Arturas Volianskis

Episodic memory deficits are not related to altered glutamatergic synaptic transmission and plasticity in the CA1 hippocampus of the APPswe/PS1ΔE9-deleted transgenic mice model of β-amyloidosis

Alzheimers disease (AD) is characterized by progressive memory impairment and the formation of amyloid plaques in the brain. Dysfunctional excitatory synaptic transmission and synaptic plasticity are generally accepted as primary events in the development of AD, and beta-amyloid is intimately involved. Here we describe age related differences in learning, memory, synaptic transmission and long-term potentiation (LTP) in wild type and APPswe/PS1DeltaE9 mice, which produce increasing amounts of Abeta1-42 with age. The mice have both age related and age-independent deficits in radial arm water maze performance. Blind studies of hippocampal slices from transgenic and wild type mice demonstrate that transgenic mice have impaired transient LTP and that the degree of impairment is not related to age from 3 to 12 months. The deficiencies in transient LTP may be related to the behavioral deficits that did not progress with age. The accumulation of beta-amyloid and the episodic memory deficits, both of which increased with age, were not accompanied by an alteration in synaptic transmission or sustained LTP in the in vitro hippocampal slices.

Transient and sustained types of long-term potentiation in the CA1 area of the rat hippocampus

Synaptic potentiation induced by high frequency stimulation was investigated by recording field excitatory postsynaptic potentials (f‐EPSPs) in rat hippocampal slices. Potentiation consisted of a transient period of decaying f‐EPSPs (short‐term potentiation, STP) that led to a plateau of continuously potentiated f‐EPSPs (long‐term potentiation, LTP). Here we show that a previously unknown type of transient, use‐dependent, long‐lasting potentiation (t‐LTP) can account for STP. t‐LTP could be stored for more than 6 h and its decay was caused by synaptic activation. Both the expression and the decay of t‐LTP were input specific. t‐LTP was induced differently from conventional LTP in that the amplitude of t‐LTP was dependent upon the stimulation frequency, whereas the magnitude of LTP was dependent on the number of stimuli in the induction train. The decay of t‐LTP could not be prevented by the blockage of glutamate receptors, but was prevented by the blockage of stimulus‐evoked neurotransmitter release, suggesting that t‐LTP is expressed presynaptically. Paired‐pulse stimulation experiments showed that the decay of t‐LTP was mediated by a decrease in the probability of neurotransmitter release. The decline of t‐LTP could be prolonged by the activation of NMDA receptors. Hence, both single and paired‐pulse stimuli prolonged the decline of the t‐LTP. This decline could be prevented by high frequency burst stimulation (200 Hz). We conclude that t‐LTP allows dynamic modulation of synaptic transmission by providing not only spatial association but also temporal convergence between synaptic inputs. Therefore, t‐LTP might be a substrate for the encoding of synaptic memory.

Long-term potentiation and the role of N-methyl-D-aspartate receptors.

N-methyl-d-aspartate receptors (NMDARs) are known for their role in the induction of long-term potentiation (LTP). Here we start by reviewing the early evidence for their role in LTP at CA1 synapses in the hippocampus. We then discuss more recent evidence that NMDAR dependent synaptic plasticity at these synapses can be separated into mechanistically distinct components. An initial phase of the synaptic potentiation, which is generally termed short-term potentiation (STP), decays in an activity-dependent manner and comprises two components that differ in their kinetics and NMDAR subtype dependence. The faster component involves activation of GluN2A and GluN2B subunits whereas the slower component involves activation of GluN2B and GluN2D subunits. The stable phase of potentiation, commonly referred to as LTP, requires activation of primarily triheteromeric NMDARs containing both GluN2A and GluN2B subunits. In new work, we compare STP with a rebound potentiation (RP) that is induced by NMDA application and conclude that they are different phenomena. We also report that NMDAR dependent long-term depression (NMDAR-LTD) is sensitive to a glycine site NMDAR antagonist. We conclude that NMDARs are not synonymous for either LTP or memory. Whilst important for the induction of LTP at many synapses in the CNS, not all forms of LTP require the activation of NMDARs. Furthermore, NMDARs mediate the induction of other forms of synaptic plasticity and are important for synaptic transmission. It is, therefore, not possible to equate NMDARs with LTP though they are intimately linked. This article is part of a Special Issue entitled SI: Brain and Memory.

NMDA receptor-dependent long-term potentiation comprises a family of temporally overlapping forms of synaptic plasticity that are induced by different patterns of stimulation.

N-methyl-d-aspartate receptor (NMDAR)-dependent long-term potentiation (LTP) is extensively studied since it is believed to use the same molecular mechanisms that are required for many forms of learning and memory. Unfortunately, many controversies exist, not least the seemingly simple issue concerning the locus of expression of LTP. Here, we review our recent work and some of the extensive literature on this topic and present new data that collectively suggest that LTP can be explained, during its first few hours, by the coexistence of at least three mechanistically distinct processes that are all triggered by the synaptic activation of NMDARs.

A novel anti-epileptic agent, perampanel, selectively inhibits AMPA receptor-mediated synaptic transmission in the hippocampus

Perampanel is a non-competitive AMPA receptor antagonist that is under development as an anti-epileptic therapy. Although it is known to reduce calcium flux mediated by AMPA receptors in cultured cortical neurons, there are no studies of its selectivity in synaptic transmission in more intact systems. In the present study using hippocampal slices, perampanel (0.01-10 μM) has been tested on pharmacologically isolated synaptic responses mediated by AMPA, NMDA or kainate receptors. Perampanel reduced AMPA receptor-mediated excitatory postsynaptic field potentials (f-EPSPs) with an IC(50) of 0.23 μM and a full block at 3 μM. This compares with an IC(50) of 7.8 μM for GYKI52466 on these responses. By contrast, perampanel at 10 μM had no effect on responses mediated by NMDA or kainate receptors, which were completely blocked by 30 μM D-AP5 and 10 μM NBQX respectively. The concentrations of perampanel required to reduce AMPA receptor-mediated responses are not dissimilar to those in plasma following anti-convulsant doses and are consistent with AMPA receptor antagonism being its primary mode of action.

Different NMDA receptor subtypes mediate induction of long-term potentiation and two forms of short-term potentiation at CA1 synapses in rat hippocampus in vitro.

N‐Methyl‐d‐aspartate receptor (NMDAR)‐dependent potentiation of synaptic transmission is widely accepted as a cellular model of learning and memory. It is most often studied in the CA1 area of rat hippocampal slices where it comprises a decremental and a sustained phase, which are commonly referred to as short‐term potentiation (STP) and long‐term potentiation (LTP), respectively. In this study we show for the first time that STP and LTP are triggered by the activation of different classes of NMDARs and that STP itself comprises two pharmacologically and kinetically distinct components. We suggest that the mechanistic separation of STP and LTP is likely to have important functional implications in that these two forms of synaptic plasticity can subserve unique physiological functions in a behaving animal.

The roles of STP and LTP in synaptic encoding

Long-term potentiation (LTP), a cellular model of learning and memory, is generally regarded as a unitary phenomenon that alters the strength of synaptic transmission by increasing the postsynaptic response to the release of a quantum of neurotransmitter. LTP, at CA3-CA1 synapses in the hippocampus, contains a stimulation-labile phase of short-term potentiation (STP, or transient LTP, t-LTP) that decays into stable LTP. By studying the responses of populations of neurons to brief bursts of high-frequency afferent stimulation before and after the induction of LTP, we found that synaptic responses during bursts are potentiated equally during LTP but not during STP. We show that STP modulates the frequency response of synaptic transmission whereas LTP preserves the fidelity. Thus, STP and LTP have different functional consequences for the transfer of synaptic information.

Coumarin-3-carboxylic acid derivatives as potentiators and inhibitors of recombinant and native N-methyl-D-aspartate receptors.

N-Methyl-d-aspartate receptors (NMDARs) are known to be involved in a range of neurological and neurodegenerative disorders and consequently the development of compounds that modulate the function of these receptors has been the subject of intense interest. We have recently reported that 6-bromocoumarin-3-carboxylic acid (UBP608) is a negative allosteric modulator with weak selectivity for GluN2A-containing NMDARs. In the present study, a series of commercially available and newly synthesized coumarin derivatives have been evaluated in a structure-activity relationship (SAR) study as modulators of recombinant NMDAR activity. The main conclusions from this SAR study were that substituents as large as iodo were accommodated at the 6-position and that 6,8-dibromo or 6,8-diiodo substitution of the coumarin ring enhanced the inhibitory activity at NMDARs. These coumarin derivatives are therefore excellent starting points for the development of more potent and GluN2 subunit selective inhibitors, which may have application in the treatment of a range of neurological disorders such as neuropathic pain, epilepsy and depression. Surprisingly, 4-methyl substitution of UBP608 to give UBP714, led to conversion of the inhibitory activity of UBP608 into potentiating activity at recombinant GluN1/GluN2 receptors. UBP714 also enhanced NMDAR mediated field EPSPs in the CA1 region of the hippocampus. UBP714 is therefore a novel template for the development of potent and subunit selective NMDAR potentiators that may have therapeutic applicability in the treatment of patients with cognitive deficits or schizophrenia.

Multiple roles of GluN2B-containing NMDA receptors in synaptic plasticity in juvenile hippocampus

ABSTRACT In the CA1 area of the hippocampus N‐methyl‐d‐aspartate receptors (NMDARs) mediate the induction of long‐term depression (LTD), short‐term potentiation (STP) and long‐term potentiation (LTP). All of these forms of synaptic plasticity can be readily studied in juvenile hippocampal slices but the involvement of particular NMDAR subunits in the induction of these different forms of synaptic plasticity is currently unclear. Here, using NVP‐AAM077, Ro 25–6981 and UBP145 to target GluN2A‐, 2B‐ and 2D‐containing NMDARs respectively, we show that GluN2B‐containing NMDARs (GluN2B) are involved in the induction of LTD, STP and LTP in slices prepared from P14 rat hippocampus. A concentration of Ro (1 &mgr;M) that selectively blocks GluN2B‐containing diheteromers is able to block LTD. It also inhibits a component of STP without affecting LTP. A higher concentration of Ro (10 &mgr;M), that also inhibits GluN2A/B triheteromers, blocks LTP. UBP145 selectively inhibits the Ro‐sensitive component of STP whereas NVP inhibits LTP. These data are consistent with a role of GluN2B diheretomers in LTD, a role of both GluN2B‐ and GluN2D‐ containing NMDARs in STP and a role of GluN2A/B triheteromers in LTP. This article is part of the Special Issue entitled ‘Ionotropic glutamate receptors’. HIGHLIGHTSInhibition of GluN2Bs in P14 is sufficient for blockade of NMDAR‐LTD.GluN2A and GluN2D subunits are not required for the induction of LTD.Induction of STP involves GluN2B and GluN2D subunits.Induction of LTP depends on GluN2A/2B triheteromers.

Differential ability of the dorsal and ventral rat hippocampus to exhibit group I metabotropic glutamate receptor–dependent synaptic and intrinsic plasticity:

Background: The hippocampus is critically involved in learning and memory processes. Although once considered a relatively homogenous structure, it is now clear that the hippocampus can be divided along its longitudinal axis into functionally distinct domains, responsible for the encoding of different types of memory or behaviour. Although differences in extrinsic connectivity are likely to contribute to this functional differentiation, emerging evidence now suggests that cellular and molecular differences at the level of local hippocampal circuits may also play a role. Methods: In this study, we have used extracellular field potential recordings to compare basal input/output function and group I metabotropic glutamate receptor-dependent forms of synaptic and intrinsic plasticity in area CA1 of slices taken from the dorsal and ventral sectors of the adult rat hippocampus. Results: Using two extracellular electrodes to simultaneously record field EPSPs and population spikes, we show that dorsal and ventral hippocampal slices differ in their basal levels of excitatory synaptic transmission, paired-pulse facilitation, and EPSP-to-Spike coupling. Furthermore, we show that slices taken from the ventral hippocampus have a greater ability than their dorsal counterparts to exhibit long-term depression of synaptic transmission and EPSP-to-Spike potentiation induced by transient application of the group I mGluR agonist (RS)-3,5-dihydroxyphenylglycine. Conclusions: Together, our results provide further evidence that the information processing properties of local hippocampal circuits differ in the dorsal and ventral hippocampal sectors, and that these differences may in turn contribute to the functional differentiation that exists along the hippocampal longitudinal axis.