Hippocampal long‐term potentiation that is elicited by perforant path stimulation or that occurs in conjunction with spatial learning is tightly controlled by beta‐adrenoreceptors and the locus coeruleus

The noradrenergic system, driven by locus coeruleus (LC) activation, plays a key role in the regulating and directing of changes in hippocampal synaptic efficacy. The LC releases noradrenaline in response to novel experience and LC activation leads to an enhancement of hippocampus‐based learning, and facilitates synaptic plasticity in the form of long‐term depression (LTD) and long‐term potentiation (LTP) that occur in association with spatial learning. The predominant receptor for mediating these effects is the β‐adrenoreceptor. Interestingly, the dependency of synaptic plasticity on this receptor is different in the hippocampal subfields whereby in the CA1 in vivo, LTP, but not LTD requires β‐adrenoreceptor activation, whereas in the mossy fiber synapse LTP and LTD do not depend on this receptor. By contrast, synaptic plasticity that is facilitated by spatial learning is highly dependent on β‐adrenoreceptor activation in both hippocampal subfields. Here, we explored whether LTP induced by perforant‐path (pp) stimulation in vivo or that is facilitated by spatial learning depends on β‐adrenoreceptors. We found that under both LTP conditions, antagonising the receptors disabled the persistence of LTP. β‐adrenoreceptor‐antagonism also prevented spatial learning. Strikingly, activation of the LC before high‐frequency stimulation (HFS) of the pp prevented short‐term potentiation but not LTP, and LC stimulation after pp‐HFS‐induced depotentiation of LTP. This depotentiation was prevented by β‐adrenoreceptor‐antagonism. These data suggest that β‐adrenoreceptor‐activation, resulting from noradrenaline release from the LC during enhanced arousal and learning, comprises a mechanism whereby the duration and degree of LTP is regulated and fine tuned. This may serve to optimize the creation of a spatial memory engram by means of LTP and LTD. This process can be expected to support the special role of the dentate gyrus as a crucial subregional locus for detecting and processing novelty within the hippocampus. © 2015 The Authors Hippocampus Published by Wiley Periodicals, Inc.     

Age-dependent alterations of long-term synaptic plasticity in thyroid-deficient rats

Thyroid hormone deficiency during a critical period of development profoundly affects cognitive functions such as attention, learning, and memory, but the synaptic alterations underlying these deficits remain unexplored. The present study examines the effect of congenital hypothyroidism on long-term synaptic plasticity. This plasticity is believed to be essential for learning and memory and for activity-dependent regulation of synapse formation in the developing brain. We found that the neonatal expression of long-term potentiation (LTP), long-term depression (LTD), depotentiation, and de-depression in hippocampal slices from hypothyroid animals was similar to that of controls. To examine the postnatal development of these plasticities, we used slices from neonatal (2-3 weeks) and adult (7-8 weeks) rats. This work demonstrates that the ability to express all these forms of synaptic plasticity is reduced in an age-dependent manner in control rats. LTP and depotentiation are also downregulated in adult hypothyroid rats, but we have found that de-depression is not affected during maturation. In addition, these animals express LTD at ages at which controls fail to induce it. In contrast, input/output experiments have shown greater levels of basal synaptic efficacy in hypothyroid adults, and this effect is probably related to the higher probability of release observed by paired-pulse experiments. Nevertheless, these effects appear to be unrelated to the differences observed in long-term synaptic plasticity, as no correlation was found between basal synaptic efficacy and the degree of LTD and de-depression. Furthermore, the NMDA-receptor antagonist amino-phosphonopentanoic acid (APV) completely blocked LTD, which suggests a postsynaptic locus of this alteration. Because LTD has been associated with novelty acquisition, we suggest that the greater LTD observed in adult hypothyroid rats might be related to the hyperactivity of these animals. However, other possibilities such as a retarded maturation of synaptic plasticity must be taken into account.     

Partial inhibition of PP1 alters bidirectional synaptic plasticity in the hippocampus

Synaptic plasticity is an important cellular mechanism that underlies memory formation. In brain areas involved in memory such as the hippocampus, long-term synaptic plasticity is bidirectional. Major forms of bidirectional plasticity encompass long-term potentiation (LTP), LTP reversal (depotentiation) and long-term depression (LTD). Protein kinases and protein phosphatases are important players in the induction of both LTP and LTD, and the serine/threonine protein phosphatase-1 (PP1), in particular, has emerged as a key phosphatase in these processes. The goal of the present study was to assess the contribution of PP1 to bidirectional plasticity and examine the impact of a partial inhibition of PP1 on LTP, LTD and depotentiation in the mouse hippocampus. For this, we used transgenic mice expressing an active PP1 inhibitor (I-1*) inducibly in forebrain neurons. We show that partial inhibition of PP1 by I-1* expression alters the properties of bidirectional plasticity by inducing a shift of synaptic responses towards potentiation. At low-frequency stimulation, PP1 inhibition decreases LTD in a frequency-dependent fashion. It favours potentiation over depression at intermediate frequencies and increases LTP at high frequency. Consistently, it also impairs depotentiation. These results indicate that the requirement of bidirectional plasticity for PP1 is frequency-dependent and that a broad range of plasticity is negatively constrained by PP1, a feature that may correlate with the property of PP1 to constrain learning efficacy and promote forgetting.     

Dynamic range of GSK3α not GSK3β is essential for bidirectional synaptic plasticity at hippocampal CA3‐CA1 synapses

Glycogen synthase kinase‐3 (GSK3), particularly the isoform GSK3β, has been implicated in a wide range of physiological systems and neurological disorders including Alzheimer's Disease. However, the functional importance of GSK3α has been largely untested. The multifunctionality of GSK3 limits its potential as a drug target because of inevitable side effects. Due to its greater expression in the CNS, GSK3β rather than GSK3α has also been assumed to be of primary importance in synaptic plasticity. Here, we investigate bidirectional long‐term synaptic plasticity in knockin mice with a point mutation in GSK3α or GSK3β that prevents their inhibitory regulation. We report that only the mutation in GSK3α affects long‐term potentiation (LTP) and depression (LTD). This stresses the importance of investigating isoform specificity for GSK3 in all systems and suggests that GSK3α should be investigated as a drug target in cognitive disorders including Alzheimer's Disease. © 2014 The Authors. Hippocampus Published by Wiley Periodicals, Inc.     

ERK1/2 but not p38 MAP kinase is essential for the long-term depression in mouse cerebellar slices

Mitogen-activated protein kinase (MAPK) cascade is essential for synaptic plasticity and learning. In the hippocampus, three different MAPK subfamilies, extracellular signal-regulated kinase 1/2 (ERK1/2), p38 MAPK and c-Jun NH2-terminal protein kinase (JNK), selectively regulate activity-dependent glutamate receptor trafficking during long-term potentiation (LTP), long-term depression (LTD), and depotentiation after LTP, respectively. Although LTP and LTD at cerebellar parallel fibre (PF)-Purkinje cell synapses are thought to be controlled by glutamate receptor trafficking, the involvement of MAPK subfamilies has not been systemically studied in cerebellar slice preparations. To clarify the role of the MAPK cascade in cerebellar LTD, we performed biochemical and electrophysiological analyses using ICR mouse cerebellar slices. Immunoblot analyses using phosphorylation-specific antibodies for MAPKs revealed that among the three MAPKs, ERK1/2 was specifically activated by phorbol ester, which could induce LTD in cerebellar slices. In addition, U0126, a specific inhibitor of the MAPK kinase-ERK1/2 pathway, abrogated the induction of LTD in cerebellar slices, whereas SB203580 and SP600125, specific inhibitors of p38 MAPK and JNK, respectively, had no effect. Although metabotropic glutamate receptor 1 (mGluR1) has been suggested as a possible downstream target of ERK1/2 in cell-culture preparations, mGluR1-activated slow excitatory postsynaptic currents (EPSCs) were not affected by U0126 treatment in slices. These findings indicate that unlike hippocampal LTD mediated by p38 MAPK, glutamate receptor trafficking during cerebellar LTD was regulated by a distinct mechanism involving ERK1/2 in slice preparations.     

Alterations in the balance of protein kinase and phosphatase activities and age-related impairments of synaptic transmission and long-term potentiation

Aging is associated with an impaired ability to maintain long-term potentiation (LTP), but the underlying cause of the impairment remains unclear. To gain a better understanding of the cellular and molecular mechanisms responsible for this impairment, the synaptic transmission and plasticity were studied in the CA1 region of hippocampal slices from adult (6-8 months) and poor-memory (PM)-aged (23-24 months) rats. The one-way inhibitory avoidance learning task was used as the behavioral paradigm to screen PM-aged rats. With intracellular recordings, CA1 neurons of PM-aged rats exhibited a more hyperpolarized resting membrane potential, reduced input resistance, and increased amplitude of afterhyperpolarization and spike threshold, compared with those in adult rats. Although a reduction in the size of excitatory synaptic response was observed in PM-aged rats, no obvious differences were found between adult and PM-aged rats in the pharmacological properties of excitatory synaptic response, paired-pulse facilitation, or frequency-dependent facilitation, which was tested with trains of 10 pulses at 1, 5, and 10 Hz. Slices from the PM-aged rats displayed significantly reduced early-phase long-term potentiation (E-LTP) and late-phase LTP (L-LTP), and the entire frequency-response curve of LTP and LTD is modified to favor LTD induction. The susceptibility of time-dependent reversal of LTP by low-frequency afferent stimulation was also facilitated in PM-aged rats. Bath application of the protein phosphatase inhibitor, calyculin A, enhanced synaptic response in slices from PM-aged, but not adult, rats. In contrast, application of the cAMP-dependent protein kinase inhibitors, Rp-8-CPT-cAMPS and KT5720, induced a decrease in synaptic transmission only in slices from the adult rats. Furthermore, the selective beta-adrenergic receptor agonist, isoproterenol, and pertussis toxin-sensitive G-protein inhibitor, N-ethylmaleimide, effectively restored the deficit in E-LTP and L-LTP of PM-aged rats. These results demonstrate that age-related impairments of synaptic transmission and LTP may result from alterations in the balance of protein kinase/phosphatase activities.     

The requirement of BDNF for hippocampal synaptic plasticity is experience‐dependent

Brain‐derived neurotrophic factor (BDNF) supports neuronal survival, growth, and differentiation and has been implicated in forms of hippocampus‐dependent learning. In vitro, a specific role in hippocampal synaptic plasticity has been described, although not all experience‐dependent forms of synaptic plasticity critically depend on BDNF. Synaptic plasticity is likely to enable long‐term synaptic information storage and memory, and the induction of persistent (>24 h) forms, such as long‐term potentiation (LTP) and long‐term depression (LTD) is tightly associated with learning specific aspects of a spatial representation. Whether BDNF is required for persistent (>24 h) forms of LTP and LTD, and how it contributes to synaptic plasticity in the freely behaving rodent has never been explored. We examined LTP, LTD, and related forms of learning in the CA1 region of freely dependent mice that have a partial knockdown of BDNF (BDNF^+/?). We show that whereas early‐LTD (<90min) requires BDNF, short‐term depression (<45 min) does not. Furthermore, BDNF is required for LTP that is induced by mild, but not strong short afferent stimulation protocols. Object‐place learning triggers LTD in the CA1 region of mice. We observed that object‐place memory was impaired and the object‐place exploration failed to induce LTD in BDNF^+/? mice. Furthermore, spatial reference memory, that is believed to be enabled by LTP, was also impaired. Taken together, these data indicate that BDNF is required for specific, but not all, forms of hippocampal‐dependent information storage and memory. Thus, very robust forms of synaptic plasticity may circumvent the need for BDNF, rather it may play a specific role in the optimization of weaker forms of plasticity. The finding that both learning‐facilitated LTD and spatial reference memory are both impaired in BDNF^+/? mice, suggests moreover, that it is critically required for the physiological encoding of hippocampus‐dependent memory. © 2015 The Authors Hippocampus Published by Wiley Periodicals, Inc.     

Maladaptive striatal plasticity and abnormal reward‐learning in cervical dystonia

In monogenetic generalized forms of dystonia, in vitro neurophysiological recordings have demonstrated direct evidence for abnormal plasticity at the level of the cortico‐striatal synapse. It is unclear whether similar abnormalities contribute to the pathophysiology of cervical dystonia, the most common type of focal dystonia. We investigated whether abnormal cortico‐striatal synaptic plasticity contributes to abnormal reward‐learning behavior in patients with focal dystonia. Forty patients and 40 controls performed a reward gain and loss avoidance reversal learning task. Participant's behavior was fitted to a computational model of the basal ganglia incorporating detailed cortico‐striatal synaptic learning rules. Model comparisons were performed to assess the ability of four hypothesized receptor specific abnormalities of cortico‐striatal long‐term potentiation (LTP) and long‐term depression (LTD): increased or decreased D1:LTP/LTD and increased or decreased D2: LTP/LTD to explain abnormal behavior in patients. Patients were selectively impaired in the post‐reversal phase of the reward task. Individual learning rates in the reward reversal task correlated with the severity of the patient's motor symptoms. A model of the striatum with decreased D2:LTP/ LTD best explained the patient's behavior, suggesting excessive D2 cortico‐striatal synaptic depotentiation could underpin biased reward‐learning in patients with cervical dystonia. Reversal learning impairment in cervical dystonia may be a behavioral correlate of D2‐specific abnormalities in cortico‐striatal synaptic plasticity. Reinforcement learning tasks with computational modeling could allow the identification of molecular targets for novel treatments based on their ability to restore normal reward‐learning behavior in these patients.     

The effects of intra‐hippocampal L‐thyroxine infusion on long‐term potentiation and long‐term depression: A possible role for the αvβ3 integrin receptor

Although the effects of long‐term experimental dysthyroidism on long‐term potentiation (LTP) and long‐term depression (LTD) have been documented, the relationship between LTP/LTD and acute administration of L‐thyroxine (T4) has not been described. Here, we investigated the effects of intra‐hippocampal administration of T4 on synaptic plasticity in the dentate gyrus of the hippocampal formation. After a 15‐minute baseline recording, LTP and LTD were induced by application of high‐ and low‐frequency stimulation protocols, respectively. Infusions of saline or T4 and tetraiodothyroacetic acid (tetrac), a T4 analog that inhibits binding of iodothyronines to the integrin αvβ3 receptor, either alone or together, were made during the stimulation protocols. The averages of the excitatory postsynaptic potential (EPSP) slopes and population spike (PS) amplitudes, between 55 to 60 minutes, were used as a measure of the LTP/LTD magnitude and were analyzed by two‐way univariate ANOVA with T4 and tetrac as between‐subjects factors. The input–output curves of the infusion groups were comparable to each other, as shown by the non significant interaction observed between stimulus intensity and infused drug. The magnitude of the LTP in T4‐infused rats was significantly lower as compared to saline‐infused rats. Both the PS amplitude and the EPSP slope were depressed more markedly with T4 infusion than with saline, tetrac, and T4 + tetrac infusion. Data of this study provide in vivo evidence that T4 can promote LTD over LTP via the integrin αvβ3 receptor, and that the effect of endogenous T4 on this receptor can be suppressed by tetrac in the hippocampus. © 2016 Wiley Periodicals, Inc.     

Diabetes mellitus concomitantly facilitates the induction of long-term depression and inhibits that of long-term potentiation in hippocampus

Memory impairments, which occur regularly across species as a result of ageing, disease (such as diabetes mellitus) and psychological insults, constitute a useful area for investigating the neurobiological basis of learning and memory. Previous studies in rats found that induction of diabetes (with streptozotocin, STZ) impairs long‐term potentiation (LTP) but enhances long‐term depression (LTD) induced by high‐ (HFS) and low‐frequency stimulations (LFS), respectively. Using a pairing protocol under whole‐cell recording conditions to induce synaptic plasticity at Schaffer collateral synapses in hippocampal CA1 slices, we show that LTD and LTP have similar magnitudes in diabetic and age‐matched control rats. But, in diabetic animals, LTD is induced at more polarized and LTP more depolarized membrane potentials (V_ms) compared with controls: diabetes produces a 10 mV leftward shift in the threshold for LTD induction and 10 mV rightward shift in the LTD–LTP crossover point of the voltage–response curve for synaptic plasticity. Prior repeated short‐term potentiations or LTP are known to similarly, though reversibly, lower the threshold for LTD induction and raise that for LTP induction. Thus, diabetes‐ and activity‐dependent modulation of synaptic plasticity (referred to as metaplasticity) display similar phenomenologies. In addition, compared with naïve synapses, prior induction of LTP produces a 10 mV leftward shift in V_ms for inducing subsequent LTD in control but not in diabetic rats. This could indicate that diabetes acts on synaptic plasticity through mechanisms involved in metaplasticity. Persistent facilitation of LTD and inhibition of LTP may contribute to learning and memory impairments associated with diabetes mellitus.     

Heterosynaptic long‐term depression mediated by ATP released from astrocytes

Heterosynaptic long‐term depression (hLTD) at untetanized synapses accompanying the induction of long‐term potentiation (LTP) spatially sharpens the activity‐induced synaptic potentiation; however, the underlying mechanism remains unclear. We found that hLTD in the hippocampal CA1 region is caused by stimulation‐induced ATP release from astrocytes that suppresses transmitter release from untetanized synaptic terminals via activation of P2Y receptors. Selective stimulation of astrocytes expressing channelrhodopsin‐2, a light‐gated cation channel permeable to Ca²⁺, resulted in LTD of synapses on neighboring neurons. This synaptic modification required Ca²⁺ elevation in astrocytes and activation of P2Y receptors, but not N‐methyl‐D ‐aspartate receptors. Furthermore, blocking P2Y receptors or buffering astrocyte intracellular Ca²⁺ at a low level prevented hLTD without affecting LTP induced by SC stimulation. Thus, astrocyte activation is both necessary and sufficient for mediating hLTD accompanying LTP induction, strongly supporting the notion that astrocytes actively participate in activity‐dependent synaptic plasticity of neural circuits. © 2012 Wiley Periodicals, Inc.     

Priming stimulation modifies synaptic plasticity in the perforant path of hippocampal slice in rat

Objective The potential of all central nervous system synapses to exhibit long term potentiation （LTP） or long term depression （LTD） is subject to modulation by prior synaptic activity, a higher-order form of plasticity that has been termed metaplasticity. This study is designed to examine the plasticity and metaplasticity in the lateral perforant path of rat. Methods Field potential was measured with different priming and conditioning stimulation protocols. Results Ten-hertz priming, which does not affect basal synaptic transmission, caused a dramatic reduction in subsequent LTP at lateral perforant path synapses in vitro, and the reduced LTP lasted for at least 2 h. The LTD was unaffected. The reduction of LTP in the lateral perforant path was also readily induced by applying priming antidromically at the mossy fibers. Conclusion Priming with 10 Hz, which is within a frequency range observed during physiological activity, can cause potent, long-lasting inhibition of LTP, but not LTD. This form of metaplasticity adds a layer of complexity to the activity-dependent modification of synapses within the dentate gyrus.     

Priming stimulation modifies synaptic plasticity in the perforant path of hippocampal slice in rat

1 Introduction The ability to modify synaptic strength in an activity- dependent manner, either as long-term depression (LTD) or as long-term potentiation (LTP) is a fundamental feature of most central nervous system synapses. The properties of different forms of LTP in the rodent hippocampus have been exceedingly well studied. A less well studied but par- ticularly intriguing finding is that the capacity of many syn- apses for plastic changes itself is subject to modulation of subsequent …     

JNK1 contributes to metabotropic glutamate receptor-dependent long-term depression and short-term synaptic plasticity in the mice area hippocampal CA1

Several recent reports implicate an important role played by c-Jun N-terminal kinases (JNKs) in long-term potentiation (LTP). However, little is known about how the isoforms of JNKs participate in synaptic plasticity. Here we showed that short-term synaptic plasticity was impaired in the hippocampal area CA1 of JNK1-deficient (JNK1-/-) mice; these mice showed normal LTP in response to a strong tetanus and no alteration of N-methyl-D-aspartate receptor-dependent long-term depression (LTD) in the hippocampus. However, LTD induced either by group I metabotropic glutamate receptors (mGluRs) agonist dihydroxyphenylglycine or by paired-pulse low-frequency stimulation was absent in both the JNK1-/- slices and in JNK inhibitor anthrax [1, 9-cd] pyrazol-6(2H)-1 (SP600125)-pretreated slices. Induction of mGluR-dependent LTD resulted in an increase in phosphorylation of JNK1 substrates, including p-c-Jun and p-ATF2 in wild-type (WT) mice, and these increases failed to occur in the JNK1-/- or SP600125-pretreated mice. These results demonstrated that JNK1 played a crucial role in the short-term synaptic plasticity and mGluR-dependent LTD, whereas hippocampus LTP was not affected by JNK1 deficiency.     

Long‐term depression of inhibitory synaptic transmission induced by spike‐timing dependent plasticity requires coactivation of endocannabinoid and muscarinic receptors

The precise timing of pre‐postsynaptic activity is vital for the induction of long‐term potentiation (LTP) or depression (LTD) at many central synapses. We show in synapses of rat CA1 pyramidal neurons in vitro that spike timing dependent plasticity (STDP) protocols that induce LTP at glutamatergic synapses can evoke LTD of inhibitory postsynaptic currents or STDP‐iLTD. The STDP‐iLTD requires a postsynaptic Ca²⁺ increase, a release of endocannabinoids (eCBs), the activation of type‐1 endocananabinoid receptors and presynaptic muscarinic receptors that mediate a decreased probability of GABA release. In contrast, the STDP‐iLTD is independent of the activation of nicotinic receptors, GABA_BRs and G protein‐coupled postsynaptic receptors at pyramidal neurons. We determine that the downregulation of presynaptic Cyclic adenosine monophosphate/protein Kinase A pathways is essential for the induction of STDP‐iLTD. These results suggest a novel mechanism by which the activation of cholinergic neurons and retrograde signaling by eCBs can modulate the efficacy of GABAergic synaptic transmission in ways that may contribute to information processing and storage in the hippocampus. © 2013 Wiley Periodicals, Inc.     

Modulatory metaplasticity induced by pregnenolone sulfate in the rat hippocampus: A leftward shift in LTP/LTD‐frequency curve

We recently have found that an acute application of the neurosteroid pregnenolone sulfate (PREGS) at 50 μM to rat hippocampal slices induces a long‐lasting potentiation (LLP_PREGS) via a sustained ERK2/CREB activation at perforant‐path/granule‐cell synapses in the dentate gyrus. This study is a follow up to investigate whether the expression of LLP_PREGS influences subsequent frequency‐dependent synaptic plasticity. Conditioning electric stimuli (CS) at 0.1–200 Hz were given to the perforant‐path of rat hippocampal slices expressing LLP_PREGS to induce long‐term potentiation (LTP) and long‐term depression (LTD). The largest LTP was induced at about 20 Hz‐CS, which is normally a subthreshold frequency, and the largest LTD at 0.5 Hz‐CS, resulting in a leftward‐shift of the LTP/LTD‐frequency curve. Furthermore, the level of LTP at 100 Hz‐CS was significantly attenuated to give band‐pass filter characteristics of LTP induction with a center frequency of about 20 Hz. The LTP induced by 20 Hz‐CS (termed 20 Hz‐LTP) was found to be postsynaptic origin and dependent on L‐type voltage‐gated calcium channel (L‐VGCC) but not on N‐methyl‐D ‐aspartate receptor (NMDAr). Moreover, the induction of 20 Hz‐LTP required a sustained activation of ERK2 that had been triggered by PREGS. In conclusion, the transient elevation of PREGS is suggested to induce a modulatory metaplasticity through a sustained activation of ERK2 in an L‐VGCC dependent manner. © 2009 Wiley‐Liss, Inc.     

Protein kinase and phosphatase activity regulate the form of synaptic plasticity expressed

Long-term potentiation (LTP) and long-term depression (LTD) are calcium-dependent forms of synaptic plasticity observed in area CA1 of the hippocampus. Low-frequency tetani (1–5 Hz) activates protein phosphatases to induce LTD, whereas high-frequency tetani (>25 Hz) activates protein kinases to induce LTP. A tetanus at an intermediate frequency (10 Hz), however, does not result in a change in synaptic efficacy [Dudek and Bear, (1992), Proc. Natl. Acad. Sci. USA, 89:4363–4367]. We hypothesized that the 10-Hz tetanus results in no long-term change in synaptic efficacy due to a balance of the activity of protein phosphatases and protein kinases. We manipulated protein kinase/phosphatase activity at a 10-Hz tetanus to test this hypothesis. A 10-Hz tetanus under normal conditions results in a transient depression which returns to baseline in 25 min. However, inhibiting kinase activity with the protein kinase inhibitor H-7, or decreasing extracellular calcium concentration, results in the 10-Hz tetanus, inducing LTD. Conversely, inhibiting phosphatase activity with the protein phosphatase inhibitor tautomycin, or increasing extracellular calcium concentration, results in the 10-Hz tetanus, inducing LTP. These results suggest that the relative balance of protein kinase and phosphatase activity (and/or the calcium levels activating them) determines the expression of specific forms of synaptic plasticity, and that these forms lie on a continuum. © 1996 Wiley-Liss, Inc.     

Long‐term depression of synaptic transmission in the adult mouse insular cortex in vitro

The insular cortex (IC) is known to play important roles in higher brain functions such as memory and pain. Activity‐dependent long‐term depression (LTD) is a major form of synaptic plasticity related to memory and chronic pain. Previous studies of LTD have mainly focused on the hippocampus, and no study in the IC has been reported. In this study, using a 64‐channel recording system, we show for the first time that repetitive low‐frequency stimulation (LFS) can elicit frequency‐dependent LTD of glutamate receptor‐mediated excitatory synaptic transmission in both superficial and deep layers of the IC of adult mice. The induction of LTD in the IC required activation of the N‐methyl‐d ‐aspartate (NMDA) receptor, metabotropic glutamate receptor (mGluR)5, and L‐type voltage‐gated calcium channel. Protein phosphatase 1/2A and endocannabinoid signaling are also critical for the induction of LTD. In contrast, inhibiting protein kinase C, protein kinase A, protein kinase Mζ or calcium/calmodulin‐dependent protein kinase II did not affect LFS‐evoked LTD in the IC. Bath application of the group I mGluR agonist (RS)‐3,5‐dihydroxyphenylglycine produced another form of LTD in the IC, which was NMDA receptor‐independent and could not be occluded by LFS‐induced LTD. Our studies have characterised the basic mechanisms of LTD in the IC at the network level, and suggest that two different forms of LTD may co‐exist in the same population of IC synapses.     

Blockade of BDNF signaling turns chemically‐induced long‐term potentiation into long‐term depression

Long‐term potentiation (LTP) is accompanied by increased spine density and dimensions triggered by signaling cascades involving activation of the neurotrophin brain‐derived neurotrophic factor (BDNF) and cytoskeleton remodeling. Chemically‐induced long‐term potentiation (c‐LTP) is a widely used cellular model of plasticity, whose effects on spines have been poorly investigated. We induced c‐LTP by bath‐application of the N‐methyl‐d ‐aspartate receptor (NMDAR) coagonist glycine or by the K⁺ channel blocker tetraethylammonium (TEA) chloride in cultured hippocampal neurons and compared the changes in dendritic spines induced by the two models of c‐LTP and determined if they depend on BDNF/TrkB signaling. We found that both TEA and glycine induced a significant increase in stubby spine density in primary and secondary apical dendrites, whereas a specific increase in mushroom spine density was observed upon TEA application only in primary dendrites. Both TEA and glycine increased BDNF levels and the blockade of tropomyosin‐receptor‐kinase receptors (TrkRs) by the nonselective tyrosine kinase inhibitor K‐252a or the selective allosteric TrkB receptor (TrkBR) inhibitor ANA‐12, abolished the c‐LTP‐induced increase in spine density. Surprisingly, a blockade of TrkBRs did not change basal spontaneous glutamatergic transmission but completely changed the synaptic plasticity induced by c‐LTP, provoking a shift from a long‐term increase to a long‐term depression (LTD) in miniature excitatory postsynaptic current (mEPSC) frequency. In conclusion, these results suggest that BDNF/TrkB signaling is necessary for c‐LTP‐induced plasticity in hippocampal neurons and its blockade leads to a switch of c‐LTP into chemical‐LTD (c‐LTD). © 2013 Wiley Periodicals, Inc.     

β3 integrin is dispensable for conditioned fear and Hebbian forms of plasticity in the hippocampus

Integrins play key roles in the developing and mature nervous system, from promoting neuronal process outgrowth to facilitating synaptic plasticity. Recently, in hippocampal pyramidal neurons, β3 integrin (ITGβ3) was shown to stabilise synaptic AMPA receptors (AMPARs) and to be required for homeostatic scaling of AMPARs elicited by chronic activity suppression. To probe the physiological function for ITGβ3-dependent processes in the brain, we examined whether the loss of ITGβ3 affected fear-related behaviours in mice. ITGβ3-knockout (KO) mice showed normal conditioned fear responses that were similar to those of control wild-type mice. However, anxiety-like behaviour appeared substantially compromised and could be reversed to control levels by lentivirus-mediated re-expression of ITGβ3 bilaterally in the ventral hippocampus. In hippocampal slices, the loss of ITGβ3 activity did not compromise Hebbian forms of plasticity - neither acute pharmacological disruption of ITGβ3 ligand interactions nor genetic deletion of ITGβ3 altered long-term potentiation (LTP) or long-term depression (LTD). Moreover, we did not detect any changes in short-term synaptic plasticity upon loss of ITGβ3 activity. In contrast, acutely disrupting ITGβ1-ligand interactions or genetic deletion of ITGβ1 selectively interfered with LTP stabilisation whereas LTD remained unaltered. These findings indicate a lack of requirement for ITGβ3 in the two robust forms of hippocampal long-term synaptic plasticity, LTP and LTD, and suggest differential roles for ITGβ1 and ITGβ3 in supporting hippocampal circuit functions.