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.     

Frequency dependency of NMDA receptor‐dependent synaptic plasticity in the hippocampal CA1 region of freely behaving mice

Hippocampal synaptic plasticity in the form of long‐term potentiation (LTP) and long‐term depression (LTD) is likely to enable synaptic information storage in support of memory formation. The mouse brain has been subjected to intensive scrutiny in this regard; however, a multitude of studies has examined synaptic plasticity in the hippocampal slice preparation, whereas very few have addressed synaptic plasticity in the freely behaving mouse. Almost nothing is known about the frequency or N‐methyl‐D‐aspartate receptor (NMDAR) dependency of hippocampal synaptic plasticity in the intact mouse brain. Therefore, in this study, we investigated the forms of synaptic plasticity that are elicited at different afferent stimulation frequencies. We also addressed the NMDAR dependency of this phenomenon. Adult male C57BL/6 mice were chronically implanted with a stimulating electrode into the Schaffer collaterals and a recording electrode into the Stratum radiatum of the CA1 region. To examine synaptic plasticity, we chose protocols that were previously shown to produce either LTP or LTD in the hippocampal slice preparation. Low‐frequency stimulation (LFS) at 1 Hz (900 pulses) had no effect on evoked responses. LFS at 3 Hz (ranging from 200 up to 2 × 900 pulses) elicited short‐term depression (STD, <45 min). LFS at 3 Hz (1,200 pulses) elicited slow‐onset potentiation, high‐frequency stimulation (HFS) at 100 Hz (100 or 200 pulses) or at 50 Hz was ineffective, whereas 100 Hz (50 pulses) elicited short‐term potentiation (STP). HFS at 100 Hz given as 2 × 30, 2 × 50, or 4 × 50 pulses elicited LTP (>24 h). Theta‐burst stimulation was ineffective. Antagonism of the NMDAR prevented STD, STP, and LTP. This study shows for the first time that protocols that effectively elicit persistent synaptic plasticity in the slice preparation elicit distinctly different effects in the intact mouse brain. Persistent LTD could not be elicited with any of the protocols tested. Plasticity responses are NMDAR dependent, suggesting that these phenomena are relevant for hippocampus‐dependent learning. © 2012 Wiley Periodicals, Inc.     

Rapid visual stimulation increases extrasynaptic glutamate receptor expression but not visual‐evoked potentials in the adult rat primary visual cortex

The model most used to study synaptic plasticity, long‐term potentiation (LTP), typically employs electrical stimulation of afferent fibers to induce changes in synaptic strength. It would be beneficial for understanding the behavioral relevance of LTP if a model could be developed that used more naturalistic stimuli. Recent evidence suggests that the adult visual cortex, previously thought to have lost most of its plasticity once past the critical period, is in fact capable of LTP‐like changes in synaptic strength in response to sensory manipulations alone. In a preliminary study, we used a photic tetanus (PT; flashing checkerboard stimulus) to induce an enhancement of the visual‐evoked potential (VEP) in the primary visual cortex of anesthetised adult rats. In the present study, we sought to compare the mechanisms of this novel sensory LTP with those of traditional electrical LTP. Unexpectedly, we found that sensory LTP was not induced as reliably as we had observed previously, as manipulations of several parameters failed to lead to significant potentiation of the VEP. However, we did observe a significant increase in visual cortex glutamate receptor expression on the surface of isolated synapses following the PT. Both AMPA receptor expression and N‐methyl‐d ‐aspartate (NMDA) receptor subunit expression were increased, specifically in extrasynaptic regions of the membrane, in PT animals. These results provide biochemical confirmation of the lack of change in the VEP in response to PT, but suggest that PT may prime synapses for strengthening upon appropriate subsequent activation, through the trafficking of glutamate receptors to the cell surface.     

Amyloid β‐protein fragments 25–35 and 31–35 potentiate long‐term depression in hippocampal CA1 region of rats in vivo

Amyloid β‐protein (Aβ) is thought to be responsible for the deficit of learning and memory in Alzheimer's disease (AD), possibly through interfering with synaptic plasticity in the brain. It has been reported that Aβ fragments suppress the long‐term potentiation (LTP) of synaptic transmission. However, it is unclear whether Aβ fragments can regulate long‐term depression (LTD), an equally important form of synaptic plasticity in the brain. The present study investigates the effects of Aβ fragments on LTD induced by low frequency stimulation (LFS) in the hippocampus in vivo. Our results showed that (1) prolonged 1–10 Hz of LFS all effectively elicited LTD, which could persist for at least 2 h and be reversed by high frequency stimulation (HFS); (2) the effectiveness of LTD induction depended mainly on the number of pulses but not the frequency of LFS; (3) pretreatment with Aβ fragment 25–35 (Aβ_25–35, 12.5 and 25 nmol) did not change baseline field excitatory postsynaptic potentials but dose‐dependently potentiated LTD; (4) Aβ fragment 31–35 (Aβ_31–35), a shorter Aβ fragment than Aβ_25–35, also dose‐dependently strengthened LFS‐induced hippocampal LTD. Thus, the present study demonstrates the enhancement of hippocampal LTD by Aβ in in vivo condition. We propose that Aβ‐induced potentiation of LTD, together with the suppression of LTP, will result in the impairment of cognitive function of the brain. Synapse 63:206–214, 2009. © 2008 Wiley‐Liss, Inc.     

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.     

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.     

Short-term and long-term plasticity interaction in human primary motor cortex

Repetitive transcranial magnetic stimulation (rTMS) over primary motor cortex (M1) elicits changes in motor evoked potential (MEP) size thought to reflect short‐ and long‐term forms of synaptic plasticity, resembling short‐term potentiation (STP) and long‐term potentiation/depression (LTP/LTD) observed in animal experiments. We designed this study in healthy humans to investigate whether STP as elicited by 5‐Hz rTMS interferes with LTP/LTD‐like plasticity induced by intermittent and continuous theta‐burst stimulation (iTBS and cTBS). The effects induced by 5‐Hz rTMS and iTBS/cTBS were indexed as changes in MEP size. We separately evaluated changes induced by 5‐Hz rTMS, iTBS and cTBS applied alone and those induced by iTBS and cTBS delivered after priming 5‐Hz rTMS. Interactions between 5‐Hz rTMS and iTBS/cTBS were investigated under several experimental conditions by delivering 5‐Hz rTMS at suprathreshold and subthreshold intensity, allowing 1 and 5 min intervals to elapse between 5‐Hz rTMS and TBS, and delivering one and ten 5‐Hz rTMS trains. We also investigated whether 5‐Hz rTMS induces changes in intracortical excitability tested with paired‐pulse transcranial magnetic stimulation. When given alone, 5‐Hz rTMS induced short‐lasting and iTBS/cTBS induced long‐lasting changes in MEP amplitudes. When M1 was primed with 10 suprathreshold 5‐Hz rTMS trains at 1 min before iTBS or cTBS, the iTBS/cTBS‐induced after‐effects disappeared. The 5‐Hz rTMS left intracortical excitability unchanged. We suggest that STP elicited by suprathreshold 5‐Hz rTMS abolishes iTBS/cTBS‐induced LTP/LTD‐like plasticity through non‐homeostatic metaplasticity mechanisms. Our study provides new information on interactions between short‐term and long‐term rTMS‐induced plasticity in human M1.     

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.     

Forebrain NR2B overexpression enhancing fear acquisition and long‐term potentiation in the lateral amygdala

N‐methyl‐d ‐aspartic acid (NMDA) receptor‐dependent long‐term potentiation (LTP) at the thalamus–lateral amygdala (T‐LA) synapses is the basis for acquisition of auditory fear memory. However, the role of the NMDA receptor NR2B subunit in synaptic plasticity at T‐LA synapses remains speculative. In the present study, using transgenic mice with forebrain‐specific overexpression of the NR2B subunit, we have observed that forebrain NR2B overexpression results in enhanced LTP but does not alter long‐term depression (LTD) at the T‐LA synapses in transgenic mice. To elucidate the cellular mechanisms underlying enhanced LTP at T‐LA synapses in these transgenic mice, AMPA and NMDA receptor‐mediated postsynaptic currents have been measured. The data show a marked increasing in the amplitude and decay time of NMDA receptor‐mediated currents in these transgenic mice. Consistent with enhanced LTP at T‐LA synapses, NR2B‐transgenic mice exhibit better performance in the acquisition of auditory fear memory than wild‐type littermates. Our results demonstrate that up‐regulation of NR2B expression facilitates acquisition of auditory cued fear memory and enhances LTP at T‐LA synapses.     

Hippocampal long-term depression is enhanced, depotentiation is inhibited and long-term potentiation is unaffected by the application of a selective c-Jun N-terminal kinase inhibitor to freely behaving rats

Synaptic plasticity is regarded as the major candidate mechanism for synaptic information storage and memory formation in the hippocampus. Mitogen‐activated protein kinases have recently emerged as an important regulatory factor in many forms of synaptic plasticity and memory. As one of the subfamilies of mitogen‐activated protein kinases, extracellular‐regulated kinase is involved in the in vitro induction of long‐term potentiation (LTP), whereas p38 mediates metabotropic glutamate receptor‐dependent long‐term depression (LTD) in vitro. Although c‐Jun N‐terminal kinase (JNK) has also been implicated in synaptic plasticity, the in vivo relevance of JNK activity to different forms of synaptic plasticity remains to be further explored. We investigated the effect of inhibition of JNK on different forms of synaptic plasticity in the dentate gyrus of freely behaving adult rats. Intracereboventricular application of c‐Jun N‐terminal protein kinase‐inhibiting peptide (D‐JNKI) (96 ng), a highly selective JNK inhibitor peptide, did not affect basal synaptic transmission but reduced neuronal excitability with a higher dose (192 ng). Application of D‐JNKI, at a concentration that did not affect basal synaptic transmission, resulted in reduced specific phosphorylation of the JNK substrates postsynaptic density 95kD protein (PSD 95) and c‐Jun, a significant enhancement of LTD and a facilitation of short‐term depression into LTD. Both LTP and short‐term potentiation were unaffected. An inhibition of depotentiation (recovery of LTP) occurred. These data suggest that suppression of JNK‐dependent signalling may serve to enhance synaptic depression, and indirectly promote LTP through impairment of depotentiation.     

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.     

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.     

Hippocampal long‐term potentiation is enhanced in urethane‐anesthetized RGS2 knockout mice

RGS2 is a member of the regulator of G‐protein signaling (RGS) family and has been implicated in cellular mechanisms associated with neuronal plasticity. Long‐term potentiation (LTP) of RGS2 knockout and wild‐type mice was examined at the Schaffer collaterals to CA1 pathway in urethane‐anesthetized mice in vivo to examine RGS2's possible role in the regulation of potentiation. As compared to wild‐type mice, RGS2 knockouts demonstrated much stronger LTP of the extracellular population spikes at the somatic and dendritic layers in CA1 region and more pronounced LTP of the population excitatory postsynaptic current sink. Under baseline conditions, RGS2 knockouts showed lower paired‐pulse facilitation of the excitatory postsynaptic potentials and associated current sinks in vivo as compared with wild‐type mice. The data show for the first time that RGS2 deficient mice in vivo differ from wild‐type mice in both short‐term and long‐term synaptic plasticity suggesting that RGS2 serves as a negative regulator of long‐term synaptic plasticity. © 2009 Wiley‐Liss, Inc.     

Diverse impact of neuronal activity at θ frequency on hippocampal long‐term plasticity

Brain oscillatory activity is considered an essential aspect of brain function, and its frequency can vary from <1 Hz to >200 Hz, depending on the brain states and projection. Episodes of rhythmic activity accompany hippocampus‐dependent learning and memory in vivo. Therefore, long‐term synaptic potentiation (LTP) and long‐term depression, which are considered viable substrates of learning and memory, are often experimentally studied in paradigms of patterned high‐frequency (>50 Hz) and low‐frequency (<5 Hz) stimulation. However, the impact of intermediate frequencies on neuronal plasticity remains less well understood. In particular, hippocampal neurons are specifically tuned for activity at θ frequency (4–8 Hz); this band contributes significantly to electroencephalographic signals, and it is likely to be involved in shaping synaptic strength in hippocampal circuits. Here, we review in vitro and in vivo studies showing that variation of θ‐activity duration may affect long‐term modification of synaptic strength and neuronal excitability in the hippocampus. Such θ‐pulse‐induced neuronal plasticity 1) is long‐lasting, 2) may be built on previously stabilized potentiation in the synapse, 3) may produce opposite changes in synaptic strength, and 4) requires complex molecular machinery. Apparently innocuous episodes of low‐frequency synaptic activity may have a profound impact on network signaling, thereby contributing to information processing in the hippocampus and beyond. In addition, θ‐pulse‐induced LTP might be an advantageous protocol in studies of specific molecular mechanisms of synaptic plasticity. © 2015 Wiley Periodicals, Inc.     

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.     

GluN2B‐containing N‐methyl‐D‐aspartate receptors compensate for the inhibitory control of synaptic plasticity during the early critical period in the rat visual cortex

In the visual cortex, synaptic plasticity is very high during the early developmental stage known as the critical period and declines with development after the critical period. Changes in the properties of N‐methyl‐D‐aspartate receptor (NMDAR) and γ‐aminobutyric acid type A receptor (GABA_AR) have been suggested to underlie the changes in the characteristics of plasticity. However, it is largely unknown how the changes in the two receptors interact to regulate synaptic plasticity. The present study investigates the changes in the properties of NMDAR and GABA_AR from 3 to 5 weeks of age in layer 2/3 pyramidal neurons of the rat visual cortex. The impact of these changes on the characteristics of long‐term potentiation (LTP) is also investigated. The amplitude and decay time constant of GABA_AR‐mediated currents increased during this period. However, the decay time constant of NMDAR‐mediated currents decreased as a result of the decrease in the proportion of the GluN2B subunit‐mediated component. Induction of NMDAR‐dependent LTP at 3 weeks depended on the GluN2B subunit, but LTP at 5 weeks did not. Enhancement of GABA_AR‐mediated inhibition suppressed the induction of LTP only at 5 weeks. However, partial inhibition of the GluN2B subunit with a low concentration of ifenprodil allowed the GABA_AR‐mediated suppression of LTP at 3 weeks. These results suggest that changes in the properties of NMDAR‐ and GABA_AR‐mediated synaptic transmission interact to determine the characteristics of synaptic plasticity during the critical period in the visual cortex. © 2015 Wiley Periodicals, Inc.     

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.     

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.