pressing for cocaine. However, in vivo GluN2B blockade did normalize A:N ratios in cocaine self-administrating rats, and dissociated the magnitude of ovBNST A:N ratios from drug-seeking behavior after protracted withdrawal. Altogether, our data demonstrate when and how bidirectional plasticity at ovBNST excitatory synapses becomes dysfunctional with cocaine self-administration and that NMDA-mediated potentiation of AMPA receptors in this region may be part of the neural circuits of drug relapse.

Long-term potentiation in hilar circuitry modulates gating by the dentate gyrus.

The dentate gyrus serves as a gateway to the hippocampus, filtering and processing sensory inputs as an animal explores its environment. The hilus occupies a strategic position within the dentate gyrus from which it can play a pivotal role in these functions. Inputs from dentate granule cells converge on the hilus, and excitatory hilar mossy cells redistribute these signals back to granule cells to transform a pattern of cortical input into a new pattern of output to the hippocampal CA3 region. Using voltage-sensitive dye to image electrical activity in rat hippocampal slices, we explored how long-term potentiation (LTP) of different excitatory synapses modifies the flow of information. Theta burst stimulation of the perforant path potentiated responses throughout the molecular layer, but left responses in the CA3 region unchanged. By contrast, theta burst stimulation of the granule cell layer potentiated responses throughout the molecular layer, as well as in the CA3 region. Theta burst stimulation of the granule cell layer potentiated CA3 responses not only to granule cell layer stimulation but also to perforant path stimulation. Potentiation of responses in the CA3 region reflected NMDA receptor-dependent LTP of upstream synapses between granule cells and mossy cells, with no detectable contribution from NMDA receptor-independent LTP of local CA3 mossy fiber synapses. Potentiation of transmission to the CA3 region required LTP in both granule cell→mossy cell and mossy cell→granule cell synapses. This bidirectional plasticity enables hilar circuitry to regulate the flow of information through the dentate gyrus and on to the hippocampus.

βCaMKII regulates bidirectional long-term plasticity in cerebellar Purkinje cells by a CaMKII/PP2B switch mechanism

It is thought that modifications in the strength of synaptic connections onto cerebellar Purkinje cells (PCs) such as long-term depression (LTD) and long-term potentiation (LTP) contribute to learning. Repeated paired stimulations of parallel fibres (PFs) and climbing fibre (CF) evoke high-amplitude calcium signals that lead to LTD in PCs, while LTP is induced by low-amplitude calcium pulses as a result of PF input alone. Although the events following these stimulation protocols are becoming clearer, the precise interactions of the molecular machinery underlying LTD and LTP induction remain something of an enigma. Calcium-calmodulin dependent protein kinase II (CaMKII) is an important component of the signalling network that is responsible for cerebellar plasticity in PCs. The CaMKII holoenzyme contains isoforms such as αCaMKII and βCaMKII. Experiments with Camk2b knockout mice that lack the β isoform of CaMKII have demonstrated that βCaMKII regulates the direction of plasticity at PF-PC synapses [1]. Stimulation protocols that induce LTD in wild-type mice, which contain both α and βCaMKII, lead to LTP in knockout mice without βCaMKII, and vice versa. In previous work, we have developed a kinetic simulation of the phosphorylation and dephosphorylation of AMPA receptors by CaMKII and protein phosphatase 2B (PP2B) to investigate how βCaMKII controls bidirectional plasticity in cerebellar PCs [2]. This bidirectional plasticity model was based on our earlier model of CaMKII activation [3,4]. Because the βCaMKII, but not αCaMKII, isoforms can bind to filamentous actin (F-actin), we have included the binding of F-actin to CaMKII to simulate plasticity induction in wild-type mice, whereas the F-actin binding was omitted in the knockout mice that lack the β isoform. Our previous simulation results have demonstrated that the binding of F-actin to βCaMKII can contribute to the regulation of bidirectional plasticity at PF-PC synapses, as suggested by Van Woerden and collaborators [1]. However, we have investigated the induction of bidirectional plasticity only in the presence of calcium signals, i.e. during the early phase of LTD and LTP. But the experimental observations in [1] have demonstrated that the bidirectional plasticity is also observed after the offset of paired PF and CF inputs and PF input alone. To analyse the persistent AMPA receptor phosphorylation after calcium stimulation protocols that last 5 min, we modified our previous model [2] because it did not simulate the CaMKII dephosphorylation, and PP2B was rapidly inactivated with the interruption of calcium signals. Here, we allow the CaMKII subunits in the autonomous form, which are not bound to calcium-calmodulin but still retain some activity levels, to be dephosphorylated and switch to the inactive state of CaMKII. The kinase is therefore gradually inactivated after calcium stimulation stops. Moreover, calcium-calmodulin slowly dissociates from PP2B, leading to a gradual deactivation of PP2B. Results of computer simulations of our mathematical model suggest that the balance of CaMKII-mediated phosphorylation and PP2B-mediated dephosphorylation of AMPA receptors determines whether LTD or LTP occurs at the PF-PC synapse. PF activity alone evokes PP2B concentration levels higher than CaMKII, leading to LTP induction. Instead, LTD occurs when the CaMKII concentration levels surpass the PP2B concentration in response to the paired activation of PF and CF. Moreover, our recent simulation results replicate the experimental observations by Van Woerden et al. [1] not only in the early phase of LTD and LTP as shown in [2], but also in their intermediate and late phases after the termination of PF and CF stimulation and PF input alone. The mechanisms observed in our previous simulations with 5 min duration are also observed in simulations that last 100 min. The loss of F-actin binding in the knockout mice enhances the availability of active CaMKII when compared to the wild-type mice at low calcium concentrations. This favours the induction of LTD rather than LTP. In contrast, the reduction in the CaMKII concentration in the knockout mice leads to AMPA receptor dephosphorylation by PP2B for high calcium concentrations, leading to the induction of LTP instead of LTD. We again demonstrate that the binding of F-actin to βCaMKII can indeed contribute to the control of bidirectional plasticity at PF-PC synapses, as suggested in [1,2].

Molecular dependence of hippocampal bidirectional plasticity

Hippocampal plasticity inducing protocols vary in their activation of signal transduction pathways and resulting dependence on signaling molecules. Many long-term potentiation (LTP) inducing paradigms require both memory kinases: calcium-calmodulin dependent protein kinase II (CaMKII) and protein kinase A (PKA) signaling pathways. Both CaMKII and PKA are activated by calcium bound calmodulin, CaMKII directly, and PKA indirectly via adenylyl cyclase production of cAMP. The adenylyl cyclase is also activated by stimulation of beta-adrenergic receptor (βAR). Curiously, not all forms of cAMP dependent LTP require PKA. Specifically, LTP induced with isoproterenol (ISO) bath application followed by 100 Hz stimulation is PKA independent [1,2], whereas both ISO followed by 3 min of 5 Hz [2] and four trains of 100 Hz stimulation do require PKA [3]. Furthermore, recent experiments suggest a novel βAR signaling pathway, in which PKA phosphorylation prevents activation of G protein subtype s (Gs), and switches the βAR to the Gi subtype of G [4], leading to recruitment of another memory kinase: extracellular signal-regulated kinase (ERK). To investigate how temporal pattern of synaptic activation determines which signaling pathways are activated, we employed a multi-compartmental stochastic reaction-diffusion model of calcium and cAMP activated signaling pathways. We investigated two model variants, one which took into account only βARcoupling to Gs, and the other which included the novel switching pathway. We performed simulations of four trains of 100 Hz, and isoproterenol application followed by either 1 train of 100 Hz or 3 min of 5 Hz, all of which produce long lasting LTP. We also simulated 3 stimulation paradigms which do not produce LTP, including 1 Hz stimulation which produces LTD. Our results using the first model could not explain and predict the direction of synaptic plasticity based only on CaMKII, PKAc and phosphatases activity, especially for paradigms that do not induce plasticity, such as bath application of isoproteronol. Experimentally, isoproteronol does not cause LTP despite βAR activation resulting in cAMP synthesis [2], suggesting that βAR undergo PKA dependent desensitization, that changes their coupling from Gs (stimulating adenylyl cyclases and cAMP synthesis) to Gi. Gi coupling both inhibits adenylyl cyclase, limiting the elevation in cAMP in response to bath application, and provides free Giβγ, which recruits molecules leading to ERK [5]. Including PKA dependent switching from Gs to Gi resulted in a model which could explain which molecules are activated in 5 LTP induction paradigms, 1 LTD induction paradigms, and 2 induction paradigms that do not produce plasticity. The model also allowed for proposing a measure of plasticity direction. The measure took into account activation of CaMKII, PKA, Giβγ (representing ERK), Epac and influence of phosphatase activity.

Firing Modes of Dopamine Neurons Drive Bidirectional GIRK Channel Plasticity

G-protein-coupled inwardly rectifying potassium (GIRK) channels contribute to the resting membrane potential of many neurons, including dopamine (DA) neurons in the ventral tegmental area (VTA). VTA DA neurons are bistable, firing in two modes: one characterized by bursts of action potentials, the other by tonic firing at a lower frequency. Here we provide evidence that these firing modes drive bidirectional plasticity of GIRK channel-mediated currents. In acute midbrain slices of mice, we observed that in vitro burst activation of VTA DA neurons potentiated GIRK currents whereas tonic firing depressed these currents. This plasticity was not specific to the metabotropic receptor activating the GIRK channels, as direct activation of GIRK channels by nonhydrolyzable GTP also potentiated the currents. The plasticity of GIRK currents required NMDA receptor and CaMKII activation, and involved protein trafficking through specific PDZ domains of GIRK2c and GIRK3 subunit isoforms. Prolonged tonic firing may thus enhance the probability to switch into burst-firing mode, which then potentiates GIRK currents and favors the return to baseline. In conclusion, activity-dependent GIRK channel plasticity may represent a slow destabilization process favoring the switch between the two firing modes of VTA DA neurons.

Beyond inhibition: GABA synapses tune the neuroendocrine stress axis

We recently described a novel form of stress-associated bidirectional plasticity at GABA synapses onto hypothalamic parvocellular neuroendocrine cells (PNCs), the apex of the hypothalamus-pituitary-adrenal axis. This plasticity may contribute to neuroendocrine adaptation. However, this GABA synapse plasticity likely does not translate into a simple more and less of inhibition because the ionic driving force for Cl(-) , the primary charge carrier for GABAA receptors, is dynamic. Specifically, stress impairs a Cl(-) extrusion mechanism in PNCs. This not only renders the steady-state GABA response less hyperpolarizing but also makes PNCs susceptible to the activity-dependent accumulation of Cl(-) . Accordingly, GABA synapse plasticity impacts both the robustness of GABA voltage response and dynamic Cl(-) loading, imposing nonlinear influences on PNC excitability during circuit activities. This theoretical consideration predicts roles for GABA transmission far more versatile than canonical inhibition. We propose potential impacts of GABA synapse plasticity on the experience-dependent fine-tuning of neuroendocrine stress responses.

Trauma exposure and sleep: using a rodent model to understand sleep function in PTSD

Post-traumatic stress disorder (PTSD) is characterized by intrusive memories of a traumatic event, avoidance behavior related to cues of the trauma, emotional numbing, and hyper-arousal. Sleep abnormalities and nightmares are core symptoms of this disorder. In this review, we propose a model which implicates abnormal activity in the locus coeruleus (LC), an important modifier of sleep-wake regulation, as the source of sleep abnormalities and memory abnormalities seen in PTSD. Abnormal LC activity may be playing a key role in symptom formation in PTSD via sleep dysregulation and suppression of hippocampal bidirectional plasticity.

Bidirectional Plasticity of Purkinje Cells Matches Temporal Features of Learning

Many forms of learning require temporally ordered stimuli. In Pavlovian eyeblink conditioning, a conditioned stimulus (CS) must precede the unconditioned stimulus (US) by at least about 100 ms for learning to occur. Conditioned responses are learned and generated by the cerebellum. Recordings from the cerebellar cortex during conditioning have revealed CS-triggered pauses in the firing of Purkinje cells that likely drive the conditioned blinks. The predominant view of the learning mechanism in conditioning is that long-term depression (LTD) at parallel fiber (PF)-Purkinje cell synapses underlies the Purkinje cell pauses. This raises a serious conceptual challenge because LTD is most effectively induced at short CS-US intervals, which do not support acquisition of eyeblinks. To resolve this discrepancy, we recorded Purkinje cells during conditioning with short or long CS-US intervals. Decerebrated ferrets trained with CS-US intervals ≥150 ms reliably developed Purkinje cell pauses, but training with an interval of 50 ms unexpectedly induced increases in CS-evoked spiking. This bidirectional modulation of Purkinje cell activity offers a basis for the requirement of a minimum CS-US interval for conditioning, but we argue that it cannot be fully explained by LTD, even when previous in vitro studies of stimulus-timing-dependent LTD are taken into account.

Visual Spatial Attention Has Opposite Effects on Bidirectional Plasticity in the Human Motor Cortex

Long-term potentiation (LTP) and long-term depression (LTD) are key mechanisms of synaptic plasticity that are thought to act in concert to shape neural connections. Here we investigated the influence of visual spatial attention on LTP-like and LTD-like plasticity in the human motor cortex. Plasticity was induced using paired associative stimulation (PAS), which involves repeated pairing of peripheral nerve stimulation and transcranial magnetic stimulation to alter functional responses in the thumb area of the primary motor cortex. PAS-induced changes in cortical excitability were assessed using motor-evoked potentials. During plasticity induction, participants directed their attention to one of two visual stimulus streams located adjacent to each hand. When participants attended to visual stimuli located near the left thumb, which was targeted by PAS, LTP-like increases in excitability were significantly enhanced, and LTD-like decreases in excitability reduced, relative to when they attended instead to stimuli located near the right thumb. These differential effects on (bidirectional) LTP-like and LTD-like plasticity suggest that voluntary visual attention can exert an important influence on the functional organization of the motor cortex. Specifically, attention acts to both enhance the strengthening and suppress the weakening of neural connections representing events that fall within the focus of attention.

Increased Transcranial Direct Current Stimulation After Effects During Concurrent Peripheral Electrical Nerve Stimulation

In this study we tested the hypothesis whether a lasting change in the excitability of cortical output circuits can be obtained in healthy humans by combining a peripheral nerve stimulation during a concomitant depolarization and/or hyperpolarization of motor cortex. To reach this aim we combined two different neurophysiological techniques each of them able to induce a lasting increase of cortical excitability by them self: namely median nerve repetitive electrical stimulation (rEPNS) and transcranial direct current stimulation (tDCS). Ten normal young volunteers were enrolled in the present study. All subjects underwent five different protocols of stimulation: (1, 2) tDCS alone (anodal or cathodal); (3) Sham tDCS plus rEPNS; (4, 5) anodal or cathodal tDCS plus rEPNS. The baseline MEP amplitude from abductor pollicis brevis (APB) and flexor carpi radialis (FCR) muscle, the FCR H-reflex were compared with that obtained immediately after and 10, 20, 30, 60 min after the stimulation protocol. Anodal tDCS alone induced a significant transient increase of MEP amplitude immediately after the end of stimulation while anodal tDCS + rEPNS determined MEP changes which persisted for up 60 min. Cathodal tDCS alone induced a significant reduction of MEP amplitude immediately after the end of stimulation while cathodal tDCS + rEPNS prolonged the effects for up to 60 min. Sham tDCS + rEPNS did not induce significant changes in corticospinal excitability. Anodal or cathodal tDCS + rEPNS and sham tDCS + rEPNS caused a lasting facilitation of H-reflex. These findings suggest that by providing afferent input to the motor cortex while its excitability level is increased or decreased by tDCS may be a highly effective means for inducing an enduring bi-directional plasticity. The mechanism of this protocol may be complex, involving either cortical and spinal after effects.

IS 14. Quadripulse stimulation (QPS) and octapulse stimulation (OPS)

We have proposed that QPS or OPS are have some superior points as compared with several stimulation methods for inducing long lasting effects (LTP?LTD like effects) in humans, especially in the motor cortex. In the present communication, I will summarize several issues for QPS or OPS. Several published papers are listed below, and see their details in those papers. I mention here some issues briefly. QPS induces LTP/LTD like effects on the primary motor cortex ( M1 ) and also the primary sensory cortex ( S1 ). It also has a metaplastic characteristic. Monophasic pulses used in QPS may explain that QPS is not influenced by BDNF polymorphism or not much influenced by voluntary contraction after QPS. We compared lasting effects between monophasic QPS and biphasic QPS. Monophasic QPS had more powerful and longer bidirectional effects than biphasic one. We compared lasting effects among several durations of QPS or OPS. The duration of period of QPS had more influenced the after-effects than the total number of pulses. This may be explained by the processes involved in the LTP/LTD. Voluntary contraction abolished some phase of lasting effects transiently, but later phase effects reappear again after some lag-time. This may explain that the LTP/LTD induction has several processes, and one process may trigger the next process non-linearly to the degree of its induction. The on-line changes in NIRS are not compatible with bi-directionality of QPS. This is compatible with the idea that the degree of LTP/LTD induction has no linear correlation with the amount of stimulation, whereas NIRS results have a linear relation with it. L-dopa intake enhanced bidirectional effects of QPS even though agonist had different effects. The duration of aftereffects by QPS may be still too short to be applied as a clinical therapeutic tool. We hypothesized that increasing the number of pulses to eight (Octo-Pulse Stimulation: OPS) within one burst prolongs the duration of aftereffects. In ten healthy subjects the effects of higher and lower frequency OPS M1 on M1 excitability were compared with those of QPS. Motor evoked potentials were used as measure for cortical excitability. Both OPS and QPS induced sustained bidirectional excitability changes of M1 depending on the stimulation frequency as compared with sham stimulation. Moreover, the duration of aftereffects was longer after OPS compared to QPS. OPS and QPS induce powerful bidirectional plasticity of M1. cuttlefish scolopendra

Filamentous actin binding enables βCaMKII to regulate bidirectional plasticity in cerebellar Purkinje cells

© 2013 Pinto et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Endocannabinoids mediate spike-timing dependent potentiation and depression: a model-based experimental approach

Activity-dependent long-term potentiation (LTP) and depression (LTD) of synaptic strength underlie multiple forms of learning and memory. Endocannabinoids (eCBs) have consistently been described as mediators of short- or long-term synaptic depression through the activation of the endocannabinoid-type-1 receptor (CB1R) or the transient receptor potential vanilloid-type-1 (TRPV1). Here we investigated whether eCBs could also promote long-term potentiation, an essential requirement for eCBs to be a genuine bidirectional system and to fully encode for learning and memory. To this aim, we combined in vitro spike timing-dependent plasticity (STDP) protocols in rodents and a biophysical model of the signaling pathways likely to be involved. The model describes the temporal dynamics of three main signaling systems: the postsynaptic NMDAR-CaMKII pathway (adapted from [1]), the postsynaptic mGluR-PLCβ system (adapted from [2]) as well as postsynaptic eCB synthesis and subsequent activation of postsynaptic TRPV1 and presynaptic CB1R in a retrograde fashion. Using the model to drive the experiments, we uncovered the existence of an eCB-mediated spike-timing dependent potentiation (eCB-LTP). This eCB-LTP is homosynaptic, astrocyte-independent and expressed in young and adult animals and across various brain regions (cortex and striatum), supporting its role as a widespread signaling system for spike-based plasticity. We deciphered the signaling pathways (pre- and postsynaptic receptors and enzymes) involved in this new form of plasticity and demonstrated that eCB plasticity has a postynaptic induction and a presynaptic maintenance. On the postsynaptic side, our results show that the dynamics of free cytosolic calcium is a key element for eCB-LTP induction. eCB-LTP is triggered when eCB transients reach sufficiently high levels. Since the enzymes that synthetize eCBs are calcium-activated, eCB-LTP induction requires large levels of cytosolic calcium. On the presynaptic side, eCBs encode for bidirectional plasticity via a triad composed of eCB levels, presynaptic PKA and presynaptic CaN: intermediate eCB levels promote presynaptic CaN activity, that yields eCB-LTD, whereas large eCB amplitudes favor presynaptic PKA activity, which leads to eCB-LTP. Both effects are predicted to rely on the inhibition exerted by activated CB1R on presynaptic adenylate cyclase and P/Q-type voltage-gated calcium channels. Moreover, we show that eCB-LTP and eCB-LTD can be induced sequentially in the same neuron, depending on the cellular conditioning paradigm. Therefore, our results demonstrate that eCBs, just like glutamatergic or GABAergic signaling, form a generic system able to encode for bidirectional plasticity and capable of genuine homeostasis. Lastly, we found that eCB-LTP is triggered by very few paired spikes (5 to 10 post-pre spikes at 1 Hz are enough). Thus, eCB-LTP provides synapses with a mechanism able to react to the very first occurrences of incoming activity. This ability strongly contrasts with NMDAR-dependent LTP which, in a classical (1 Hz) STDP context, requires the iteration of at least 75-100 paired stimulations to be expressed, at odds with the observations that new associative memories and behavioral rules can be learned within few or even a single trials in mammals (e.g. [3]). Our results suggest that eCB-LTP may represent a neuronal substrate for such rapid learning abilities.

Regulation of Metabotropic Glutamate Receptor 7 (mGluR7) Internalization and Surface Expression by Ser/Thr Protein Phosphatase 1

The metabotropic glutamate receptor type 7 (mGluR7) is the predominant group III mGluR in the presynaptic active zone, where it serves as an autoreceptor to inhibit neurotransmitter release. Our previous studies show that PKC phosphorylation of mGluR7 on Ser-862 is a key mechanism controlling constitutive and activity-dependent surface expression of mGluR7 by regulating a competitive interaction of calmodulin and protein interacting with C kinase (PICK1). As receptor phosphorylation and dephosphorylation are tightly coordinated through the precise action of protein kinases and phosphatases, dephosphorylation by phosphatases is likely to play an active role in governing the activity-dependent or agonist-induced changes in mGluR7 receptor surface expression. In the present study, we find that the serine/threonine protein phosphatase 1 (PP1) has a crucial role in the constitutive and agonist-induced dephosphorylation of Ser-862 on mGluR7. Treatment of neurons with PP1 inhibitors leads to a robust increase in Ser-862 phosphorylation and increased surface expression of mGluR7. In addition, Ser-862 phosphorylation of both mGluR7a and mGluR7b is a target of PP1. Interestingly, agonist-induced dephosphorylation of mGluR7 is regulated by PP1, whereas NMDA-mediated activity-induced dephosphorylation is not, illustrating there are multiple signaling pathways that affect receptor phosphorylation and trafficking. Importantly, PP1γ1 regulates agonist-dependent Ser-862 dephosphorylation and surface expression of mGluR7.

Learning-Induced Bidirectional Plasticity of Intrinsic Neuronal Excitability Reflects the Valence of the Outcome

Long-term memory is supported not only by modulation of synaptic strength, but also by modifications in intrinsic neuronal properties. Learning-induced enhancement of neuronal excitability has been shown in the hippocampus and the piriform cortex, where it lasts for days and is involved in maintaining the learned skills. The basolateral amygdala (BLA) is suggested to encode positive and negative significance of information, thus forming a unique experimental setting to monitor bidirectional changes as a function of the valence change. In rodents, olfaction is a major modality that guides goal-directed behavior. Here, we show that intrinsic neuronal excitability in BLA pyramidal neurons is differentially modified by positive and negative olfactory learning and explore the cellular mechanisms of such bidirectional intrinsic neuronal plasticity. Learning of complex olfactory-discrimination task, in which success was rewarded with drinking water, resulted with enhanced intrinsic excitability. Such enhancement is mediated by reduction in the slow potassium current. In contrast, olfactory fear conditioning, in which the animal learned to associate the odor with an electric shock, resulted in decreased intrinsic excitability, mediated by activation of the µ-opioid-sensitive potassium current. We suggest that positive and negative changes in BLA excitability contribute to the encoding of opposite odor-value behaviors.

Bidirectional plasticity of intrinsic excitability controls sensory inputs efficiency in layer 5 barrel cortex neurons in vivo.

Responsiveness of cortical neurons to sensory inputs can be altered by experience and learning. While synaptic plasticity is generally proposed as the underlying cellular mechanism, possible contributions of activity-dependent changes in intrinsic excitability remain poorly investigated. Here, we show that periods of rhythmic firing in rat barrel cortex layer 5 pyramidal neurons can trigger a long-lasting increase or decrease in their membrane excitability in vivo. Potentiation of cortical excitability consisted of an increased firing in response to intracellular stimulation and a reduction in threshold current for spike initiation. Conversely, depression of cortical excitability was evidenced by an augmented firing threshold leading to a reduced current-evoked spiking. The direction of plasticity depended on the baseline level of spontaneous firing rate and cell excitability. We also found that changes in intrinsic excitability were accompanied by corresponding modifications in the effectiveness of sensory inputs. Potentiation and depression of cortical neuron excitability resulted, respectively, in an increased or decreased firing probability on whisker-evoked synaptic responses, without modifications in the synaptic strength itself. These data suggest that bidirectional intrinsic plasticity could play an important role in experience-dependent refinement of sensory cortical networks.

The repetition timing of high frequency afferent stimulation drives the bidirectional plasticity at central synapses in the rat medial vestibular nuclei

In this study we show that high frequency stimulation (HFS, 100Hz) of afferent fibers to the medial vestibular nucleus (MVN) can induce opposite long-term modifications of synaptic responses in the type B neurons depending upon the stimulation pattern. Long burst stimulation (LBS: 2s) and short burst stimulation (SBS: 0.55s) were applied with different burst number (BN) and inter-burst intervals (IBI). It results that both LBS and SBS can induce either N-methyl-d aspartate receptors (NMDARs)-mediated long-term potentiation (LTP) or long-term depression (LTD), depending on temporal organization of repetitive bursts. In particular, the IBI plays a relevant role in guiding the shift from LTP to LTD since by using both LBS and SBS LTP is induced by shorter IBI than LTD. By contrast, the sign of long-term effect does not depend on the mean impulse frequency evaluated within the entire stimulation period. Therefore, the patterns of repetitive vestibular activation with different ratios between periods of increased activity and periods of basal activity may lead to LTP or LTD probably causing different levels of postsynaptic Ca2+. On the whole, this study demonstrates that glutamatergic vestibular synapse in the MVN can undergo NMDAR-dependent bidirectional plasticity and puts forward a new aspect for understanding the adaptive and compensatory plasticity of the oculomotor responses.

50. Central motor conduction delay and peripheral neuropathy in case of an adult-onset Krabbe disease

cortical excitability. Both OPS and QPS induced sustained bidirectional excitability changes of M1 depending on the stimulation frequency as compared with sham stimulation. Moreover, the duration of aftereffects was longer after OPS compared to QPS. In conclusion, OPS and QPS induce powerful bidirectional plasticity of M1. The number of stimuli within one burst may be of particular importance for the duration of the induced plasticity.

Plasticity of NMDA receptor‐mediated excitatory postsynaptic currents at perforant path inputs to dendrite‐targeting interneurons

Synaptic plasticity of NMDA receptors (NMDARs) has been recently described in a number of brain regions and we have previously characterised LTP and LTD of glutamatergic NMDA receptor-mediated EPSCs (NMDAR-EPSCs) in granule cells of dentate gyrus. The functional significance of NMDAR plasticity at perforant path synapses on hippocampal network activity depends on whether this is a common feature of perforant path synapses on all postsynaptic target cells or if this plasticity occurs only at synapses on principal cells. We recorded NMDAR-EPSCs at medial perforant path synapses on interneurons in dentate gyrus which had significantly slower decay kinetics compared to those recorded in granule cells. NMDAR pharmacology in interneurons was consistent with expression of both GluN2B- and GluN2D-containing receptors. In contrast to previously described high frequency stimulation-induced bidirectional plasticity of NMDAR-EPSCs in granule cells, only LTD of NMDAR-EPSCs was induced in interneurons in our standard experimental conditions. In interneurons, LTD of NMDAR-EPSCs was associated with a loss of sensitivity to a GluN2D-selective antagonist and was inhibited by the actin stabilising agent, jasplakinolide. While LTP of NMDAR-EPSCs can be readily induced in granule cells, this form of plasticity was only observed in interneurons when extracellular calcium was increased above physiological concentrations during HFS or when PKC was directly activated by phorbol ester, suggesting that opposing forms of plasticity at inputs to interneurons and principal cells may act to regulate granule cell dendritic integration and processing.