Synaptic Plasticity at Hippocampal Synapses: Experimental Background

British Journal of Pharmacology (2003) 140, 781–789. doi:10.1038/sj.bjp.0705466

Behavioural experience (e.g. chronic stress, environmental enrichment) can have long-lasting effects on cognitive functions. Because activity-dependent persistent changes in synaptic strength are believed to mediate memory processes in brain areas such as hippocampus, we tested whether behaviour has also long-lasting effects on synaptic plasticity by examining the induction of long-term potentiation (LTP) and long-term depression (LTD) in slices of hippocampal CA1 obtained from rats either 7-9 months after social defeat (behavioural stress) or 3-5 weeks after 5-week exposure to environmental enrichment. Compared with age-matched controls, defeated rats showed markedly reduced LTP. LTP was even completely impaired but LTD was enhanced in defeated and, subsequently, individually housed (during the 7-9-month period after defeat) rats. However, increasing stimulus intensity during 100-Hz stimulation resulted in significant LTP. This suggests that the threshold for LTP induction is still raised and that for LTD lowered several months after a short stressful experience. Both LTD and LTP were enhanced in environmentally enriched rats, 3-5 weeks after enrichment, as compared with age-matched controls. Because enrichment reduced paired-pulse facilitation, an increase in presynaptic release, facilitating both LTD and LTP induction, might contribute to enhanced synaptic changes. Consistently, enrichment reduced the number of 100-Hz stimuli required for inducing LTP. But enrichment may also actually enhance the range of synaptic modification. Repeated LTP and LTD induction produced larger synaptic changes in enriched than in control rats. These data reveal that exposure to very different behavioural experiences can produce long-lasting effects on the susceptibility to synaptic plasticity, involving pre- and postsynaptic processes.

The postsynaptic density protein PSD-95 influences synaptic AMPA receptor (AMPAR) content and may play a critical role in LTD. Here we demonstrate that the effects of PSD-95 on AMPAR-mediated synaptic responses and LTD can be dissociated. Our findings suggest that N-terminal-domain-mediated dimerization is important for PSD-95's effect on basal synaptic AMPAR function, whereas the C-terminal SH(3)-GK domains are also necessary for localizing PSD-95 to synapses. We identify PSD-95 point mutants (Q15A, E17R) that maintain PSD-95's influence on basal AMPAR synaptic responses yet block LTD. These point mutants increase the proteolysis of PSD-95 within its N-terminal domain, resulting in a C-terminal fragment that functions as a dominant negative likely by scavenging critical signaling proteins required for LTD. Thus, the C-terminal portion of PSD-95 serves a dual function. It is required to localize PSD-95 at synapses and as a scaffold for signaling proteins that are required for LTD.

A Positive Feedback Signal Transduction Loop Determines Timing of Cerebellar Long-Term Depression

Metaplasticity of Hypothalamic Synapses following In Vivo Challenge

We reported previously that orphanin FQ (OFQ) inhibited NMDA receptor-mediated synaptic currents and consequently suppressed induction of long-term potentiation (LTP) in the hippocampal dentate gyrus. This study examines the effect of OFQ on several other forms of long-term synaptic plasticity in the lateral perforant path of mouse hippocampal dentate gyrus. (1) Long-term depression (LTD): a low frequency stimulation (1 Hz, 15 min) applied to the lateral perforant path induced a long-lasting reduction in the dentate field potentials in slices from 22- to 30-day-old mice. This LTD was sensitive to the NMDA receptor blocker D-AP5, and could be significantly attenuated by bath application of OFQ (1 microM, 25 min). (2) Primed LTD: induction of LTD in slices from 50- to 65-day-old mice required a priming procedure consisting of multiple high frequency stimulus trains delivered in the presence of D-AP5 before the low-frequency stimulation. OFQ applied during the low-frequency stimulation, but not during the priming trains, blocked induction of primed LTD. (3) Depotentiation: high-frequency train-induced dentate LTP could be reversed by a subsequent low-frequency stimulation. This depotentiation was also attenuated by either OFQ or D-AP5 applied during low-frequency stimulation. These results, together with our previous findings, suggest that OFQ inhibits bidirectional changes in synaptic strength in the dentate; and its multiple actions on NMDA receptor-dependent, long-term synaptic plasticity might work in tandem to regulate hippocampus-dependent learning and memory.

Hippocampal synaptic plasticity, in the form of long-term potentiation (LTP) and long-term depression (LTD), enables spatial memory formation, whereby LTP and LTD are likely to contribute different elements to the resulting spatial representation. Dopamine, released from the ventral tegmental area particularly under conditions of reward, acts on the hippocampus, and may specifically influence the encoding of information into long-term memory. The dentate gyrus (DG), as the "gateway" to the hippocampus is likely to play an important role in this process. D1/D5 dopamine receptors are importantly involved in the regulation of synaptic plasticity thresholds in the CA1 region of the hippocampus and determine the direction of change in synaptic strength that occurs during novel spatial learning. Here, we explored whether D1/D5-receptors influence LTD that is induced in the DG following patterned afferent stimulation of the perforant path of freely behaving adult rats, or influence LTD that occurs in association with spatial learning. We found that LTD that is induced by afferent stimulation, and LTD that is facilitated by learning about novel landmark configurations, were both prevented by D1/D5-receptor antagonism, whereas agonist activation of the D1/D5-receptor had no effect on basal tonus or short-term depression. Other studies have reported that in the DG, D1/D5-receptor agonism or antagonism do not affect LTP, but agonism prevents depotentiation. These findings suggest that the dopaminergic system, acting via D1/D5-receptors, influences information gating by the DG and modulates the direction of change in synaptic strength that underlies information storage in this hippocampal substructure. Information encoded by robust forms of LTD is especially dependent on D1/D5-receptor activation. Thus, dopamine acting on D1/D5-receptors is likely to support specific experience-dependent encoding, and may influence the content of hippocampal representations of experience.

An Essential Role for PICK1 in NMDA Receptor-Dependent Bidirectional Synaptic Plasticity

ATP hydrolysis is required for the rapid regulation of AMPA receptors during basal synaptic transmission and long-term synaptic plasticity

Spike bursting is an important physiological mode of the hippocampus. Whereas the rules of spike timing-dependent synaptic plasticity are well defined for pairs of single action potentials (APs) and excitatory postsynaptic potentials (EPSPs), long-term modification of synaptic responses is much less understood for more complex pre- and postsynaptic spike patterns. We induced a burst stimulation (BS)-associated form of synaptic plasticity in rat CA1 hippocampal slices by repeatedly pairing three EPSPs with a burst of APs induced by postsynaptic current injection. In distinct groups of cells, this induction paradigm resulted in long-term potentiation (LTP), long-term depression (LTD) or no change in synaptic strength. LTP was N-methyl-d-aspartate receptor-dependent, whereas LTD could be blocked by a metabotropic glutamate receptor antagonist or inhibition of Ca(2+) influx through voltage-activated Ca(2+) channels. LTP was predicted by a more depolarized membrane potential and a higher initial AP frequency. LTD was facilitated by a larger time interval between the last EPSP and its preceding AP. We conclude from these findings that associative BS induces a bidirectional form of long-term synaptic plasticity that cannot be fully explained by spike timing rules. Postsynaptic membrane potential and Ca(2+) influx further influence the sign and magnitude of synaptic modification. LTP and LTD have distinct mechanisms and can be selectively modulated. This supports the concept of two independent coincidence detectors for LTP and LTD, and extends the physiological options to modulate synaptic plasticity and maintain a putative balance between potentiation and depression in synaptic networks.

Long-term potentiation (LTP) and long-term depression (LTD) are activity-dependent changes in synaptic strength that may serve as the cellular mechanisms of information storage in the vertebrate brain. The mossy fibre-CA3 synapse displays NMDA (M-methyl-D-aspartate) receptor-independent forms of LTP and LTD that were thought to be non-associative. Here we report that the mossy fibre-CA3 synapse displays each of the known types of LTD in vivo, including associative, heterosynaptic and homosynaptic LTD. These types of LTD are induced when only two of the three conditions necessary for mossy fibre LTP induction are provided. Because some of these conditions can be provided by convergent CA3 afferents, each type of LTD can be induced in an associative manner, which suggests that LTD is involved in associative information storage. Similar to the induction of NMDA receptor-dependent LTD and LTP at other cortical synapses, mossy fibre LTD occurs when synaptic conditions are insufficient to induce LTP, and both LTP and LTD induction are influenced by previous synaptic activity, consistent with the view that common principles govern activity-dependent plasticity at cortical synapses.

The synaptic phenomena of long-term potentiation (LTP) and long-term depression (LTD) have been intensively studied for over twenty-five years. Although many diverse aspects of these forms of plasticity have been observed, no single theory has offered a unifying explanation for them. Here, a statistical "bin" model is proposed to account for a variety of features observed in LTP and LTD experiments performed with field potentials in mammalian cortical slices. It is hypothesized that long-term synaptic changes will be induced when statistically unlikely conjunctions of pre- and postsynaptic activity occur. This hypothesis implies that finite changes in synaptic strength will be proportional to information transmitted by conjunctions and that excitatory synapses will obey a Hebbian rule (Hebb, 1949). Using only one set of constants, the bin model offers an explanation as to why synaptic strength decreases in a decelerating manner during LTD induction (Mulkey & Malenka, 1992); why the induction protocols for LTP and LTD are asymmetric (Dudek & Bear, 1992; Mulkey & Malenka, 1992); why stimulation over a range of frequencies produces a frequency-response curve similar to that proposed by the BCM theory (Bienenstock, Cooper, & Munro, 1982; Dudek & Bear, 1992); and why this curve would shift as postsynaptic activity is changed (Kirkwood, Rioult, & Bear, 1996). In addition, the bin model offers an alternative to the BCM theory by predicting that changes in postsynaptic activity will produce vertical shifts in the curve rather than merely horizontal shifts.

Event Abstract Back to Event Locus coeruleus and beta-adrenoreceptor-mediated regulation of synaptic plasticity and learning in the hippocampus Denise Manahan-Vaughan1* 1 Ruhr University, Department of Experimental Neurophysiology, Germany Spatial memory formation is believed to occur by means of synaptic information processing, in the form of persistent strengthening and weakening of synapses, within the hippocampus. Long-term potentiation (LTP) and long-term depression (LTD) that last for hours, days and weeks are favoured candidate mechanisms that underlie long-term memory. The hippocampus receives a vast amount of sensory information, which must be filtered, prioritised and appropriately processed into information that is irrelevant, or relevant for storage in the form of short- or long-term memories. Our recent data suggest that the locus coeruleus may be particularly important in providing the saliency signal required to promote hippocampal encoding of relevant information through changes in synaptic strength. Coupling of hippocampal stimulation, that normally does not elicit changes in synaptic strength, with activation of the locus coeruleus, thus results in LTD at CA1 Stratum radiatum synapses in freely behaving adult rats [1]. Microdialysis revealed that locus coeruleus stimulation resulted in elevations of noradrenalin in the hippocampus. Application of a ß-adrenergic receptor antagonist prevented the expression of CA1 LTD following locus coeruleus stimulation. We additionally found that learning of a spatial task was enhanced by locus coeruleus stimulation, and that effects were also prevented by application of a ß-adrenergic receptor antagonist (Lemon et al, 2009).Independently of locus coeruleus stimulation, we found very pronounced effects of ß-adrenergic receptor antagonism effects on learning –facilitated plasticity in the hippocampus. Exploration of a novel environment facilitated LTP in the CA1 region, whereas exploration of novel spatial object constellations facilitated LTD [2]. Both phenomena were prevented by application of an antagonist of ß-adrenergic receptors Our results demonstrate that the locus coeruleus plays a key role in the induction of hippocampal LTD and in promoting the encoding of spatial information. This locus coeruleus -hippocampal interaction may reflect a means by which salient information is distinguished for subsequent synaptic processing. The ß-adrenergic receptor plays a critical role in mediated these, and other plasticity-related information encoding events in the hippocampus.

Long-term depression (LTD), a key form of synaptic plasticity, is typically induced through regulated Ca2+ entry via NMDA receptors and achieved by prolonged (up to hundreds of seconds) low-frequency presynaptic stimulation or bath application of NMDA receptor agonists. Electrophysiological approach to LTD induction requires specialized equipment, while bath applications limit productivity, as only one neuron per sample may be recorded. Here, we present a simple and effective protocol for pharmacological modeling of LTD in primary cultured neurons. This approach relies on highly localized iontophoretic application of NMDA, which induces LTD in individual cells, enhancing experimental throughput. We have analyzed spatio-temporal patterns of iontophoretic drug delivery and demonstrated how this technique may be combined with electrophysiological and live-cell imaging approaches to investigate LTD-related changes in synaptic strength and Ca2+-dependent signaling of neuronal Ca2+ sensor proteins. Key features • Easy, fast, and reliable induction of LTD in primary cultured neurons using iontophoretic NMDA application. • Suitable for the application of any ionic water-soluble compound and compatible with simultaneous multicolor fluorescence imaging and electrophysiological recording. • This protocol enables pharmacological targeting of individual neurons, substantially increasing experimental throughput.

The induction of long-term potentiation (LTP) and long-term depression (LTD) at excitatory synapses in the hippocampus can be strongly modulated by patterns of synaptic stimulation that otherwise have no direct effect on synaptic strength. Likewise, patterns of synaptic stimulation that induce LTP or LTD not only modify synaptic strength but can also induce lasting changes that regulate how synapses will respond to subsequent trains of stimulation. Collectively known as metaplasticity, these activity-dependent processes that regulate LTP and LTD induction allow the recent history of synaptic activity to influence the induction of activity-dependent changes in synaptic strength and may thus have an important role in information storage during memory formation. To explore the cellular and molecular mechanisms underlying metaplasticity, we investigated the role of metaplasticity in the induction of LTP by theta-frequency (5-Hz) synaptic stimulation in the hippocampal CA1 region. Our results show that brief trains of theta-frequency stimulation not only induce LTP but also activate a process that inhibits the induction of additional LTP at potentiated synapses. Unlike other forms of metaplasticity, the inhibition of LTP induction at potentiated synapses does not appear to arise from activity-dependent changes in NMDA receptor function, does not require nitric oxide signaling, and is strongly modulated by beta-adrenergic receptor activation. Together with previous findings, our results indicate that mechanistically distinct forms of metaplasticity regulate LTP induction and suggest that one way modulatory transmitters may act to regulate synaptic plasticity is by modulating metaplasticity.