Forms Of Synaptic Plasticity Research Articles

CaMKII: the Swiss army knife of synaptic plasticity

CaMKII: the Swiss army knife of synaptic plasticity

Distinct subsynaptic localization of type 1 metabotropic glutamate receptors at glutamatergic and GABAergic synapses in the rodent cerebellar cortex.

Type 1 metabotropic glutamate (mGlu1) receptors play a pivotal role in different forms of synaptic plasticity in the cerebellar cortex, e.g. long-term depression at glutamatergic synapses and rebound potentiation at GABAergic synapses. These various forms of plasticity might depend on the subsynaptic arrangement of the receptor in Purkinje cells that can be regulated by protein-protein interactions. This study investigated, by means of the freeze-fracture replica immunogold labelling method, the subcellular localization of mGlu1 receptors in the rodent cerebellum and whether Homer proteins regulate their subsynaptic distribution. We observed a widespread extrasynaptic localization of mGlu1 receptors and confirmed their peri-synaptic enrichment at glutamatergic synapses. Conversely, we detected mGlu1 receptors within the main body of GABAergic synapses onto Purkinje cell dendrites. Although Homer proteins are known to interact with the mGlu1 receptor C-terminus, we could not detect Homer3, the most abundant Homer protein in the cerebellar cortex, at GABAergic synapses by pre-embedding and post-embedding immunoelectron microscopy. We then hypothesized a critical role for Homer proteins in the peri-junctional localization of mGlu1 receptors at glutamatergic synapses. To disrupt Homer-associated protein complexes, mice were tail-vein injected with the membrane-permeable dominant-negative TAT-Homer1a. Freeze-fracture replica immunogold labelling analysis showed no significant alteration in the mGlu1 receptor distribution pattern at parallel fibre-Purkinje cell synapses, suggesting that other scaffolding proteins are involved in the peri-synaptic confinement. The identification of interactors that regulate the subsynaptic localization of the mGlu1 receptor at neurochemically distinct synapses may offer new insight into its trafficking and intracellular signalling.

Opposite regulation of inhibitory synaptic plasticity by α and β subunits of Ca(2+)/calmodulin-dependent protein kinase II.

Induction of several forms of synaptic plasticity, a cellular basis for learning and memory, depends on the activation of Ca(2+)/calmodulin (CaM)-dependent protein kinase II (CaMKII). CaMKII acts as a holoenzyme consisting of α and β subunits (α- and βCaMKII). However, it remains elusive how the subunit composition of a CaMKII holoenzyme affects its activation and hence synaptic plasticity. We addressed this issue by focusing on long-term potentiation (LTP) at inhibitory synapses on cerebellar Purkinje neurons (PNs) (called rebound potentiation, RP). The contribution of each subunit to RP was examined by selective knock-down or overexpression of that subunit. Electrophysiological recording from a rat cultured PN demonstrated that βCaMKII is essential for RP induction, whereas αCaMKII suppresses it. Thus, RP was negatively regulated due to the greater relative abundance of αCaMKII compared to βCaMKII, suggesting a critical role of CaMKII subunit composition in RP. The higher affinity of βCaMKII to Ca(2+)/CaM compared with αCaMKII was responsible for the predominant role in RP induction. Live-cell imaging of CaMKII activity based on the Förster resonance energy transfer (FRET) technique revealed that βCaMKII enrichment enhances the total CaMKII activation upon a transient conditioning depolarization. Taken together, these findings clarified that α- and βCaMKII oppositely regulate CaMKII activation, controlling the induction of inhibitory synaptic plasticity in a PN, which might contribute to the adaptive information processing of the cerebellar cortex.

Neuronal activity induces synaptic delivery of hnRNP A2/B1 by a BDNF-dependent mechanism in cultured hippocampal neurons.

Dendritic protein synthesis plays a critical role in several forms of synaptic plasticity, including BDNF (brain-derived neurotrophic factor)-mediated long-term synaptic potentiation (LTP). Dendritic transcripts are typically transported in a repressed state as components of large ribonucleoprotein complexes, and then translated upon stimulation at, or in the vicinity, of activated synapses. Heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNP A2/B1) is a trans-acting factor involved in dendritic mRNA trafficking, but how the distribution of the protein in dendrites is regulated has not been characterized. Here we found that a fraction of hnRNP A2/B1 is present at the synapse under resting conditions in cultured hippocampal neurons. Accordingly, this ribonucleoprotein was detected in free mRNP, monosomal, and polyribosomal fractions obtained from synaptoneurosomes. Neuronal activity and BDNF treatment increased hnRNP A2/B1 protein levels in the cell body and dendritic compartments, and induced the delivery of this protein to synaptic sites. The activity-dependent accumulation of hnRNP A2/B1 at the synapse required, at least in part, the activation of TrkB receptors, presumably by BDNF. This neurotrophin also upregulated the hnRNP A2/B1 mRNA in the soma but was without effect on the abundance of neuritic hnRNP A2/B1 transcripts. These results show that the distribution of hnRNP A2/B1 is regulated by BDNF and by neuronal activity, an effect that may have a role in BDNF-induced synaptic plasticity events.

Functional Effects of a Pathogenic Mutation in Cereblon (CRBN) on the Regulation of Protein Synthesis via the AMPK-mTOR Cascade

Initially identified as a protein implicated in human mental deficit, cereblon (CRBN) was recently recognized as a negative regulator of adenosine monophosphate-activated protein kinase (AMPK) in vivo and in vitro. Here, we present results showing that CRBN can effectively regulate new protein synthesis through the mammalian target of rapamycin (mTOR) signaling pathway, a downstream target of AMPK. Whereas deficiency of Crbn repressed protein translation via activation of the AMPK-mTOR cascade in Crbn-knock-out mice, ectopic expression of the wild-type CRBN increased protein synthesis by inhibiting endogenous AMPK. Unlike the wild-type CRBN, a mutant CRBN found in human patients, which lacks the last 24 amino acids, failed to rescue mTOR-dependent repression of protein synthesis in Crbn-deficient mouse fibroblasts. These results provide the first evidence that Crbn can activate the protein synthesis machinery through the mTOR signaling pathway by inhibiting AMPK. In light of the fact that protein synthesis regulated by mTOR is essential for various forms of synaptic plasticity that underlie the cognitive functions of the brain, the results of this study suggest a plausible mechanism for CRBN involvement in higher brain function in humans, and they may help explain how a specific mutation in CRBN can affect the cognitive ability of patients.

Interplay between short- and long-term plasticity in cell-assembly formation.

Various hippocampal and neocortical synapses of mammalian brain show both short-term plasticity and long-term plasticity, which are considered to underlie learning and memory by the brain. According to Hebb’s postulate, synaptic plasticity encodes memory traces of past experiences into cell assemblies in cortical circuits. However, it remains unclear how the various forms of long-term and short-term synaptic plasticity cooperatively create and reorganize such cell assemblies. Here, we investigate the mechanism in which the three forms of synaptic plasticity known in cortical circuits, i.e., spike-timing-dependent plasticity (STDP), short-term depression (STD) and homeostatic plasticity, cooperatively generate, retain and reorganize cell assemblies in a recurrent neuronal network model. We show that multiple cell assemblies generated by external stimuli can survive noisy spontaneous network activity for an adequate range of the strength of STD. Furthermore, our model predicts that a symmetric temporal window of STDP, such as observed in dopaminergic modulations on hippocampal neurons, is crucial for the retention and integration of multiple cell assemblies. These results may have implications for the understanding of cortical memory processes.

LTD expression is independent of glutamate receptor subtype.

Long-term depression (LTD) is a form of synaptic plasticity that plays a major role in the activity-dependent reshaping of synaptic transmission. LTD is expressed as a decrease in synaptic AMPA receptor number, though the exact mechanism remains controversial. Several lines of evidence have suggested necessary roles for both the GluA1 and GluA2 subunits, and specifically certain interactions with their cytoplasmic tails. However, it is unclear if either GluA1 or GluA2 are absolutely required for LTD. We tested this hypothesis using constitutive knock-outs and single-cell molecular replacement of AMPA receptor subunits in mouse hippocampus. We found that neither GluA1 or GluA2 are required for normal expression of LTD, and indeed a normal decrease in synaptic transmission was observed in cells in which all endogenous AMPA receptors have been replaced by kainate receptors. Thus, LTD does not require removal of specific AMPA receptor subunits, but likely involves a more general modification of the synapse and its ability to anchor a broad range of receptor proteins.

Distinct molecular components for thalamic- and cortical-dependent plasticity in the lateral amygdala.

N-methyl-D-aspartate receptor (NMDAR)-dependent long-term depression (LTD) in the lateral nucleus of the amygdala (LA) is a form of synaptic plasticity thought to be a cellular substrate for the extinction of fear memory. The LA receives converging inputs from the sensory thalamus and neocortex that are weakened following fear extinction. Combining field and patch-clamp electrophysiological recordings in mice, we show that paired-pulse low-frequency stimulation can induce a robust LTD at thalamic and cortical inputs to LA, and we identify different underlying molecular components at these pathways. We show that while LTD depends on NMDARs and activation of the protein phosphatases PP2B and PP1 at both pathways, it requires NR2B-containing NMDARs at the thalamic pathway, but NR2C/D-containing NMDARs at the cortical pathway. LTD appears to be induced post-synaptically at the thalamic input but presynaptically at the cortical input, since post-synaptic calcium chelation and NMDAR blockade prevent thalamic but not cortical LTD. These results highlight distinct molecular features of LTD in LA that may be relevant for traumatic memory and its erasure, and for pathologies such as post-traumatic stress disorder (PTSD).

Domain Contributions to Signaling Specificity Differences Between Ras-Guanine Nucleotide Releasing Factor (Ras-GRF) 1 and Ras-GRF2

Ras-GRF1 (GRF1) and Ras-GRF2 (GRF2) constitute a family of similar calcium sensors that regulate synaptic plasticity. They are both guanine exchange factors that contain a very similar set of functional domains, including N-terminal pleckstrin homology, coiled-coil, and calmodulin-binding IQ domains and C-terminal Dbl homology Rac-activating domains, Ras-exchange motifs, and CDC25 Ras-activating domains. Nevertheless, they regulate different forms of synaptic plasticity. Although both GRF proteins transduce calcium signals emanating from NMDA-type glutamate receptors in the CA1 region of the hippocampus, GRF1 promotes LTD, whereas GRF2 promotes θ-burst stimulation-induced LTP (TBS-LTP). GRF1 can also mediate high frequency stimulation-induced LTP (HFS-LTP) in mice over 2-months of age, which involves calcium-permeable AMPA-type glutamate receptors. To add to our understanding of how proteins with similar domains can have different functions, WT and various chimeras between GRF1 and GRF2 proteins were tested for their abilities to reconstitute defective LTP and/or LTD in the CA1 hippocampus of Grf1/Grf2 double knock-out mice. These studies revealed a critical role for the GRF2 CDC25 domain in the induction of TBS-LTP by GRF proteins. In contrast, the N-terminal pleckstrin homology and/or coiled-coil domains of GRF1 are key to the induction of HFS-LTP by GRF proteins. Finally, the IQ motif of GRF1 determines whether a GRF protein can induce LTD. Overall, these findings show that for the three forms of synaptic plasticity that are regulated by GRF proteins in the CA1 hippocampus, specificity is encoded in only one or two domains, and a different set of domains for each form of synaptic plasticity.

CaMKII binding to GluN2B is differentially affected by macromolecular crowding reagents.

Binding of the Ca2+/calmodulin(CaM)-dependent protein kinase II (CaMKII) to the NMDA-type glutamate receptor (NMDAR) subunit GluN2B controls long-term potentiation (LTP), a form of synaptic plasticity thought to underlie learning and memory. Regulation of this interaction is well-studied biochemically, but not under conditions that mimic the macromolecular crowding found within cells. Notably, previous molecular crowding experiments with lysozyme indicated an effect on the CaMKII holoenzyme conformation. Here, we found that the effect of molecular crowding on Ca2+/CaM-induced CaMKII binding to immobilized GluN2B in vitro depended on the specific crowding reagent. While binding was reduced by lysozyme, it was enhanced by BSA. The ATP content in the BSA preparation caused CaMKII autophosphorylation at T286 during the binding reaction; however, enhanced binding was also observed when autophosphorylation was blocked. Importantly, the positive regulation by nucleotide and BSA (as well as other macromolecular crowding reagents) did not alleviate the requirement for CaMKII stimulation to induce GluN2B binding. The differential effect of lysozyme (14 kDa) and BSA (66 kDa) was not due to size difference, as both dextran-10 and dextran-70 enhanced binding. By contrast, crowding with immunoglobulin G (IgG) reduced binding. Notably, lysozyme and IgG but not BSA directly bound to Ca2+/CaM in an overlay assay, suggesting a competition of lysozyme and IgG with the Ca2+/CaM-stimulus that induces CaMKII/GluN2B binding. However, lysozyme negatively regulated binding even when it was instead induced by CaMKII T286 phosphorylation. Alternative modes of competition would be with CaMKII or GluN2B, and the negative effects of lysozyme and IgG indeed also correlated with specific or non-specific binding to the immobilized GluN2B. Thus, the effect of any specific crowding reagent can differ, depending on its additional direct effects on CaMKII/GluN2B binding. However, the results of this study also indicate that, in principle, macromolecular crowding enhances CaMKII binding to GluN2B.

Life Extension Factor Klotho Enhances Cognition

Aging is the primary risk factor for cognitive decline, an emerging health threat to aging societies worldwide. Whether anti-aging factors such as klotho can counteract cognitive decline is unknown. We show that a lifespan-extending variant of the human KLOTHO gene, KL-VS, is associated with enhanced cognition in heterozygous carriers. Because this allele increased klotho levels in serum, we analyzed transgenic mice with systemic overexpression of klotho. They performed better than controls in multiple tests of learning and memory. Elevating klotho in mice also enhanced long-term potentiation, a form of synaptic plasticity, and enriched synaptic GluN2B, an N-methyl-D-aspartate receptor (NMDAR) subunit with key functions in learning and memory. Blockade of GluN2B abolished klotho-mediated effects. Surprisingly, klotho effects were evident also in young mice and did not correlate with age in humans, suggesting independence from the aging process. Augmenting klotho or its effects may enhance cognition and counteract cognitive deficits at different life stages.

Contrasting actions of group I metabotropic glutamate receptors in distinct mouse striatal neurones

In mouse striatum, metabotropic glutamate receptor (mGluR) activation leads to several modulatory effects in synaptic transmission. These effects range from dampening of glutamate release from excitatory terminals to depolarization of divergent classes of interneurones. We compared the action of group I mGluR activation on several populations of striatal neurones using a combination of genetic identification, electrophysiology, and Ca(2+) imaging techniques. Patch-clamp recordings from spiny projection neurones (SPNs) and various interneurone populations demonstrated that the group I mGluR agonist (RS)-3,5-dihydroxyphenylglycine (DHPG) robustly depolarizes several interneurone classes that form GABAergic synapses onto SPNs. We further utilized the genetic reporter mouse strain Ai38, which expresses the calcium indicator protein GCaMP3 in a Cre-dependent manner. Breeding Ai38 mice with various neurone selective, promoter-driven Cre recombinase mice resulted in GCaMP3 expression in defined cell populations in striatum. Consistent with our electrophysiological findings, group I agonist applications increased intracellular levels of calcium ([Ca(2+)]i) in all interneurone populations tested. We also found that acute DHPG application evoked a transient, rapid increase in [Ca(2+)]i from only a small percentage of identifiable SPNs. Surprisingly, this fast [Ca(2+)]i response exhibited a robust enhancement or sensitization, in a calcium-dependent fashion. Following several procedures to increase [Ca(2+)]i, the vast majority of SPNs responded with rapid changes in [Ca(2+)]i to mGluR agonists in a time-dependent fashion. These findings extend our understanding on group I mGluR influence of striatal output via powerful, local GABAergic connections in addition to [Ca(2+)]i dynamics that impact on activity or spike-timing-dependent forms of synaptic plasticity.

Activation of dopaminergic D2/D3 receptors modulates dorsoventral connectivity in the hippocampus and reverses the impairment of working memory after nerve injury.

Dopamine plays an important role in several forms of synaptic plasticity in the hippocampus, a crucial brain structure for working memory (WM) functioning. In this study, we evaluated whether the working-memory impairment characteristic of animal models of chronic pain is dependent on hippocampal dopaminergic signaling. To address this issue, we implanted multichannel arrays of electrodes in the dorsal and ventral hippocampal CA1 region of rats and recorded the neuronal activity during a food-reinforced spatial WM task of trajectory alternation. Within-subject behavioral performance and patterns of dorsoventral neuronal activity were assessed before and after the onset of persistent neuropathic pain using the Spared Nerve Injury (SNI) model of neuropathic pain. Our results show that the peripheral nerve lesion caused a disruption in WM and in hippocampus spike activity and that this disruption was reversed by the systemic administration of the dopamine D2/D3 receptor agonist quinpirole (0.05 mg/kg). In SNI animals, the administration of quinpirole restored both the performance-related and the task-related spike activity to the normal range characteristic of naive animals, whereas quinpirole in sham animals caused the opposite effect. Quinpirole also reversed the abnormally low levels of hippocampus dorsoventral connectivity and phase coherence. Together with our finding of changes in gene expression of dopamine receptors and modulators after the onset of the nerve injury model, these results suggest that disruption of the dopaminergic balance in the hippocampus may be crucial for the clinical neurological and cognitive deficits observed in patients with painful syndromes.

A PKA activity sensor for quantitative analysis of endogenous GPCR signaling via 2-photon FRET-FLIM imaging.

Neuromodulators have profound effects on behavior, but the dynamics of their intracellular effectors has remained unclear. Most neuromodulators exert their function via G-protein-coupled receptors (GPCRs). One major challenge for understanding neuromodulator action is the lack of dynamic readouts of the biochemical signals produced by GPCR activation. The adenylate cyclase/cyclic AMP/protein kinase A (PKA) module is a central component of such biochemical signaling. This module is regulated by several behaviorally important neuromodulator receptors. Furthermore, PKA activity is necessary for the induction of many forms of synaptic plasticity as well as for the formation of long-term memory. In order to monitor PKA activity in brain tissue, we have developed a 2-photon fluorescence lifetime imaging microscopy (2pFLIM) compatible PKA sensor termed FLIM-AKAR, which is based on the ratiometric FRET sensor AKAR3. FLIM-AKAR shows a large dynamic range and little pH sensitivity. In addition, it is a rapidly diffusible cytoplasmic protein that specifically reports net PKA activity in situ. FLIM-AKAR expresses robustly in various brain regions with multiple transfection methods, can be targeted to genetically identified cell types, and responds to activation of both endogenous GPCRs and spatial-temporally specific delivery of glutamate. Initial experiments reveal differential regulation of PKA activity across subcellular compartments in response to neuromodulator inputs. Therefore, the reporter FLIM-AKAR, coupled with 2pFLIM, enables the study of PKA activity in response to neuromodulator inputs in genetically identified neurons in the brain, and sheds light on the intracellular dynamics of endogenous GPCR activation.

Functional effects of a pathogenic mutation in Cereblon on the regulation of protein synthesis via the AMPK‐mTOR cascade (LB223)

Initially identified as a protein implicated in human mental deficit, cereblon (CRBN) was recently recognized as a negative regulator of adenosine monophosphate‐activated protein kinase (AMPK) in vivo and in vitro. Here, we present results showing that CRBN can effectively regulate new protein synthesis through the mammalian target of rapamycin (mTOR) signaling pathway, a downstream target of AMPK. Whereas deficiency of Crbn repressed protein translation via activation of the AMPK‐mTOR cascade in Crbn‐knockout mice, ectopic expression of the wild‐type CRBN increased protein synthesis by repressing endogenous AMPK. Unlike the wild‐type CRBN, a mutant CRBN found in human patients, which lacks the last 24 amino acids, failed to rescue mTOR‐dependent repression of protein synthesis in Crbn‐deficient mouse fibroblasts. These results provide the first evidence that Crbn can activate the protein synthesis machinery through the mTOR signaling pathway by inhibiting AMPK. In light of the fact that protein synthesis regulated by mTOR is essential for various forms of synaptic plasticity that underlie the cognitive functions of the brain, the results of this study suggest a plausible mechanism for CRBN involvement in higher brain function in humans, and they may help explain how a specific mutation in CRBN can affect the cognitive ability of patients.Grant Funding Source: Supported by Ministry for Health and Welfare [HI13C1412] and Ministry of Science, ICT & Future Planning of Korea [2007‐0056157] [2011‐0028665] of Korea.

Prenatal cocaine exposure initiates the release of TIMP‐1 and MMP‐9 in primary neuronal and glial cell cultures (651.21)

Drug addiction is a complex phenomenon that is mediated by biochemical events sequential to repeated exposure to a drug. The mechanisms underlying drug addiction include processes similar to those operating in forms of synaptic plasticity. Recently, pro‐addicitve cytokines, tissue inhibitors of matrix metalloproteinases (TIMPs) and matrix metalloproteinases (MMPs) have been shown to influence neuronal plasticity consequent to repeated cocaine injections in animal models. The present study was designed to investigate the role of TIMP‐1 and MMP‐9 in the addiction neurobiology of offspring exposed to cocaine during gestation. Time pregnant Sprague‐Dawley rats were treated with 40 mg/kg of cocaine HCl on gestational day (GD) 10‐21. On postnatal day (PND) 2, the brain tissue of the pups was harvested to yield mixed primary neuronal and glial cell cultures. Primary cell cultures were also exposed to a second sub‐lethal dose of cocaine in vitro and their response was measured. An increase in TIMP‐1 and MMP‐9 expression was observed in prenatally exposed primary neuronal and glial cell cultures. Through in vivo and in vitro studies, these findings suggest that exposure to cocaine in utero initiates the release of pro‐addictive cytokines increasing the incidence of addiction in the affected offspring.Grant Funding Source: NIH‐NIMHD G12MD007582

Modulating excitation through plasticity at inhibitory synapses.

Learning is believed to depend on lasting changes in synaptic efficacy such as long-term potentiation and long-term depression. As a result, a profusion of studies has tried to elucidate the mechanisms underlying these forms of plasticity. Traditionally, experience-dependent changes at excitatory synapses were assumed to underlie learning and memory formation. However, with the relatively more recent investigation of inhibitory transmission, it had become evident that inhibitory synapses are not only plastic, but also provide an additional way to modulate excitatory transmission and the induction of plasticity at excitatory synapses. Thanks to recent technological advances, progress has been made in understanding synaptic transmission and plasticity from particular interneuron subtypes. In this review article, we will describe various forms of synaptic plasticity that have been ascribed to two fairly well characterized populations of interneurons in the hippocampus, those expressing cholecystokinin (CCK) and parvalbumin (PV). We will discuss the resulting changes in the strength and plasticity of excitatory transmission that occur in the local circuit as a result of the modulation of inhibitory transmission. We will focus on the hippocampus because this region has a relatively well-understood circuitry, numerous forms of activity-dependent plasticity and a multitude of identified interneuron subclasses.

Clinically relevant concentrations of ketamine mainly affect long-term potentiation rather than basal excitatory synaptic transmission and do not change paired-pulse facilitation in mouse hippocampal slices

Ketamine, an analgesic/anesthetic drug, is increasingly popular in clinical practice due to its analgesic properties and importance for emergency procedures. The impact of ketamine on basal excitatory synaptic transmission and synaptic plasticity are not yet fully understood. Therefore we investigated the effects of different concentrations of ketamine on basal excitatory synaptic transmission and on two forms of synaptic plasticity: paired-pulse facilitation (PPF) and long-term potentiation (LTP). Evoked field excitatory postsynaptic potentials (fEPSP) were recorded in Schaffer fiber – CA1 pyramid synapses of mouse hippocampal slices and the initial slope of the fEPSP was measured to estimate the percentage of inhibition of the basal synaptic transmission. Presynaptic volley amplitude, PPF and LTP induction and maintenance were also calculated. For basal synaptic transmission and PPF increasing concentrations of ketamine (1, 3, 10, 30, 100, 200, 300 and 600μM) were applied to each slice and for LTP individual slices were used for each concentration (3, 10, 30 or 100μM). Clinically relevant concentrations of ketamine decreased LTP in a concentration-dependent manner without changing PPF, whereas basal excitatory synaptic transmission and presynaptic volley amplitude was affected only with high concentrations of ketamine (300 and 600μM). These results allow dissociating the blockade of LTP from a reduced synaptic input in the action of clinically relevant concentrations of ketamine in the CA1 region of the mouse hippocampus. Moreover, this work shows that the effects of ketamine on LTP and on basal synaptic transmission are dependent of the concentration used.

5-HT4-receptors modulate induction of long-term depression but not potentiation at hippocampal output synapses in acute rat brain slices.

The subiculum is the principal target of CA1 pyramidal cells and mediates hippocampal output to various cortical and subcortical regions of the brain. The majority of subicular pyramidal cells are burst-spiking neurons. Previous studies indicated that high frequency stimulation in subicular burst-spiking cells causes presynaptic NMDA-receptor dependent long-term potentiation (LTP) whereas low frequency stimulation induces postsynaptic NMDA-receptor-dependent long-term depression (LTD). In the present study, we investigate the effect of 5-hydroxytryptamine type 4 (5-HT4) receptor activation and blockade on both forms of synaptic plasticity in burst-spiking cells. We demonstrate that neither activation nor block of 5-HT4 receptors modulate the induction or expression of LTP. In contrast, activation of 5-HT4 receptors facilitates expression of LTD, and block of the 5-HT4 receptor prevents induction of short-term depression and LTD. As 5-HT4 receptors are positively coupled to adenylate cyclase 1 (AC1), 5-HT4 receptors might modulate PKA activity through AC1. Since LTD is blocked in the presence of 5-HT4 receptor antagonists, our data are consistent with 5-HT4 receptor activation by ambient serotonin or intrinsically active 5-HT4 receptors. Our findings provide new insight into aminergic modulation of hippocampal output.

Chapter 7 - Decorrelation Learning in the Cerebellum: Computational Analysis and Experimental Questions

Many cerebellar models use a form of synaptic plasticity that implements decorrelation learning. Parallel fibers carrying signals positively correlated with climbing-fiber input have their synapses weakened (long-term depression), whereas those carrying signals negatively correlated with climbing input have their synapses strengthened (long-term potentiation). Learning therefore ceases when all parallel-fiber signals have been decorrelated from climbing-fiber input. This is a computationally powerful rule for supervised learning and can be cast in a spike-timing dependent plasticity form for comparison with experimental evidence. Decorrelation learning is particularly well suited to sensory prediction, for example, in the reafference problem where external sensory signals are interfered with by reafferent signals from the organism's own movements, and the required circuit appears similar to the one found to mediate classical eye blink conditioning. However, for certain stimuli, avoidance is a much better option than simple prediction, and decorrelation learning can also be used to acquire appropriate avoidance movements. One example of a stimulus to be avoided is retinal slip that degrades visual processing, and decorrelation learning appears to play a role in the vestibulo-ocular reflex that stabilizes gaze in the face of unpredicted head movements. Decorrelation learning is thus suitable for both sensory prediction and motor control. It may also be well suited for generic spatial and temporal coordination, because of its ability to remove the unwanted side effects of movement. Finally, because it can be used with any kind of time-varying signal, the cerebellum could play a role in cognitive processing.