Calcium Channel-Dependent Induction of Long-Term Synaptic Plasticity at Excitatory Golgi Cell Synapses of Cerebellum

Golgi cells, together with granule cells and mossy fibers, form a neuronal microcircuit regulating information transfer at the cerebellum input stage. Despite theoretical predictions, little was known about long-term synaptic plasticity at Golgi cell synapses. Here, we have used whole-cell patch-clamp recordings and calcium imaging to investigate long-term synaptic plasticity at excitatory synapses impinging on Golgi cells. In acute mouse cerebellar slices, mossy fiber theta-burst stimulation (TBS) could induce either long-term potentiation (LTP) or long-term depression (LTD) at mossy fiber-Golgi cell and granule cell-Golgi cell synapses. This synaptic plasticity showed a peculiar voltage dependence, with LTD or LTP being favored when TBS induction occurred at depolarized or hyperpolarized potentials, respectively. LTP required, in addition to NMDA channels, activation of T-type Ca²⁺ channels, while LTD required uniquely activation of L-type Ca²⁺ channels. Notably, the voltage dependence of plasticity at the mossy fiber-Golgi cell synapses was inverted with respect to pure NMDA receptor-dependent plasticity at the neighboring mossy fiber-granule cell synapse, implying that the mossy fiber presynaptic terminal can activate different induction mechanisms depending on the target cell. In aggregate, this result shows that Golgi cells show cell-specific forms of long-term plasticity at their excitatory synapses, that could play a crucial role in sculpting the response patterns of the cerebellar granular layer.SIGNIFICANCE STATEMENT This article shows for the first time a novel form of Ca²⁺ channel-dependent synaptic plasticity at the excitatory synapses impinging on cerebellar Golgi cells. This plasticity is bidirectional and inverted with respect to NMDA receptor-dependent paradigms, with long-term depression (LTD) and long-term potentiation (LTP) being favored at depolarized and hyperpolarized potentials, respectively. Furthermore, LTP and LTD induction requires differential involvement of T-type and L-type voltage-gated Ca²⁺ channels rather than the NMDA receptors alone. These results, along with recent computational predictions, support the idea that Golgi cell plasticity could play a crucial role in controlling information flow through the granular layer along with cerebellar learning and memory.     

Relation Between Dendritic Ca2+ Levels and the Polarity of Synaptic Long-term Modifications in Rat Visual Cortex Neurons

Long-term changes of synaptic efficacy, in particular when they are use-dependent, are candidate mechanisms for the storage of information in the nervous system. In a variety of brain structures, including the neocortex and hippocampus, synapses are susceptible to long-term potentiation (LTP) and long-term depression (LTD). It has been hypothesized that the polarity of the synaptic gain change depends on the amplitude of the postsynaptic [Ca²⁺]_i rise, the threshold for the induction of LTD being lower than that for the induction of LTP. To test this assumption, we characterized Ca²⁺ signals in layer II/III pyramidal cells of rat visual cortex slices, using the fluorescent Ca²⁺ indicator fura-2, during application of stimulation protocols that had been adjusted to reliably induce either LTP or LTD in cells not loaded with fura-2. At dendritic sites activated by the stimulated afferents the intracellular [Ca²⁺] concentration ([Ca²⁺]_i) reached higher amplitudes and decayed more slowly with stimuli inducing LTP than with those inducing LTD. To directly analyse the functional significance of the observed difference in the Ca²⁺ signal amplitude, we examined whether a tetanization protocol suitable for the induction of LTP can be converted into a protocol inducing LTD by injecting the postsynaptic cells with Ca²⁺ chelators that reduce the concentration of effective free Ca²⁺. In the presence of fura-2 or BAPTA [bis(2-aminophenoxy) ethane-N,N,N′,N′-tetraacetate], the stimulation protocol that would normally produce LTP induced either LTD or failed to induce synaptic modifications altogether. These results support the hypothesis that the amplitude of the postsynaptic rise in [Ca²⁺]_i is a key factor in the determination of the polarity of synaptic gain change.     

On the Induction of Postsynaptic Granule Cell–Purkinje Neuron LTP and LTD

In the last decade, several experimental studies have demonstrated that particular patterns of synaptic activity can induce postsynaptic parallel fiber (PF) long-term potentiation (LTP). This form of plasticity can reverse postsynaptic PF long-term depression (LTD), which has been traditionally considered as the principal form of plasticity underlying cerebellar learning. Postsynaptic PF-LTP requires a transient increase in intracellular Ca²⁺ concentration and, in contrast to PF-LTD, is induced without concomitant climbing fiber (CF) activation. Thus, it has been postulated that the polarity of long-term synaptic plasticity is determined by the amplitude of the Ca²⁺ transient during the induction protocol, with PF-LTP induced by smaller Ca²⁺ signals without concomitant CF activation. However, this hypothesis is contradicted by recent studies. A quantitative analysis of Ca²⁺ signals associated with induction of PF-LTP indicates that the bidirectional induction of long-term plasticity is regulated by more complex mechanisms. Here we review the state-of-the-art of research on postsynaptic PF-LTP and PF-LTD and discuss the principal open questions on this topic.     

Impact of deviation from precise balance of spike-timing-dependent plasticity.

Recent biological experimental findings have shown that synaptic plasticity depends on the relative timing of pre- and post-synaptic spikes and this is called spike-timing-dependent plasticity (STDP). Many authors have claimed that a precise balance between long-term potentiation (LTP) and long-term depression (LTD) of STDP is crucial in the storage of spatio-temporal patterns. Some authors have numerically investigated the impact of an imbalance between LTP and LTD on the network properties. However, the mathematical mechanism remains unknown. We analytically show that an associative memory network has the robust retrieval properties of spatio-temporal patterns, and these properties make the network less vulnerable to any deviation from a precise balance between LTP and LTD when the network contains a finite number of neurons.     

Biophysical modeling of neural plasticity induced by transcranial magnetic stimulation

Transcranial magnetic stimulation (TMS) is a widely used noninvasive brain stimulation method capable of inducing plastic reorganisation of cortical circuits in humans. Changes in neural activity following TMS are often attributed to synaptic plasticity via process of long-term potentiation and depression (LTP/LTD). However, the precise way in which synaptic processes such as LTP/LTD modulate the activity of large populations of neurons, as stimulated en masse by TMS, are unclear. The recent development of biophysical models, which incorporate the physiological properties of TMS-induced plasticity mathematically, provide an excellent framework for reconciling synaptic and macroscopic plasticity. This article overviews the TMS paradigms used to induce plasticity, and their limitations. It then describes the development of biophysically-based numerical models of the mechanisms underlying LTP/LTD on population-level neuronal activity, and the application of these models to TMS plasticity paradigms, including theta burst and paired associative stimulation. Finally, it outlines how modeling can complement experimental work to improve mechanistic understandings and optimize outcomes of TMS-induced plasticity.     

Relations Between Long-term Synaptic Modifications and Paired-pulse Interactions in the Rat Neocortex

The phenomenon of paired-pulse facilitation (PPF) was exploited to investigate the role of presynaptic mechanisms in the induction and maintenance of long-term synaptic plasticity in the neocortex. Long-term potentiation (LTP) and depression (LTD) were induced without afferent activation by applying tetani of intracellular pulses. Our results show that synaptic modifications closely resembling LTP and LTD can be induced by postsynaptic activation alone. The polarity of these synaptic modifications depends on initial properties of the input, as indicated by a correlation between initial PPF ratio and post-tetanic amplitude changes: inputs exhibiting strong PPF, which might be associated with low release probability tend to be potentiated, while inputs with small PPF are more likely to show depression. Maintenance of both LTP and LTD involve presynaptic mechanisms, as indicated by changes in PPF ratios and in failure rate after LTP or LTD induction. Presynaptic mechanisms could include changes in release probability and/or in the number of active release sites. Because induction was postsynaptic, this supports the notion of a retrograde signal. The relative contribution of pre- and postsynaptic mechanisms in the maintenance of long-term synaptic modifications depends on the initial state of the synaptic input and on LTP magnitude. PPF changes were especially pronounced in inputs which had initially high PPF and underwent strong potentiation. Since LTP and LTD are associated with changes of PPF ratios these synaptic modifications do not only alter the gain but also the temporal properties of synaptic transmission. Because of the LTP associated reduction of PPF, potentiated inputs profit less from temporal summation, favouring transmission of synchronized, low frequency activity.     

Extracellular recordings of rodents in vivo: their contribution to integrative neuroscience

The prevalent theory in learning and memory processes is that they are underlain by short and long-term changes in synaptic weight, which continuously modulates neural networks during acquisition and recall. This synaptic plasticity has been revealed by recording extracellular field potentials. The enhancement of synaptic transmission was primarily noted in the hippocampus and was named long-term potentiation (LTP). The opposite mechanism, long-term depression (LTD), a reduction of synaptic transmission, was first discovered in the cerebellum. Since then, the LTP-model has been studied mainly using in vitro and acute anesthetized in vivo preparations. This approach has led to remarkable progress in the comprehension of intracellular molecular processes during LTP and LTD. In this review, we focus mainly on what we can learn about molecular events using extracellular field potential recordings with a more ecological model, i.e., studies using the freely behaving animal, with animals that are genetically modified or not, in several behavioral paradigms aimed at gaining insight into some of the conflicting results obtained with in vitro and in vivo preparations.     

Long-lasting modulation of the induction of LTD and LTP in rat hippocampal CA1 by behavioural stress and environmental enrichment

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.     

Metabotropic glutamate receptors contribute to neocortical synaptic plasticity in vivo

Metabotropic glutamate receptors (mGluRs) have been shown to be important for hippocampus-dependent memory, as well as activity-dependent synaptic plasticity in the hippocampus. In this study, we examined the role of mGluRs in the induction of two forms of activity-dependent synaptic plasticity, long-term potentiation (LTP) and long-term depression (LTD), in the neocortex of awake, freely-moving rats. The mGluR antagonist AIDA was administered during the induction of LTP or LTD in the motor cortex. There was a 50% reduction of LTP induced in the early component of the evoked response, but there was no effect on the late component and no effect on the induction of LTD. Thus, mGluRs contribute to at least one form of activity dependent synaptic plasticity in the neocortex.     

Induction mechanisms and modulation of bidirectional burst stimulation-induced synaptic plasticity in the hippocampus

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 Ca²⁺ influx through voltage-activated Ca²⁺ 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 Ca²⁺ 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.     

NMDA Receptor-dependent LTD in different subfields of hippocampus in vivo and in vitro

In simulations with artificial neural networks, efficient information processing and storage has been shown to require that the strength of connections between network elements has the capacity to both increase and decrease in a use-dependent manner. In contrast to long-term potentiation (LTP) of excitatory synaptic transmission, activity-dependent long-term depression (LTD) has been difficult to demonstrate in forebrain in vivo. Theoretical arguments indicate that coincidence of presynaptic excitation and low-magnitude postsynaptic activation are the necessary prerequisites for LTD induction. Here we report that stimulation paradigms which cause 1) sufficient excitation to result in NMDA receptor activation and simultaneously 2) attenuate the level of postsynaptic activation by recruitment of GABA_A receptor-mediated inhibition consistently produce LTD of commissural input to area CA1 in the hippocampus of anesthetized adult rats, and of the perforant path input to the dentate gyrus in the hippocampus of anesthetized and unanesthetized adult rabbits. A functionally similar pre- and postsynaptic activation pattern applied to the hippocampal slice preparation by injecting hyperpolarizing current into the postsynaptic cell during NMDA receptor-mediated excitation also was effective in consistently inducing LTD. Results of studies in vitro show that Ca²⁺ influx through the NMDA channel is necessary for the induction of LTD, and moreover, that NMDA receptors also participate in the expression of LTD. Our findings demonstrate a general mechanism for the implementation of a theoretically derived learning rule in adult forebrain in vivo and in vitro and provide justification for the inclusion of use-dependent decreases of connection weights in formal models of cognitive processing. © 1996 Wiley-Liss, Inc.     

Distinct mechanisms of bidirectional activity-dependent synaptic plasticity in superficial and deep layers of rat entorhinal cortex

The entorhinal cortex plays a key role in processing memory information in the brain; superficial layers relay information to, and deep layers receive information from, the hippocampus. The cellular mechanisms of memory are thought to include a number that produce long-term potentiation (LTP) and depression (LTD) of synaptic strength. Our work presents evidence that LTP and LTD occur simultaneously at memory-relevant synapses. We report here that low frequency stimulation generates NMDA receptor-dependent LTD in Wistar rat superficial (layers II and III), and LTP in the deep entorhinal cortex layers (layers V and VI). LTP in deep layers is masked by simultaneously occurring voltage-gated calcium channel-dependent LTD. Our data support a novel mechanism for the sliding-threshold (BCM) model of synaptic plasticity: The sliding thresholds for induction of LTP and LTD in entorhinal cortex deep layers will be driven by the relative activation state of NMDA receptors and voltage-gated calcium channels. The co-expression of LTD and LTP at presynaptic sites in the entorhinal cortex deep layers reveals an intriguing mechanism for differential processing of synaptic information, which may underlie the vast dynamic capacity for information storage by this cortical structure.     

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.     

Permissive role of interneurons in corticostriatal synaptic plasticity

Two different forms of synaptic plasticity have been found at corticostriatal synapses: long-term depression (LTD) and long-term potentiation (LTP). Both these enduring changes in the efficacy of excitatory neurotransmission in the striatum have a major impact on the physiological activity of the basal ganglia and are triggered by the stimulation of complex and independent cascades of intracellular second messenger systems. Striatal LTD and LTP are evoked following the repetitive stimulation of corticostriatal fibers and are dependent on the glutamate ionotropic receptor subtype activated. Recent experimental evidence indicates that two different subtypes of interneurons attend in the correct processing of information flow arising from the cortex and leading to striatal LTD or LTP. Acetylcholine (Ach) and nitric oxide (NO) producing striatal interneurons, in fact, are activated by the cortex during the induction phase of striatal plasticity, and stimulate, in turn, the intracellular changes in projection neurons required for LTD or LTP. Interneurons, therefore, exerts a feed-forward control of the excitability of striatal projection neurons ensuring the coordinate expression of two alternative forms of synaptic plasticity at the same type of excitatory synapse.     

Interleukin-1β Promotes Long-Term Potentiation in Patients with Multiple Sclerosis

The immune system shapes synaptic transmission and plasticity in experimental autoimmune encephalomyelitis (EAE), the mouse model of multiple sclerosis (MS). These synaptic adaptations are believed to drive recovery of function after brain lesions, and also learning and memory deficits and excitotoxic neurodegeneration; whether inflammation influences synaptic plasticity in MS patients is less clear. In a cohort of 59 patients with MS, we found that continuous theta-burst transcranial magnetic stimulation did not induce the expected long-term depression (LTD)-like synaptic phenomenon, but caused persisting enhancement of brain cortical excitability. The amplitude of this long-term potentiation (LTP)-like synaptic phenomenon correlated with the concentration of the pro-inflammatory cytokine interleukin-1β (IL-1β) in the cerebrospinal fluid. In MS and EAE, the brain and spinal cord are typically enriched of CD3⁺ T lymphocyte infiltrates, which are, along with activated microglia and astroglia, a major cause of inflammation. Here, we found a correlation between the presence of infiltrating T lymphocytes in the hippocampus of EAE mice and synaptic plasticity alterations. We observed that T lymphocytes from EAE, but not from control mice, release IL-1β and promote LTP appearance over LTD, thereby mimicking the facilitated LTP induction observed in the cortex of MS patients. EAE-specific T lymphocytes were able to suppress GABAergic transmission in an IL-1β-dependent manner, providing a possible synaptic mechanism able to lower the threshold of LTP induction in MS brains. Moreover, in vivo blockade of IL-1β signaling resulted in inflammation and synaptopathy recovery in EAE hippocampus. These data provide novel insights into the pathophysiology of MS.     

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.     

Long-term depression: multiple forms and implications for brain function

Long-term potentiation (LTP) and long-term depression (LTD) remain widely accepted vertebrate models for the cellular and molecular mechanisms that underlie synaptic changes during learning and memory. Although LTD is a phenomenon that occurs in many regions of the CNS, it is clear that the mechanisms recruited in its induction and expression can vary, depending on many factors, including brain region and developmental time point. LTD in the hippocampus and cerebellum is probably the best characterized, although there are also other brain areas where mechanisms of LTD are well understood, and where it is thought to have a functional role.     

Homosynaptic LTD and depotentiation: Do they differ in name only?

Long-term depression (LTD) now occupies a major place in theories of the cellular basis of learning and memory and other nervous system phenomena involving persistent changes in synaptic responsiveness. LTD can be induced using a variety of stimulation paradigms. Homosynaptic LTD in this review refers to a depression of basal responses that is restricted to the pathway that has been stimulated by a low-frequency (1 Hz) stimulus train. Despite the intensive interest in LTD, there has been controversy about the ease with which LTD can be induced and reports range from no success to routine success. There has been much less controversy about a related form of response depression now called “depotentiation” which shares many similarities with LTD. Depotentiation is the response reduction that affects, not the basal responses affected by LTD, but responses that have been increased by the process of long-term potentiation (LTP). LTD and depotentiation can be induced by similar stimulation and have many biochemical properties in common, but it has not been clear whether or not they represent the same phenomenon, in part because it often occurs that the same preparation that does not undergo LTD readily expresses depotentiation. We review work that indicates that the major differences between LTD and depotentiation involve age-dependence, the need for priming stimulation and sensitivity to GABA receptor antagonists. We present a hypothetical model that can reconcile the apparent disparities between LTD and de-potentiation. © 1996 Wiley-Liss, Inc.