Search

Given the importance of the cerebellum in controlling movements, it might be expected that its main role in eating would be the control of motor elements such as chewing and swallowing. Whilst such functions are clearly important, there is more to eating than these actions, and more to the cerebellum than motor control. This review will present evidence that the cerebellum contributes to homeostatic, motor, rewarding and affective aspects of food consumption.Prediction and feedback underlie many elements of eating, as food consumption is influenced by expectation. For example, circadian clocks cause hunger in anticipation of a meal, and food consumption causes feedback signals which induce satiety. Similarly, the sight and smell of food generate an expectation of what that food will taste like, and its actual taste will generate an internal reward value which will be compared to that expectation. Cerebellar learning is widely thought to involve feed-forward predictions to compare expected outcomes to sensory feedback. We therefore propose that the overarching role of the cerebellum in eating is to respond to prediction errors arising across the homeostatic, motor, cognitive, and affective domains.

Epilepsy is a brain disorder in which patients undergo frequent seizures. Around 30% of patients affected with epilepsy cannot be treated with medicines/surgical procedures. Abnormal activity, known as the preictal state starts few minutes before the seizure actually occurs. Therefore, it may be possible to deliver medication prior to the occurrence of a seizure if initiation of the preictal state can predicted before the seizure onset. We propose an epileptic seizure prediction method that predicts the preictal state before the seizure onset using electroencephalogram (EEG) monitoring of brain activity. It involves three steps including preprocessing of EEG signals, feature extraction classification of preictal and interictal states. In our proposed method, we have used (i) Empirical model decomposition to remove noise from the EEG signals and Generative Adversarial Networks to generate preictal samples to deal with the class imbalance problem; (ii) Automated features have been extracted with three layer Convolutional Neural Networks and (iii) Classification between preictal and interictal states is done with Long Short Term Memory units. In this study, we have used CHBMIT dataset of scalp EEG signals and have validated our proposed method on 22 subjects of dataset. Our proposed seizure prediction method is able to achieve 93% sensitivity and 92.5% specificity with average time of 32 min to predict the seizure's onset. Results obtained from our method have been compared with recent state-of-the-art epileptic seizure prediction methods. Our proposed method performs better in terms of sensitivity, specificity and average anticipation time.

The discrimination of similar episodes and places, and their representation as distinct memories, depend on a process called pattern separation that relies on the circuitry of the hippocampal dentate gyrus (DG). Mossy cells (MCs) are key neurons in the circuitry, but how they influence DG network dynamics, function, and seizure risk has not been fully elucidated. We found the net impact of MCs was inhibitory at physiological frequencies connected with learning and behaviour, and their absence associated with deficits in pattern separation and spatial memory; at higher frequencies, their net impact was excitatory, and their absence protected against seizures. Thus, MCs influence DG outputs in a highly dynamic manner that varies with frequency and context.One-Sentence SummaryHippocampal mossy cells are required for learning and memory; but their absence protects against seizures.

Recognition of previously encountered stimuli and their associated spatial and temporal information depends on neural activity within a brain-wide network in which the CA1 region of the hippocampus, nucleus reuniens of the thalamus (NRe) and medial prefrontal cortex (mPFC) are key nodes. However, the pathways crucial for coordinating activity during memory encoding and/or retrieval phases have been little explored. Here we opto- or chemo associative recognition memory. We discovered that encoding, but not retrieval depended on the CA1 to mPFC and NRe to mPFC projections. In contrast, retrieval depended on the mPFC to NRe projection. Interestingly the NRe to CA1 pathway was required for both memory phases. Our findings therefore reveal that encoding and retrieval engage dissociable sub-networks within a hippocampal-thalamo-cortical recognition memory circuit in order to enable binding of recent and related information, whilst ensuring a separation of processing.

Summary It is well established that long-term depression (LTD) can be initiated by either NMDA or mGluR activation. Here we report that sustained activation of GluK2 subunit-containing kainate receptors (KARs) leads to α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) endocytosis and induces LTD of AMPARs (KAR-LTDAMPAR) in hippocampal neurons. The KAR-evoked loss of surface AMPARs is blocked by the ionotropic KAR inhibitor UBP 310 indicating that KAR-LTDAMPAR requires KAR channel activity. Interestingly, however, blockade of PKC or PKA also reduces GluA2 surface expression and occludes the effect of KAR activation. In acute hippocampal slices, kainate application caused a significant loss of GluA2-containing AMPARs from synapses and long-lasting depression of AMPAR excitatory postsynaptic currents in CA1. These data, together with our previously reported KAR-LTPAMPAR, demonstrate that KARs can bidirectionally regulate synaptic AMPARs and synaptic plasticity via different signaling pathways., Graphical abstract, Highlights • Sustained kainate receptor (KAR) activation downregulates surface AMPARs • KAR ionotropic signaling induces AMPAR LTD (KAR-LTDAMPAR) • KAR-LTDAMPAR is dependent on the GluK2 KAR subunit and calcineurin, Molecular neuroscience; Cellular neuroscience

The endosome-associated cargo adaptor sorting nexin-27 (SNX27) is linked to various neuropathologies through sorting of integral proteins to the synaptic surface, most notably AMPA receptors. To provide a broader view of SNX27-associated pathologies we have performed unbiased proteomics to identify new neuronal SNX27-dependent cargoes, and identified proteins linked to excitotoxicity (SLC1A3, SLC4A7, SLC6A11), epilepsy, intellectual disabilities and working memory deficits (KCNT2, ADAM22, KIDINS220, LRFN2). Focusing on the synaptic adhesion molecule leucine-rich repeat and fibronectin type-III domain-containing protein 2 (LRFN2), we establish that SNX27 binds to LRFN2 and is responsible for regulating its endosomal sorting. LRFN2 associates with AMPA receptors and knockdown of LRFN2 phenocopies SNX27 depletion in decreasing surface expression of AMPA receptors, reducing synaptic activity and attenuating hippocampal long-term potentiation. Our evidence suggests that, in contrast to previous reports, SNX27 does not directly bind to AMPA receptors, and instead controls AMPA receptor-mediated synaptic transmission and plasticity indirectly through the endosomal sorting of LRFN2. Overall, our study provides new molecular insight into the perturbed function of SNX27 and LRFN2 in a range of neurological conditions.

Patients suffering from epileptic seizures are usually treated with medication and/or surgical procedures. However, in more than 30% of cases, medication or surgery does not effectively control seizure activity. A method that predicts the onset of a seizure before it occurs may prove useful as patients might be alerted to make themselves safe or seizures could be prevented with therapeutic interventions just before they occur. Abnormal neuronal activity, the preictal state, starts a few minutes before the onset of a seizure. In recent years, different methods have been proposed to predict the start of the preictal state. These studies follow some common steps, including recording of EEG signals, preprocessing, feature extraction, classification, and postprocessing. However, online prediction of epileptic seizures remains a challenge as all these steps need further refinement to achieve high sensitivity and low false positive rate. In this paper, we present a comparison of state-of-the-art methods used to predict seizures using both scalp and intracranial EEG signals and suggest improvements to existing methods.

The nucleus reuniens and rhomboid nuclei of the thalamus (ReRh) are reciprocally connected to a range of higher order cortices including hippocampus (HPC) and medial prefrontal cortex (mPFC). The physiological function of ReRh is well predicted by requirement for interactions between mPFC and HPC, including associative recognition memory, spatial navigation, and working memory. Although anatomical and electrophysiological evidence suggests ReRh makes excitatory synapses in mPFC there is little data on the physiological properties of these projections, or whether ReRh and HPC target overlapping cell populations and, if so, how they interact. We demonstrate in ex vivo mPFC slices that ReRh and HPC afferent inputs converge onto more than two-thirds of layer 5 pyramidal neurons, show that ReRh, but not HPC, undergoes marked short-term plasticity during theta frequency transmission, and that HPC, but not ReRh, afferents are subject to neuromodulation by acetylcholine acting via muscarinic receptor M2. Finally, we demonstrate that pairing HPC followed by ReRh (but not pairing ReRh followed by HPC) at theta frequency induces associative, NMDA receptor dependent synaptic plasticity in both inputs to mPFC. These data provide vital physiological phenotypes of the synapses of this circuit and provide a novel mechanism for HPC–ReRh–mPFC encoding.

Long-Term Depression (LTD) is well known to be initiated by either NMDA or mGlu receptor activation. Here we report that sustained activation of GluK2 subunit-containing kainate receptors leads to AMPA receptor endocytosis and a novel form of long-term depression (KAR-LTDAMPAR) in hippocampal neurons. The KAR-evoked loss of surface AMPA receptors is blocked by the ionotropic KAR inhibitor UBP 310 indicating that KAR-LTDAMPAR requires KAR channel activity. Interestingly, however, blockade of PKC or PKA also reduces GluA2 surface expression and occludes the effect of KAR activation. In acute hippocampal slices kainate application caused a significant and long lasting depression of AMPA EPSCs in CA1. These data, together with our previously reported KAR-LTPAMPAR, demonstrate that KARs can bidirectionally regulate synaptic AMPARs and synaptic plasticity via different signaling pathways.

The nucleus reuniens of the thalamus (NRe) is reciprocally connected to a range of higher order cortices including hippocampus (HPC) and medial prefrontal cortex (mPFC). The physiological function of NRe is well predicted by requirement for interactions between mPFC and HPC, including associative recognition memory, spatial navigation and working memory. Although anatomical and electrophysiological evidence suggests NRe makes excitatory synapses in mPFC there is little data on the physiological properties of these projections, or whether NRe and HPC target overlapping cell populations and, if so, how they interact. We demonstrate in ex vivo mPFC slices that NRe and HPC afferent inputs converge onto more than two-thirds of layer 5 pyramidal neurons, show that NRe, but not HPC, undergoes marked short-term plasticity at theta, and that HPC, but not NRe, afferents are subject to neuromodulation by acetylcholine acting via muscarinic receptor M2. Finally, we demonstrate that pairing HPC followed by NRe (but not pairing NRe followed by HPC) at theta frequency induces associative, NMDA receptor dependent synaptic plasticity in both inputs to mPFC. These data provide vital physiological phenotypes of the synapses of this circuit and provide a novel mechanism for HPC-NRe-mPFC encoding.

Summary In this review we consider the various roles played by N-methyl- d -aspartate receptors (NMDARs) located on pyramidal neurones in medial prefrontal cortex (mPFC). We focus on recent data from our lab that has investigated how NMDARs contribute to ongoing synaptic transmission in a frequency dependent manner, the plasticity of NMDARs and how this impacts their contribution to synaptic transmission, and finally consider how NMDARs contribute to plasticity induced by synchronous activation of two separate inputs to mPFC

Acid-sensing ion channels (ASICs), members of the degenerin/epithelial Na+ channel superfamily, are widely distributed in the mammalian nervous system. ASIC1a are highly permeable to Ca2+ and are thought to be important in a variety of physiological processes, including synaptic plasticity, learning and memory. To further understand the role of ASIC1a in synaptic transmission and plasticity, we investigated metabotropic glutamate (mGlu) receptor-dependent long-term depression (LTD) in the hippocampus. We found that ASIC1a channels mediate a component of LTD in P30-40 animals, since the ASIC1a selective blocker psalmotoxin-1 (PcTx1) reduced the magnitude of LTD induced by application of the group I mGlu receptor agonist (S)-3,5-Dihydroxyphenylglycine (DHPG) or induced by paired-pulse low frequency stimulation (PP-LFS). Conversely, PcTx1 did not affect LTD in P13-18 animals. We also provide evidence that ASIC1a is involved in group I mGlu receptor-induced increase in action potential firing. However, blockade of ASIC1a did not affect DHPG-induced polyphosphoinositide hydrolysis, suggesting the involvement of some other molecular partners in the functional crosstalk between ASIC1a and group I mGlu receptors. Notably, PcTx1 was able to prevent the increase in GluA1 S845 phosphorylation at the post-synaptic membrane induced by group I mGlu receptor activation. These findings suggest a novel function of ASIC1a channels in the regulation of group I mGlu receptor synaptic plasticity and intrinsic excitability.

Episodic memory formation depends on information about a stimulus being integrated within a precise spatial and temporal context, a process dependent on the hippocampus and prefrontal cortex. Investigations of putative functional interactions between these regions are complicated by multiple direct and indirect hippocampal-prefrontal connections. Here application of a pharmaco-genetic deactivation technique enabled an investigation of the mnemonic contributions of two direct hippocampal-medial prefrontal cortex (mPFC) pathways; one arising in the dorsal CA1 (dCA1), the other in the intermediate CA1 (iCA1). While, deactivation of either pathway impaired episodic memory, the resulting pattern of mnemonic deficits was significantly different; deactivation of the dCA1→mPFC pathway selecƟvely disrupted temporal order judgements, while iCA1→mPFC pathway deactivation disrupted spatial memory. These findings reveal a major, previously unsuspected division of function among A1 neurons that project directly to the mPFC. Such sub-networks may enable the distinctiveness of contextual information to be maintained within an episodic memory circuit.

NMDA receptors are composed of multiple subunits and are crucial in the induction of synaptic plasticity and learning and memory. In this study, application of the group I mGlu receptor agonist, DHPG, caused LTD of NMDA-EPSCs (DHPG-LTDNMDA) of the Schaffer collateral, but not of NMDA-EPSCs of the temperoammonic pathway onto CA1 neurons of the hippocampus. DHPG-LTDNMDA did not alter the sensitivity of NMDA-EPSC to the GluN2B-antagonist, Ro25-6981, indicating that the postsynaptic NMDA receptor subunit composition remained unchanged following DHPG-LTDNMDA. Furthermore, blockade of GluN2B receptors did not affect the induction of DHPG-LTDNMDA. These results demonstrate a difference in the plasticity of NMDA receptors between two synapses onto the same CA1 neuron, but indicate that the subunit composition of NMDA receptors does not account for this difference.

Hippocampal CA1 pyramidal neurons receive inputs from entorhinal cortex directly via the temporoammonic (TA) pathway and indirectly via the Schaffer collateral (SC) pathway from CA3. NMDARs at synapses of both pathways are critical for the induction of synaptic plasticity, information processing, and learning and memory. We now demonstrate that, in the rat hippocampus, activity-dependent mGlu1 receptor-mediated LTD (mGlu1-LTD) of NMDAR-mediated transmission (EPSCNMDA) at the SC-CA1 input prevents subsequent LTP of AMPAR-mediated transmission. In contrast, there was no activity-dependent mGlu1-LTD of EPSCNMDAat the TA-CA1 pathway, or effects on subsequent plasticity of AMPAR-mediated transmission. Therefore, the two major pathways delivering information to CA1 pyramidal neurons are subject to very different plasticity rules.

Synaptic plasticity in perirhinal cortex is essential for recognition memory. Nitric oxide and endocannabinoids (eCBs), which are produced in the postsynaptic cell and act on the presynaptic terminal, are implicated in mechanisms of long-term potentiation (LTP) and long-term depression (LTD) in other brain regions. In this study, we examine these two retrograde signalling cascades in perirhinal cortex synaptic plasticity and in visual recognition memory in the rat. We show that inhibition of NO-dependent signalling prevented both carbachol- and activity (5 Hz)-dependent LTD but not activity (100 Hz theta burst)-dependent LTP in the rat perirhinal cortex in vitro. In contrast, inhibition of the eCB-dependent signalling prevented LTP but not the two forms of LTD in vitro. Local administration into perirhinal cortex of the nitric oxide synthase inhibitor NPA (2 μm) disrupted acquisition of long-term visual recognition memory. In contrast, AM251 (10 μm), a cannabinoid receptor 1 antagonist, did not impair visual recognition memory. The results of this study demonstrate dissociation between putative retrograde signalling mechanisms in LTD and LTP in perirhinal cortex. Thus, LTP relies on cannabinoid but not NO signalling, whilst LTD relies on NO- but not eCB-dependent signalling. Critically, these results also establish, for the first time, that NO- but not eCB-dependent signalling is important in perirhinal cortex-dependent visual recognition memory.

Traditionally, neurotransmitters are associated with a fast, or phasic, type of action on neurons in the central nervous system (CNS). However, accumulating evidence indicates that γ-aminobutyric acid (GABA) and glutamate can also have a continual, or tonic, influence on these cells. Here, in voltage- and current-clamp recordings in rat brain slices, we identify three types of tonically active receptors in a single CNS structure, the thalamic reticular nucleus (TRN). Thus, TRN contains constitutively active GABAA receptors (GABAA Rs), which are located on TRN neurons and generate a persistent outward Cl(-) current. When TRN neurons are depolarized, blockade of this current increases their action potential output in response to current injection. Furthermore, TRN contains tonically active GluN2B-containing N-methyl-D-aspartate receptors (NMDARs). These are located on reticuloreticular GABAergic terminals in TRN and generate a persistent facilitation of vesicular GABA release from these terminals. In addition, TRN contains tonically active metabotropic glutamate type 2 receptors (mGlu2Rs). These are located on glutamatergic cortical terminals in TRN and generate a persistent reduction of vesicular glutamate release from these terminals. Although tonically active GABAA Rs, NMDARs and mGlu2Rs operate through different mechanisms, we propose that the continual and combined activity of these three receptor types ultimately serves to hyperpolarize TRN neurons, which will differentially affect the output of these cells depending upon the current state of their membrane potential. Thus, when TRN cells are relatively depolarized, their firing in single-spike tonic mode will be reduced, whereas when these cells are relatively hyperpolarized, their ability to fire in multispike burst mode will be facilitated.

Work is reviewed that relates recognition memory to studies of synaptic plasticity mechanisms in perirhinal and prefrontal cortices. The aim is to consider evidence that perirhinal cortex and medial prefrontal cortex store rather than merely transmit information necessary for recognition memory and, if so, to consider what mechanisms are potentially available within these cortices for producing such storage through synaptic change. Interventions with known actions on plasticity mechanisms are reviewed in relation to their effects on recognition memory processes. These interventions importantly include those involving antagonism of glutamatergic and cholinergic receptors but also inhibition of plasticity consolidation and expression mechanisms. It is concluded that there is strong evidence that perirhinal cortex is involved in information storage necessary for object recognition memory and, moreover, that such storage involves synaptic weakening mechanisms including the removal of AMPA glutamate receptors from synapses. There is good evidence that medial prefrontal cortex is necessary for associative and temporal order recognition memory and that this cortex expresses plasticity mechanisms that potentially allow the storage of information. However, the case for medial prefrontal cortex acting as a store requires further support.

Emotionally salient experiences are better remembered than events that have little emotional context. Several lines of evidence indicate that the amygdala plays an important role in this emotional enhancement of memory. Visual recognition memory relies on synaptic plasticity in the perirhinal cortex, but little is known about the mechanisms involved in emotional enhancement of this form of memory. The results of the present study, performed in rat brain slices, show for the first time that the amygdala input to the perirhinal cortex undergoes synaptic plasticity. Stimulation in the amygdala resulted in long-term potentiation (LTP) in perirhinal cortex that was dependent on β-adrenoceptors and L-type voltage-dependent calcium channels (L-VDCCs) but was NMDAR-independent. In contrast, intracortical perirhinal stimulation resulted in LTP that was NMDAR-dependent but β-adrenoceptor- and L-VDCC-independent. In addition, the present results provide the first evidence that stimulation of the amygdala can reduce the threshold for LTP in the perirhinal cortex. Interestingly, this associative form of LTP requires β-adrenoceptor activation but not NMDA or L-VDCC activation. Knowing the mechanisms that control amygdala-perirhinal cortex interactions will allow better understanding of how emotionally charged visual events are remembered, and may help to understand how memories can consolidate and become intrusive in anxiety-related disorders.

Evidence suggests that the acquisition of recognition memory depends upon CREB-dependent long-lasting changes in synaptic plasticity in the perirhinal cortex. The CREB-responsive microRNA miR-132 has been shown to regulate synaptic transmission and we set out to investigate a role for this microRNA in recognition memory and its underlying plasticity mechanisms. To this end we mediated the specific overexpression of miR-132 selectively in the rat perirhinal cortex and demonstrated impairment in short-term recognition memory. This functional deficit was associated with a reduction in both long-term depression and long-term potentiation. These results confirm that microRNAs are key coordinators of the intracellular pathways that mediate experience-dependent changes in the brain. In addition, these results demonstrate a role for miR-132 in the neuronal mechanisms underlying the formation of short-term recognition memory.

The mechanisms of long-term depression (LTD) underlie various aspects of normal brain function. Therefore, it is important to understand the signaling that underpins LTD. The study by Scholz et al. in this issue of Neuron describes how BRAG2, mGluRs, and AMPARs come together to produce LTD through AMPAR internalization.

We applied the group-I metabotropic glutamate (mGlu) receptor agonist, 3,5-dihydroxyphenylglycine (DHPG), to neonatal or adult rat hippocampal slices at concentrations (10 μm) that induced a short-term depression (STD) of excitatory synaptic transmission at the Schaffer collateral/CA1 synapses. DHPG-induced STD was entirely mediated by the activation of mGlu5 receptors because it was abrogated by the mGlu5 receptor antagonist, MPEP [2-methyl-6-(phenylethynyl)pyridine], but not by the mGlu1 receptor antagonist, CPCCOEt [7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester]. Knowing that ephrin-Bs functionally interact with group-I mGlu receptors (Calò et al., 2005), we examined whether pharmacological activation of ephrin-Bs could affect DHPG-induced STD. We activated ephrin-Bs using their cognate receptor, EphB1, under the form of a preclustered EphB1/Fc chimera. Addition of clustered EphB1/Fc alone to the slices induced a small but nondecremental depression of excitatory synaptic transmission, which differed from the depression induced by 10 μmDHPG. Surprisingly, EphB1/Fc-induced synaptic depression was abolished by MPEP (but not by CPCCOEt) suggesting that it required the endogenous activation of mGlu5 receptors. In addition, coapplication of DHPG and EphB1/Fc, resulted in a large and nondecremental long-term depression. The effect of clustered EphB1/Fc was specific because it was not mimicked by unclustered EphB1/Fc or clustered EphA1/Fc. These findings raise the intriguing possibility that changes in synaptic efficacy mediated by mGlu5 receptors are under the control of the ephrin/Eph receptor system, and that the neuronal actions of ephrins can be targeted by drugs that attenuate mGlu5 receptor signaling.

Recent, convergent evidence places the anterior thalamic nuclei at the heart of diencephalic amnesia. However, the reasons for the severe memory loss in diencephalic amnesia remain unknown. A potential clue comes from the dense, reciprocal connections between the anterior thalamic nuclei and retrosplenial cortex, another region vital for memory. We now report a loss of synaptic plasticity [long-term depression (LTD)] in rat retrosplenial cortex slices months following an anterior thalamic lesion. The loss of LTD was lamina-specific, occurring only in superficial layers of the cortex and was associated with a decrease in GABA(A)-mediated inhibitory transmission. As retrosplenial cortex is itself vital for memory, this distal lesion effect will amplify the impact of anterior thalamic lesions. These findings not only provide novel insights into the functional pathology of diencephalic amnesia and have implications for the aetiology of the posterior cingulate hypoactivity in Alzheimer's disease, but also show how distal changes in plasticity could contribute to diaschisis.

Long-term depression (LTD) can be induced at hippocampal CA1 synapses by activation of either NMDA receptors (NMDARs) or group I metabotropic glutamate receptors (mGluRs), using their selective agonists NMDA and (RS)-3,5-dihydroxyphenylglycine (DHPG), respectively. Recent studies revealed that DHPG-LTD is dependent on activation of postsynaptic protein tyrosine phosphatases (PTPs), which transiently dephosphorylate tyrosine residues in AMPA receptors (AMPARs). Here we show that while both endogenous GluR2 and GluR3 AMPAR subunits are tyrosine phosphorylated at basal activity, only GluR2 is dephosphorylated in DHPG-LTD. The tyrosine dephosphorylation of GluR2 does not occur in NMDA-LTD. Conversely, while NMDA-LTD is associated with the dephosphorylation of GluR1-serine-845, DHPG-LTD does not alter the phosphorylation of this site. The increased AMPAR endocytosis in DHPG-LTD is PTP-dependent and involves tyrosine dephosphorylation of cell surface AMPARs. Together, these results indicate that the subunit selective tyrosine dephosphorylation of surface GluR2 regulates AMPAR internalisation in DHPG-LTD but not in NMDA-LTD in the hippocampus.

Long-term potentiation (LTP) and long-term depression (LTD) are forms of synaptic plasticity thought to contribute to learning and memory. Much is known about the mechanisms of NMDA receptor-dependent LTD in the CA1 region of rat hippocampus but there is still considerable uncertainty about the mechanisms of LTD induced by mGluR activation (mGluR-LTD). Furthermore, data on mGluR-LTD derives largely from studies using pharmacologically induced LTD. To investigate mGluR-LTD that is more physiologically relevant we have examined, in CA1 of adult rat hippocampus, mechanisms of synaptically induced mGluR-LTD. We provide the first demonstration that activation of protein tyrosine phosphatase (PTP) is essential for the induction of synaptically induced mGluR-LTD. In addition, we show that activation of p38 MAPK is also required for this form of LTD. Furthermore, LTD can be mimicked and occluded by activation of p38 MAPK, provided that protein tyrosine kinases (PTKs) are inhibited. These data therefore demonstrate that a novel combination of signalling cascades, requiring both activation of p38 MAPK and tyrosine de-phosphorylation, underlies the induction of synaptically induced mGluR-LTD.

The role of NMDA receptors in the induction of long-term potentiation (LTP) and long-term depression (LTD) is well established but which particular NR2 subunits are involved in these plasticity processes is still a matter of controversy. We have studied the effects of subtype selective NMDA receptor antagonists on LTP induced by high frequency stimulation (100 Hz for 1s) and LTD induced by low frequency stimulation (1 Hz for 15 min) in the CA1 region of hippocampal slices from 14 day old Wistar rats. Against recombinant receptors in HEK293 cells NVP-AAM077 (NVP) was approximately 14-fold selective for NR2A vs NR2B receptors, whilst Ro 25-6981 (Ro) was highly selective for NR2B receptors. On NMDA receptor-mediated EPSCs from Schaffer collaterals in CA1 neurones, NVP and Ro both reduced the amplitude but differentially affected the time constant of decay. The data are compatible with the selective effect of NVP (0.1 microM) and Ro (4 microM) on native NR2A and NBR2B receptors, respectively. NVP reduced both LTP and LTD whereas Ro reduced only LTP. Thus, LTP was reduced by 63% at 0.1 microM NVP and almost completely at 0.4 microM whereas 5 microM Ro reduced LTP by 45%. These data are consistent with a role for both NR2A and NR2B in the induction of LTP, under our experimental conditions. In comparison, LTD was unaffected by Ro (5 microM) even in the presence of a glutamate uptake inhibitor threo-beta-benzylaspartic acid (TBOA) to increase the concentration of glutamate at NR2B containing receptors. NVP (0.2-0.4 microM), however, produced a concentration dependent inhibition of LTD which was complete at 0.4 microM. The lack of effect of 0.1 microM NVP on LTD contrasts with its marked effect on LTP and raises the possibility that different NVP-sensitive NR2 subunit-containing NMDA receptors are required for LTP and LTD in this preparation.

Significance Synaptic transmission between the hippocampus and prefrontal cortex is required for many executive cognitive functions. It is believed that disruption of this communication contributes to symptoms observed in psychiatric disorders including schizophrenia. Hyperdopaminergic tone and hypofunction of NMDA receptor-mediated glutamate transmission are distinctive elements of schizophrenia. Here we demonstrate that activation of low-affinity D2-like dopamine receptors leads to a lasting depression of NMDA receptors at the hippocampal–prefrontal projection of juvenile rats, leading to a marked disruption of synaptic transmission. These data demonstrate a link between dopamine and hypofunction of NMDA receptor-mediated transmission with potential implications for psychiatric disease.

Two forms of long-term depression (LTD), triggered by activation of NMDA receptors (NMDARs) and metabotropic glutamate receptors (mGluRs), respectively, can be induced at CA1 synapses in the hippocampus. Compared with NMDAR-LTD, relatively little is known about mGluR-LTD. Here, we show that protein tyrosine phosphatase (PTP) inhibitors, orthovanadate and phenylarsine oxide, selectively block mGluR-LTD induced by application of the group I mGluR agonist (RS)-3,5-dihydroxyphenylglycine (DHPG-LTD), because NMDAR-LTD is unaffected by these inhibitors. Furthermore, DHPG-LTD measured using whole-cell recording is similarly blocked by either bath-applied or patch-loaded PTP inhibitors. These inhibitors also block the changes in paired-pulse facilitation and coefficient of variation that are associated with the expression of DHPG-LTD. DHPG treatment of hippocampal slices was associated with a decrease in the level of tyrosine phosphorylation of GluR2 AMPA receptor (AMPAR) subunits, an effect blocked by orthovanadate. Finally, in dissociated hippocampal neurons, orthovanadate blocked the ability of DHPG to reduce the number of AMPA receptor clusters on the surface of dendrites. Again, the effects of PTP blockade were selective, because NMDA-induced decreases in surface AMPAR clusters was unaffected by orthovanadate. Together, these data suggest that activation of postsynaptic PTP results in tyrosine dephosphorylation of AMPARs and their removal from the synapse.

Benzodiazepines, including lorazepam, are widely used in human medicine as anxiolytics or sedatives, and at higher doses can produce amnesia. Here we demonstrate that in rats lorazepam impairs both recognition memory and synaptic plastic processes (long-term depression and long-term potentiation). Both impairments are produced by actions in perirhinal cortex. The findings thus establish a mechanism by means of which benzodiazepines impair recognition memory. The findings also strengthen the hypotheses that the familiarity discrimination component of recognition memory is dependent on reductions in perirhinal neuronal responses when stimuli are repeated and that these response reductions are due to a plastic mechanism also used in long-term depression.

Long-term depression (LTD) induction relies upon receptor cross-talk between group I and group II metabotropic glutamate receptors (mGluRs) in perirhinal cortex. The molecular mechanism of this mGluR interplay is not clear. Here, we show that the mGluR subtypes postulated to be involved in this mechanism are developmentally regulated and mGluR2 has a preferential role over mGluR3 in the synergistic interaction with mGluR5. We have identified a >70% reduction in basal cAMP levels following mGluR2 stimulation, which could lead to increased mGluR5 function via reduced PKA mediated phosphorylation and decreased desensitisation of mGluR5. To further investigate the roles of mGluRs in downstream intracellular signalling, we have examined the effects of mGluRs on the phosphorylation state of cAMP response element-binding protein (CREB). Both group I and group II agonists increased the phosphorylation of CREB, which indicates a cAMP- and PKA-independent signalling mechanism. These results suggest a convergence of signalling mechanisms from surface mGluRs to CREB-mediated transcription.

We establish the importance of cholinergic neurotransmission to both recognition memory and plasticity within the perirhinal cortex of the temporal lobe. The muscarinic receptor antagonist scopolamine impaired the preferential exploration of novel over familiar objects, disrupted the normal reduced activation of perirhinal neurones to familiar compared to novel pictures, and blocked production of long-term depression (LTD) but not long-term potentiation (LTP) of synaptic transmission in perirhinal slices. The consistency of these effects across the behavioral, systems, and cellular levels of analysis provides strong evidence for the involvement of cholinergic mechanisms in synaptic plastic processes within perirhinal cortex that are necessary for recognition memory.

It has previously been shown that the neuropeptide galanin plays a role in the age-dependent regulation of hippocampal synaptic plasticity and spatial memory. Here, we further extend these studies by demonstrating that galanin knockout mice also have deficits in an object-in-place spatial memory task. In contrast however, there is no deficit in single item object recognition memory, a memory that depends on perirhinal cortex. Furthermore, in perirhinal cortex slices there are no differences in activity-dependent long-term potentiation or depotentiation, nor in muscarinic receptor-dependent long-term depression between galanin knockout mice and wild-type litter-mates. Therefore, these results suggest that galanin has a differential role in hippocampal-dependent and perirhinal cortex-dependent memory.

Many studies indicate that recognition memory involves at least two separable processes, familiarity discrimination and recollection. Aspects of what is known of potential neuronal substrates of familiarity discrimination are reviewed. Lesion studies have established that familiarity discrimination for individual visual stimuli is effected by a system centred on the perirhinal cortex of the temporal lobe. The fundamental change that encodes prior occurrence of such stimuli appears to be a reduction in the response of neurons in anterior inferior temporal (including perirhinal) cortex when a stimulus is repeated. The neuronal responses rapidly signal the presence of a novel stimulus, and are evidence of long–lasting learning after a single exposure. Computational modelling indicates that a neuronal network based on such a change in responsiveness is potentially highly efficient in information theoretic terms. Processes that occur in long–term depression within the perirhinal cortex provide candidate synaptic plastic mechanisms for that underlying the change, but such linkage remains to be experimentally established.

A form of long-term depression (LTD) of synaptic transmission can be induced by bath application of the group I metabotropic glutamate (mGlu) receptor agonist (RS)-3,5-dihydroxyphenylglycine (DHPG). The mechanisms responsible for the induction and expression of DHPG-induced LTD in the CA1 region of the hippocampus are currently the subject of intense investigation. Here we show that two protein tyrosine kinase (PTK) inhibitors (10 microM lavendustin A or 30 microM genistein) have little effect on DHPG-induced LTD. In contrast two protein tyrosine phosphatase (PTP) inhibitors (1 mM orthovanadate or 15 microM phenyl-arsine oxide) significantly inhibited DHPG-induced LTD. These data suggest that DHPG-induced LTD involves activation of a protein tyrosine phosphatase.

We have investigated properties of GABAergic synaptic transmission in perirhinal cortex evoked by stimulation of temporal and entorhinal cortex sides. GABA A IPSCs were isolated by blockade of glutamatergic transmission in slices of adult perirhinal cortex; IPSC decay was best fitted with two exponentials. Interestingly, temporal IPSCs had a larger slow component of decay (P < 0.05) compared to entorhinal IPSCs. Depression of IPSCs by the GABA B receptor agonist baclofen was greater (P < 0.05) in the temporal input (79 ′ 4% depression) than the entorhinal input (65 ′ 3% depression). Furthermore, baclofen abolished the slow component of IPSC decay in both inputs. Activity-dependent depression of IPSCs at 5 Hz was greater (P < 0.05) in the temporal input [paired pulse ratio (PPR) 0.5 ′ 0.04] compared to that in the entorhinal input (PPR 0.67 ′ 0.02, n = 10). The differences in paired pulse depression between the inputs were removed by the GABA B receptor antagonist CGP55845A. This study demonstrates several differences in GABA transmission between temporal and entorhinal inputs including the differential activation of presynaptic GABA B receptors and differential regulation of inhibitory synaptic transmission. These properties may be important in the control of neuronal activity within perirhinal cortex.

Some of the outstanding questions in neuroscience today are aimed at understanding the cellular and network mechanisms responsible for learned behaviours. Being able to identify and subsequently manipulate those specific neurones previously activated in a behavioural episode is key to this endeavour. A number of different methods have now been developed that enable this to be achieved. In this article, we highlight the Daun02–daunorubicin method of disrupting neuronal activity. Despite the fact that the Daun02–daunorubicin method has been used for a number of years and has been applied across a number of different experimental systems, the mechanism by which Daun02–daunorubicin disrupts neuronal activity is not clear. In this article, we summarise some of the advances that have been made by using this technology and we discuss potential mechanisms by which Daun02–daunorubicin disrupts neuronal function.

Emotional events are better remembered than emotionally neutral events. The ability of memory enhancement by emotion is dependent on amygdala-mediated alterations of synaptic activity., Visual recognition memory relies on long-term depression-like mechanisms within the perirhinal cortex and the activation of the lateral amygdala can enhance visual recognition memory. How the lateral amygdala regulates recognition memory is not known, but synaptic plasticity at amygdala−perirhinal synapses may provide a mechanism for the emotional enhancement of recognition memory. In this study, we investigate the mechanisms of long-term depression (LTD) at the amygdala−perirhinal synapse in male Lister Hooded rats. We demonstrate that LTD at this input relies on NR2A-containing NMDARs, located presynaptically. Therefore, the underlying mechanisms of LTD, at the amygdala−perirhinal input, which may regulate the emotional context for recognition memory, are different to previously described postsynaptic NR2B−NMDAR mechanisms of intraperirhinal LTD that subserve recognition memory.

Learning is widely believed to involve synaptic plasticity, employing mechanisms such as those used in long-term potentiation (LTP) and long-term depression (LTD). In this chapter, we will review work on mechanisms of synaptic plasticity in perirhinal cortex in vitro and relate these findings to studies underlying recognition memory in vivo. We describe how antagonism of different glutamate and acetylcholine receptors, inhibition of nitric oxide synthase, inhibition of CREB phosphorylation, and interfering with glutamate AMPA receptor internalization can produce deficits in synaptic plasticity in vitro. Inhibition of each of these different mechanisms in vivo also results in recognition memory deficits. Therefore, we provide strong evidence that synaptic plastic mechanisms are necessary for the information processing and storage that underlies object recognition memory.

The driving force behind this book is the enduring question of whether synaptic plasticity is a suitable model for understanding the basis of learning and memory. In this book synaptic plasticity is taken almost exclusively to mean long-term potentiation (LTP) and there is virtually no discussion of, for example, long-term depression or the cerebellum. The book begins with an introduction by Holscher in which some of the main arguments contained within the rest of the book are rehearsed. This begins with an assessment of the validity of in vitro slice techniques and then questions whether in vitro studies are relevant to learning; whether models of LTP are relevant to learning; and whether knockout techniques and the employment of these are useful for understanding firstly LTP and then learning? This is followed by a critique of the different approaches that have attempted to correlate LTP with the cellular processes that may be involved with learning. Most people in this field will recognize the problems and limitations of the systems that we work with, be these in vivo or in vitro . Most realize that it is not a simple matter to relate synaptic plasticity in a dish or in anaesthetized animals to learning in animals or in humans. Nevertheless, the Introduction is a readable account and provides a useful summary of some of the main issues. The rest of the book is divided into five sections. The first of these deals with `Long-term potentiation in vitro and in vivo '. Abraham discusses the different types of LTP that are found in different brain regions, the types of stimuli usually employed to induce LTP and the underlying mechanisms of induction in different regions. There is an interesting section on neurogenesis (unique …

There is strong evidence that decrements in neuronal activation in perirhinal cortex when a novel stimulus is repeated provide a neural substrate of visual recognition memory. There is also strong evidence that muscarinic acetylcholine (ACh) receptors are involved in learning and memory. However, the mechanisms underlying neuronal decrements in the perirhinal cortex and the basis of ACh involvement in learning and memory are not understood. In an in vitro preparation of rat perirhinal cortex we now demonstrate that activation of ACh receptors by carbachol (CCh) produces long-lasting depression (LLD) of synaptic transmission that is dependent on muscarinic M1 receptor activation. Crucially, the induction of this form of LLD requires neither N-methyl-D-aspartate receptor activation nor synaptic stimulation. CCh-induced LLD was not blocked by the protein kinase C inhibitors staurosporine or BIM, or by the protein phosphatase inhibitor okadaic acid. However, each of cyclopiazonic acid (an agent that depletes intracellular calcium stores) and anisomycin (an inhibitor of protein synthesis) significantly reduced the magnitude of CCh-induced LLD. These mechanisms triggered by muscarinic receptor activation could play a role in the induction and/or expression of certain forms of activity-dependent long-term depression in perirhinal cortex. An understanding of CCh-induced LLD may thus provide clues to the mechanisms underlying lasting neuronal decrements that occur in the perirhinal cortex and hence for neural substrates of visual recognition memory.

1 We have investigated the prediction of a relationship between the magnitude of activity-dependent increases in postsynaptic calcium and both the magnitude and direction of synaptic plastic change in the central nervous system. Activity-dependent increases in calcium were buffered to differing degrees using a range of concentrations of EGTA and the effects on synaptic plasticity were assessed. 2 Activity-dependent synaptic plasticity was induced during whole-cell recording in rat perirhinal cortex in vitro. In control conditions (0.5 mm EGTA) low frequency stimulation (LFS; 200 stimuli) delivered to neurones held at -40 or -70 mV induced long-term depression (LTD) or, at -10 mV, induced long-term potentiation (LTP). 3 The relationship between EGTA concentration (0.2 to 10 mm) and the magnitude of LTD was examined. This relationship described a U-shaped curve, as predicted by models of synaptic plasticity. This provides strong evidence that the magnitude of LTD is determined by the magnitude of the increase in intracellular calcium concentration. 4 LFS paired with depolarisation to -10 mV induced LTD, no change or LTP as activity-dependent postsynaptic calcium levels were allowed to increase progressively by the use of progressively lower concentrations of buffer (10 to 0.2 mm EGTA). 5 We investigated if the lack of plasticity that occurs at the transition between LTD and LTP is due to induction of both of these processes with zero net change, or is due to neither LTD nor LTP being induced. These experiments were possible as LTP but not LTD was blocked by the protein kinase inhibitor staurosporine while LTD but not LTP was blocked by the mGlu receptor antagonist MCPG. At the transition between LTD and LTP, blocking LTP mechanisms did not uncover LTD whilst blocking LTD mechanisms did not uncover LTP. This suggests that the transition between LTD and LTP is due to the lack of induction of both of these processes and also suggests that these two processes are induced independently of one another.

Excitatory synaptic transmission in the perirhinal cortex exhibits marked homosynaptic paired pulse depression (PPD) at inter-pulse intervals between 100 and 1000 ms, being maximal at 200 ms. Additionally, there is greater PPD with stimulation of the pathway from the temporal cortex side than with stimulation of the pathway from the entorhinal cortex side. We establish that this frequency-dependent depression relies on the activation of GABAB (gamma-aminobutyric acid) receptors. PPD in both temporal and entorhinal pathways is abolished by either of the selective GABAB receptor antagonists, 3-N[1-(S)-(3, 4-dichlorophenyl)ethyl]amino-2-(S)-hydroxypropyl-p-benzyl-phosphinic acid (CGP55845A) or 3-amino-propyl(diethoxymethyl)phosphinic acid (CGP35348). Barium which blocks G-protein-coupled, inwardly rectifying potassium channels, does not block PPD. Heterosynaptic depression mediated by GABAB receptors was also observed. The depression of the entorhinal pathway by stimulation of the temporal pathway is greater than depression of the temporal pathway by stimulation of the entorhinal pathway. Moreover, PPD increases with stimulus strength and the depression is enhanced by short trains of stimuli, consistent with stronger stimulation resulting in more GABA reaching GABAB receptors on excitatory glutamatergic synapses. Synaptic activation of GABAB receptors may be important in regulating excitability in a frequency-dependent manner with maximal depression occurring at approximately 5 Hz, which approximates to the theta rhythm. That homosynaptic and heterosynaptic depression by stimulation of the temporal pathway is greater than by stimulation of the entorhinal pathway suggests that activation of temporal feedforward connections to the perirhinal cortex can dominate the GABAergic control of synaptic activity within the perirhinal cortex.

In this study, we have investigated the developmental range over which different stimulus protocols induce long-term depression (LTD). Low-frequency stimulation (LFS; 900 stimuli, 1 Hz) produced LTD in hippocampal slices from rats younger than approximately 40 days old, but not in animals aged between approximately 40 days and 16 weeks. We demonstrate, however, that different stimulus protocols can result in LTD in the adult hippocampus. Whilst one paired-pulse low-frequency stimulus protocol [PP-LFS; 50 ms paired-pulse interval (PPI), 900 pairs of stimuli] produced N-methyl-D-aspartate (NMDA) receptor-independent LTD, another PP-LFS protocol (200 ms PPI; 900 pairs) produced NMDA receptor-dependent LTD. Furthermore, the saturation of NMDA receptor-dependent LTD did not prevent the induction of further NMDA receptor-independent LTD. This lack of occlusion suggests that different mechanisms of expression may underlie each of the above forms of LTD in the adult hippocampus. In contrast to the adult hippocampus, NMDA receptor-dependent LTD was induced by both LFS and PP-LFS (50 ms PPI) in slices from young animals (12-20 days). Although they share a common induction mechanism, LTD induced by PP-LFS may be expressed through other mechanisms in addition to those underlying LFS-induced LTD in the young hippocampus. In conclusion, the results in this study demonstrate that mechanisms of long-term synaptic depression within the hippocampus can alter radically with development of the central nervous system and with the use of different induction protocols.