NMDA Receptor-dependent Long-term Potentiation Research Articles

PI3K couples long-term synaptic potentiation with cofilin recruitment and actin polymerization in dendritic spines via its regulatory subunit p85α

Long-term synaptic plasticity is typically associated with morphological changes in synaptic connections. However, the molecular mechanisms coupling functional and structural aspects of synaptic plasticity are still poorly defined. The catalytic activity of type I phosphoinositide-3-kinase (PI3K) is required for specific forms of synaptic plasticity, such as NMDA receptor-dependent long-term potentiation (LTP) and mGluR-dependent long-term depression (LTD). On the other hand, PI3K signaling has been linked to neuronal growth and synapse formation. Consequently, PI3Ks are promising candidates to coordinate changes in synaptic strength with structural remodeling of synapses. To investigate this issue, we targeted individual regulatory subunits of type I PI3Ks in hippocampal neurons and employed a combination of electrophysiological, biochemical and imaging techniques to assess their role in synaptic plasticity. We found that a particular regulatory isoform, p85α, is selectively required for LTP. This specificity is based on its BH domain, which engages the small GTPases Rac1 and Cdc42, critical regulators of the actin cytoskeleton. Moreover, cofilin, a key regulator of actin dynamics that accumulates in dendritic spines after LTP induction, failed to do so in the absence of p85α or when its BH domain was overexpressed as a dominant negative construct. Finally, in agreement with this convergence on actin regulatory mechanisms, the presence of p85α in the PI3K complex determined the extent of actin polymerization in dendritic spines during LTP. Therefore, this study reveals a molecular mechanism linking structural and functional synaptic plasticity through the coordinate action of PI3K catalytic activity and a specific isoform of the regulatory subunits.

Hippocampal hyperphosphorylated tau-induced deficiency is rescued by L-type calcium channel blockade.

Aging and Alzheimer's disease are associated with chronic elevations in neuronal calcium influx via L-type calcium channels. The hippocampus, a primary memory encoding structure in the brain, is more vulnerable to calcium dysregulation in Alzheimer's disease. Recent research has suggested a link between L-type calcium channels and tau hyperphosphorylation. However, the precise mechanism of L-type calcium channel-mediated tau toxicity is not understood. In this study, we seeded a human tau pseudophosphorylated at 14 amino acid sites in rat hippocampal cornu ammonis 1 region to mimic soluble pretangle tau. Impaired spatial learning was observed in human tau pseudophosphorylated at 14 amino acid sites-infused rats as early as 1-3 months and worsened at 9-10 months post-infusion. Rats infused with wild-type human tau exhibited milder behavioural deficiency only at 9-10 months post-infusion. No tangles or plaques were observed in all time points examined in both human tau pseudophosphorylated at 14 amino acid sites and human tau-infused brains. However, human tau pseudophosphorylated at 14 amino acid sites-infused hippocampus exhibited a higher amount of tau phosphorylation at S262 and S356 than the human tau-infused rats at 3 months post-infusion, paralleling the behavioural deficiency observed in human tau pseudophosphorylated at 14 amino acid sites-infused rats. Neuroinflammation indexed by increased Iba1 in the cornu ammonis 1 was observed in human tau pseudophosphorylated at 14 amino acid sites-infused rats at 1-3 but not 9 months post-infusion. Spatial learning deficiency in human tau pseudophosphorylated at 14 amino acid sites-infused rats at 1-3 months post-infusion was paralleled by decreased neuronal excitability, impaired NMDA receptor-dependent long-term potentiation and augmented L-type calcium channel-dependent long-term potentiation at the cornu ammonis 1 synapses. L-type calcium channel expression was elevated in the soma of the cornu ammonis 1 neurons in human tau pseudophosphorylated at 14 amino acid sites-infused rats. Chronic L-type calcium channel blockade with nimodipine injections for 6 weeks normalized neuronal excitability and synaptic plasticity and rescued spatial learning deficiency in human tau pseudophosphorylated at 14 amino acid sites-infused rats. The early onset of L-type calcium channel-mediated pretangle tau pathology and rectification by nimodipine in our model have significant implications for preclinical Alzheimer's disease prevention and intervention.

Coenzyme Q10 supplementation improves the motor function of middle-aged mice by restoring the neuronal activity of the motor cortex

Physiological aging causes motor function decline and anatomical and biochemical changes in the motor cortex. We confirmed that middle-aged mice at 15–18 months old show motor function decline, which can be restored to the young adult level by supplementing with mitochondrial electron transporter coenzyme Q10 (CoQ10) as a water-soluble nanoformula by drinking water for 1 week. CoQ10 supplementation concurrently improved brain mitochondrial respiration but not muscle strength. Notably, we identified an age-related decline in field excitatory postsynaptic potential (fEPSP) amplitude in the pathway from layers II/III to V of the primary motor area of middle-aged mice, which was restored to the young adult level by supplementing with CoQ10 for 1 week but not by administering CoQ10 acutely to brain slices. Interestingly, CoQ10 with high-frequency stimulation induced NMDA receptor-dependent long-term potentiation (LTP) in layer V of the primary motor cortex of middle-aged mice. Importantly, the fEPSP amplitude showed a larger input‒output relationship after CoQ10-dependent LTP expression. These data suggest that CoQ10 restores the motor function of middle-aged mice by improving brain mitochondrial function and the basal fEPSP level of the motor cortex, potentially by enhancing synaptic plasticity efficacy. Thus, CoQ10 supplementation may ameliorate the age-related decline in motor function in humans.

Muscarinic acetylcholine receptor-dependent and NMDA receptor-dependent LTP and LTD share the common AMPAR trafficking pathway

The forebrain cholinergic system promotes higher brain function in part by signaling through the M1 muscarinic acetylcholine receptor (mAChR). Long-term potentiation (LTP) and long-term depression (LTD) of excitatory synaptic transmission in the hippocampus are also induced by mAChR. An AMPA receptor (AMPAR) trafficking model for hippocampal neurons has been proposed to simulate N-methyl-D-aspartate receptor (NMDAR)-dependent synaptic plasticity in the early phase. In this study, we demonstrated the validity of the hypothesis that the mAChR-dependent LTP/LTD shares a common AMPAR trafficking pathway associated with NMDAR-dependent LTP/LTD. However, unlike NMDAR, Ca2+ influx into the spine cytosol occurs owing to the Ca2+ stored inside the ER and is induced via the activation of inositol 1,4,5-trisphosphate (IP3) receptors during M1 mAChR activation. Moreover, the AMPAR trafficking model implies that alterations in LTP and LTD observed in Alzheimer's disease could be attributed to age-dependent reductions in AMPAR expression levels.

Long-term potentiation in neurogliaform interneurons modulates excitation-inhibition balance in the temporoammonic pathway.

Apical dendrites of pyramidal neurons integrate information from higher‐order cortex and thalamus, and gate signalling and plasticity at proximal synapses. In the hippocampus, neurogliaform cells and other interneurons located within stratum lacunosum‐moleculare (SLM) mediate powerful inhibition of CA1 pyramidal neuron distal dendrites. Is the recruitment of such inhibition itself subject to use‐dependent plasticity, and if so, what induction rules apply? Here we show that interneurons in mouse SLM exhibit Hebbian NMDA receptor‐dependent long‐term potentiation (LTP). Such plasticity can be induced by selective optogenetic stimulation of afferents in the temporoammonic pathway from the entorhinal cortex (EC), but not by equivalent stimulation of afferents from the thalamic nucleus reuniens. We further show that theta‐burst patterns of afferent firing induces LTP in neurogliaform interneurons identified using neuron‐derived neurotrophic factor (Ndnf)‐Cre mice. Theta‐burst activity of EC afferents led to an increase in disynaptic feed‐forward inhibition, but not monosynaptic excitation, of CA1 pyramidal neurons. Activity‐dependent synaptic plasticity in SLM interneurons thus alters the excitation–inhibition balance at EC inputs to the apical dendrites of pyramidal neurons, implying a dynamic role for these interneurons in gating CA1 dendritic computations. Key points Electrogenic phenomena in distal dendrites of principal neurons in the hippocampus have a major role in gating synaptic plasticity at afferent synapses on proximal dendrites. Apical dendrites also receive powerful feed‐forward inhibition, mediated in large part by neurogliaform neurons.Here we show that theta‐burst activity in afferents from the entorhinal cortex (EC) induces ‘Hebbian’ long‐term potentiation (LTP) at excitatory synapses recruiting these GABAergic cells.LTP in interneurons innervating apical dendrites increases disynaptic inhibition of principal neurons, thus shifting the excitation–inhibition balance in the temporoammonic (TA) pathway in favour of inhibition, with implications for computations and learning rules in proximal dendrites.

Acetylation of calmodulin regulates synaptic plasticity and fear learning

Synaptic plasticity is critical for brain function, including learning and memory. It is regulated by gene transcription and protein synthesis as well as posttranslational modifications at synapses. Although protein acetylation has been shown to be involved in the regulation of synaptic plasticity, this was mainly for histone protein acetylation. To investigate whether acetylation of nonhistone proteins is important for synaptic plasticity, we analyzed mouse brain acetylome and found that calmodulin (CaM), a ubiquitous Ca2+ sensor, was acetylated on three lysine residues, which were conserved across species. NMDA receptor-dependent long-term potentiation (LTP) is considered the most compelling form of synaptic plasticity. During LTP induction, activation of NMDA receptor triggers Ca2+ influx, and the Ca2+ binds with CaM and activates calcium/calmodulin-dependent protein kinase IIα (CaMKIIα), which is essential for LTP induction. By using home-generated and site-specific antibodies against acetylated CaM, we show that CaM acetylation is upregulated by neural activities in an NMDA receptor-dependent manner. Moreover, mutation of acetyllysines in CaM1 proteins disrupts synaptic plasticity and fear learning in a mouse model. We further demonstrate that acetylation of CaM reduces the binding free energy and increases the binding affinity toward CaMKIIα, a protein kinase pivotal to synaptic plasticity and learning. Taken together, our results demonstrate importance of CaM acetylation in regulating synaptic plasticity and learning.

TRPM4 Expression During Postnatal Developmental of Mouse CA1 Pyramidal Neurons.

TRPM4 is a non-selective cation channel activated by intracellular calcium and permeable to monovalent cations. This channel participates in the control of neuronal firing, neuronal plasticity, and neuronal death. TRPM4 depolarizes dendritic spines and is critical for the induction of NMDA receptor-dependent long-term potentiation in CA1 pyramidal neurons. Despite its functional importance, no subcellular localization or expression during postnatal development has been described in this area. To examine the localization and expression of TRPM4, we performed duplex immunofluorescence and patch-clamp in brain slices at different postnatal ages in C57BL/6J mice. At P0 we found TRPM4 is expressed with a somatic pattern. At P7, P14, and P35, TRPM4 expression extended from the soma to the apical dendrites but was excluded from the axon initial segment. Patch-clamp recordings showed a TRPM4-like current active at the resting membrane potential from P0, which increased throughout the postnatal development. This current was dependent on intracellular Ca2+ (ICAN) and sensitive to 9-phenanthrol (9-Ph). Inhibiting TRPM4 with 9-Ph hyperpolarized the membrane potential at P14 and P35, with no effect in earlier stages. Together, these results show that TRPM4 is expressed in CA1 pyramidal neurons in the soma and apical dendrites and associated with a TRPM4-like current, which depolarizes the neurons. The expression, localization, and function of TRPM4 throughout postnatal development in the CA1 hippocampal may underlie an important mechanism of control of membrane potential and action potential firing during critical periods of neuronal development, particularly during the establishment of circuits.

Oligomer β-amyloid Induces Hyperactivation of Ras to Impede NMDA Receptor-Dependent Long-Term Potentiation in Hippocampal CA1 of Mice.

The activity of Ras, a small GTPase protein, is increased in brains with Alzheimer’s disease. The objective of this study was to determine the influence of oligomeric Aβ1-42 on the activation of Ras, and the involvement of the Ras hyperactivity in Aβ1-42-induced deficits in spatial cognition and hippocampal synaptic plasticity. Herein, we show that intracerebroventricular injection of Aβ1-42 in mice (Aβ-mice) enhanced hippocampal Ras activation and expression, while 60 min incubation of hippocampal slices in Aβ1-42 (Aβ-slices) only elevated Ras activity. Aβ-mice showed deficits in spatial cognition and NMDA receptor (NMDAR)-dependent long-term potentiation (LTP) in hippocampal CA1, but basal synaptic transmission was enhanced. The above effects of Aβ1-42 were corrected by the Ras inhibitor farnesylthiosalicylic acid (FTS). ERK2 phosphorylation increased, and Src phosphorylation decreased in Aβ-mice and Aβ1-42-slices. Both were corrected by FTS. In CA1 pyramidal cells of Aβ1-42-slices, the response of AMPA receptor and phosphorylation of GluR1 were enhanced with dependence on Ras activation rather than ERK signaling. In contrast, NMDA receptor (NMDAR) function and GluN2A/2B phosphorylation were downregulated in Aβ1-42-slices, which was recovered by application of FTS or the Src activator ouabain, and mimicked in control slices treated with the Src inhibitor PP2. The administration of PP2 impaired the spatial cognition and LTP induction in control mice and FTS-treated Aβ-mice. The treatment of Aβ-mice with ouabain rescued Aβ-impaired spatial cognition and LTP. Overall, the results indicate that the oligomeric Aβ1-42 hyperactivates Ras and thereby causes the downregulation of Src which impedes NMDAR-dependent LTP induction resulting in cognitive deficits.

NMDA Receptor Dependent Long-term Potentiation in Chronic Pain

Since the discovery of NMDA receptor (NMDAR) dependent long-term potentiation (LTP) in the hippocampus, many studies have demonstrated that NMDAR dependent LTP exists throughout central synapses, including those involved in sensory transmission and perception. NMDAR LTP has been reported in spinal cord dorsal horn synapses, anterior cingulate cortex and insular cortex. Behavioral, genetic and pharmacological studies show that inhibiting or reducing NMDAR LTP produced analgesic effects in animal models of chronic pain. Investigation of signalling mechanisms for NMDAR LTP may provide novel targets for future treatment of chronic pain.

Akt3 deletion in mice impairs spatial cognition and hippocampal CA1 long long-term potentiation through downregulation of mTOR.

Loss-of-function mutation of Akt3 in humans has been associated with microcephaly and cognitive defects. Two Akt isoforms, Akt1 and Akt3, are highly expressed in hippocampal pyramidal cells. We explored the roles of Akt1 and Akt3, respectively, in spatial cognition and underlying mechanisms. We used Akt1 knockout (Akt1-KO) and Akt3 knockout (Akt3-KO) mice to examine the influence of Akt1 and Akt3 deficiency on spatial memory, as well as induction and maintenance of hippocampal CA1 NMDA receptor-dependent and protein synthesis-dependent long-term potentiation (LTP). Long-term spatial memory was impaired in Akt3-KO mice, but not in Akt1-KO mice, as assessed by the Morris water maze task. Akt3-KO and Akt1-KO mice displayed reductions in brain size without concurrent changes in the number of pyramidal cells or basal properties of synaptic transmission. One-train high-frequency stimulation (HFS × 1) induced NMDA receptor-dependent LTP in Akt3-KO mice and Akt1-KO mice. Four-train HFS (HFS × 4) induced rapamycin-sensitive long-LTP in Akt1-KO mice, but not Akt3-KO mice. Basal level of mTOR phosphorylation was reduced in Akt3-KO mice rather than Akt1-KO mice. HFS × 4 induced an elevation of mTOR and p70S6K phosphorylation in Akt1-KO mice, which led to enhanced 4EBP2 and eIF4E phosphorylation along with an increase in AMPA receptor protein. However, the same protocol of HFS × 4 failed to trigger the mTOR-p70S6K signalling cascade or increase 4EBP2 and eIF4E phosphorylation in Akt3-KO mice. The Akt3 deficiency via inactivation of mTOR suppresses HFS × 4-induced mTOR-p70S6K signalling to reduce phosphorylation of 4EBP and eIF4E, which impairs protein synthesis-dependent long-LTP and long-term spatial cognitive function.

Distinct Roles of NMDAR and mGluR5 in Light Exposure Reversal of Feedforward Synaptic Strength in V1 of Juvenile Mice after Binocular Vision Deprivation

In the visual cortex, sensory deprivation causes global augmentation of the amplitude of AMPA receptor-mediated miniature EPSCs in layer 2/3 pyramidal cells and enhancement of NMDA receptor-dependent long-term potentiation (LTP) in cells activated in layer 4, effects that are both rapidly reversed by light exposure. Layer 2/3 pyramidal cells receive both feedforward input from layer 4 and intra-cortical lateral input from the same layer, LTP is mainly induced by the former input. Whether feedforward excitatory synaptic strength is affected by visual deprivation and light exposure, how this synaptic strength correlates with the magnitude of LTP in this pathway, and the underlying mechanism have not been explored. Here, we showed that in juvenile mice, both dark rearing and dark exposure reduced the feedforward excitatory synaptic strength, and the effects can be reversed completely by 10–12 h and 6–8 h light exposure, respectively. However, inhibition of NMDA receptors by CPP or mGluR5 by MPEP, prevented the effect of light exposure on the mice reared in the dark from birth, while only inhibition of NMDAR prevented the effect of light exposure on dark-exposed mice. These results suggested that the activation of both NMDAR and mGluR5 are essential in the light exposure reversal of feedforward excitatory synaptic strength in the dark reared mice from birth; while in the dark exposed mice, only activation of NMDAR is required.

β-adrenergic receptors reduce the threshold for induction and stabilization of LTP and enhance its magnitude via multiple mechanisms in the ventral but not the dorsal hippocampus.

The hippocampus is a functionally heterogeneous structure with the cognitive and emotional signal processing ascribed to the dorsal (DH) and the ventral hippocampus (VH) respectively. However, the underlying mechanisms are poorly understood. Noradrenaline is released in hippocampus during emotional arousal modulating synaptic plasticity and memory consolidation through activation of β adrenergic receptors (β-ARs). Using recordings of field excitatory postsynaptic potentials from the CA1 field of adult rat hippocampal slices we demonstrate that long-term potentiation (LTP) induced either by theta-burst stimulation (TBS) that mimics a physiological firing pattern of hippocampal neurons or by high-frequency stimulation is remarkably more sensitive to β-AR activation in VH than in DH. Thus, pairing of subthreshold primed burst stimulation with activation of β-ARs by their agonist isoproterenol (1 μM) resulted in a reliable induction of NMDA receptor-dependent LTP in the VH without affecting LTP in the DH. Activation of β-ARs by isoproterenol during application of intense TBS increased the magnitude of LTP in both hippocampal segments but facilitated voltage-gated calcium channel-dependent LTP in VH only. Endogenous β-AR activation contributed to the stabilization and the magnitude of LTP in VH but not DH as demonstrated by the effects of the β-ARs antagonist propranolol (10 μM). Exogenous (but not endogenous) β-AR activation strongly increased TBS-induced facilitation of postsynaptic excitability in VH. In DH, isoproterenol only produced a moderate and GABAergic inhibition-dependent enhancement in the facilitation of synaptic burst responses. Paired-pulse facilitation did not change with LTP at any experimental condition suggesting that expression of LTP does not involve presynaptic mechanisms. These findings suggest that β-AR may act as a switch that selectively promotes synaptic plasticity in VH through multiple ways and provide thus a first clue to mechanisms that underlie VH involvement in emotionality.

Dendritic spikes in hippocampal granule cells are necessary for long-term potentiation at the perforant path synapse.

Long-term potentiation (LTP) of synaptic responses is essential for hippocampal memory function. Perforant-path (PP) synapses on hippocampal granule cells (GCs) contribute to the formation of associative memories, which are considered the cellular correlates of memory engrams. However, the mechanisms of LTP at these synapses are not well understood. Due to sparse firing activity and the voltage attenuation in their dendrites, it remains unclear how associative LTP at distal synapses occurs. Here, we show that NMDA receptor-dependent LTP can be induced at PP-GC synapses without backpropagating action potentials (bAPs) in acute rat brain slices. Dendritic recordings reveal substantial attenuation of bAPs as well as local dendritic Na+ spike generation during PP-GC input. Inhibition of dendritic Na+ spikes impairs LTP induction at PP-GC synapse. These data suggest that dendritic spikes may constitute a key cellular mechanism for memory formation in the dentate gyrus.

Long term potentiation, but not depression, in interlamellar hippocampus CA1

Synaptic plasticity in the lamellar CA3 to CA1 circuitry has been extensively studied while interlamellar CA1 to CA1 connections have not yet received much attention. One of our earlier studies demonstrated that axons of CA1 pyramidal neurons project to neighboring CA1 neurons, implicating information transfer along a longitudinal interlamellar network. Still, it remains unclear whether long-term synaptic plasticity is present within this longitudinal CA1 network. Here, we investigate long-term synaptic plasticity between CA1 pyramidal cells, using in vitro and in vivo extracellular recordings and 3D holography glutamate uncaging. We found that the CA1-CA1 network exhibits NMDA receptor-dependent long-term potentiation (LTP) without direction or layer selectivity. By contrast, we find no significant long-term depression (LTD) under various LTD induction protocols. These results implicate unique synaptic properties in the longitudinal projection suggesting that the interlamellar CA1 network could be a promising structure for hippocampus-related information processing and brain diseases.

The C-terminal tails of endogenous GluA1 and GluA2 differentially contribute to hippocampal synaptic plasticity and learning.

Long-term potentiation (LTP) and depression (LTD) at glutamatergic synapses are intensively investigated processes for understanding the synaptic basis for learning and memory, but the underlying molecular mechanisms remain poorly understood. We have made three mouse lines where the C-terminal domains (CTDs) of endogenous AMPA receptors (AMPARs), the principal mediators of fast excitatory synaptic transmission, are specifically exchanged. These mice display profound deficits in synaptic plasticity without any effects on basal synaptic transmission. Our study reveals that the CTDs of GluA1 and GluA2, the key subunits of AMPARs, are necessary and sufficient to drive NMDA receptor-dependent LTP and LTD, respectively. In addition, these domains exert differential effects on spatial and contextual learning and memory. These results establish dominant roles of AMPARs in governing bidirectional synaptic and behavioral plasticity in the CNS.

Theta burst stimulation-induced LTP: Differences and similarities between the dorsal and ventral CA1 hippocampal synapses.

The hippocampal synapses display a conspicuous ability for long-term plasticity, which is thought to contribute to learning and memory. Previous research has shown that long-term potentiation (LTP) greatly differs between the dorsal (DH) and ventral (VH) CA1 hippocampal synapses when induced by high-frequency stimulation. In this study, using rat hippocampal slices and more physiologically relevant activity patterns based on the frequency of the theta rhythm (i.e., theta-burst stimulation, TBS) we found that the DH compared with the VH displayed a higher ability for induction and stability of NMDA receptor-dependent LTP of the field excitatory postsynaptic potential. Nevertheless, the maximal magnitude of LTP was similar in the two hippocampal segments. Blockade of GABAB receptors prevented the LTP induction by the minimal effective TBS and reduced the magnitude of LTP induced by longer TBS. TBS produced a three-fold higher facilitation of the synaptic burst responses in the DH compared with the VH, accompanied by a strong enhancement in the postsynaptic excitation in the DH but mostly depression in the VH. The DH displayed NMDA receptor-dependent and NMDA receptor-independent facilitation, but the facilitation in the VH was only NMDA receptor-dependent. Also, the TBS-associated activity of GABAB receptors was higher in the DH than in the VH. The different response profiles during TBS could underlie the differences in LTP between the two hippocampal segments. L-type voltage-dependent calcium channels (L-VDCC) and the metabotropic glutamate receptor-5 (mGluR5) equally contributed in DH and VH to compound LTP induced by relatively long TBS. We propose that these dorsoventral differences in synaptic plasticity reflect specializations of the intrinsic circuitry of the hippocampus, that are involved in the distinct information processing performed by the two hippocampal segments and could effectively support the contribution of the dorsal and the ventral hippocampal segment to single event memory and to emotional memory respectively. © 2016 Wiley Periodicals, Inc.

Dopamine D1-like Receptors Regulate Constitutive, μ-Opioid Receptor-Mediated Repression of Use-Dependent Synaptic Plasticity in Dorsal Horn Neurons: More Harm than Good?

The current study reports on a synaptic mechanism through which D1-like receptors (D1LRs) modulate spinal nociception and plasticity by regulating activation of the μ-opioid receptor (MOR).D1LR stimulation with agonist SKF 38393 concentration-dependently depressed C-fiber-evoked potentials in rats receiving spinal nerve ligation (SNL), but not in uninjured rats. Depression was prevented by MOR- but not GABA-receptor blockade. Neurons expressing the D1 subtype were immunopositive for met-enkephalin and vesicular glutamate transporter VGLUT2, but not for GABAergic marker vGAT.Nerve ligation was followed by increased immunoreactivity for D1 in synaptic compartment (P3) in dorsal horn homogenates and presynaptic met-enkephalin-containing boutons. SNL led to increased immunoreactivity for met-enkephalin in dorsal horn homogenates, which was dose-dependently attenuated by selective D1LR antagonist SCH 23390. During blockade of either D1R or MOR, low-frequency (0.2 or 3 Hz) stimulation (LFS) to the sciatic nerve induced long-term potentiation (LTP) of C-fiber-evoked potentials, revealing a constituent role of both receptors in repressing afferent-induced synaptic plasticity. LFS consistently induced NMDA receptor-dependent LTP in nerve-injured rats. The ability of MOR both to prevent LTP and to modulate mechanical and thermal pain thresholds in behavioral tests was preserved in nerve-ligated rats that were postoperatively treated with SCH 23390. D1LR priming for 30 min sufficed to disrupt MOR function in otherwise naive rats via a mechanism involving receptor overuse.The current data support that, whereas D1LR-modulated MOR activation is instrumental in antinociception and endogenous repression of synaptic plasticity, this mechanism deteriorates rapidly by sustained use, generating increased vulnerability to afferent input. The current study shows that dopamine D1-like receptors (D1LRs) and μ-opioid receptors (MOR) in the spinal dorsal horn constitutively repress the expression of synaptic long-term potentiation (LTP) of C-fiber-evoked potentials. Anatomical data are provided supporting that the D1 subtype regulates MOR function by modulating met-enkephalin release. Sustained neuropathic pain induced by spinal nerve ligation is accompanied by D1R and met-enkephalin upregulation, acquired D1LR-mediated antinociception, and a loss of endogenous repression of further synaptic plasticity. We show that the ability of MOR to oppose LTP is rapidly impaired by sustained D1LR activation via a mechanism involving sustained MOR activation.

The L-type voltage-dependent calcium channel long-term potentiation is higher in the dorsal compared with the ventral associational/commissural CA3 hippocampal synapses

The diversification between dorsal (DH) and ventral (VH) hippocampus includes the different ability to support NMDA receptor-dependent long-term synaptic potentiation (LTP). In this study, we assessed the ability of associational/commissural connections in the CA3 hippocampal field to show NMDA receptor-independent LTP. We found that high-frequency stimulation under blockade of NMDA receptors induced greater LTP in DH (40.7±8.5%) than in VH (17.1±4.6%). The blocker of L-type voltage-dependent calcium channels (VDCC) nifedipine prevented the induction of LTP. We hypothesize that the different ability for VDCC-LTP between DH and VH might have important implications in the memory-related information processing performed by the circuits of the two hippocampal segments.

Putting heterosynaptic plasticity in its place - as easy as PIE.

Since Milner and Scoville published their observations of Henry Molaison's profound memory deficits following bilateral removal of the hippocampal formation (Scoville & Milner, 1957), generations of neuroscientists have sought to understand how the hippocampus executes its essential role in learning and memory. Central to that understanding is elaboration of the functions performed by the circuitry of the hippocampal CA3 region. A signature feature of CA3 is that its principal cells, the pyramidal cells (PCs), generate a highly recurrent network, by giving off and receiving excitatory collateral inputs to and from myriad other CA3 PCs. Inputs to this recurrent network come primarily from layer 2 neurons in nearby entorhinal cortex (EC) via the perforant pathway (PP), which bifurcates into two distinct excitatory pathways: a monosynaptic pathway onto the distal apical dendrites of the PCs; and a disynaptic pathway, where EC inputs synapse onto granule cells in the dentate gyrus, which, in turn, synapse onto the proximal apical dendrites of CA3 PCs via mossy fibre (MF) axons. Owing to their strength and location, the MF inputs strongly drive activity in the PCs despite there being only several dozen of these inputs per neuron (as opposed to thousands of inputs from the PP and recurrent collaterals).

Functional optical probing of the hippocampal trisynaptic circuit in vitro: network dynamics, filter properties, and polysynaptic induction of CA1 LTP.

Decades of brain research have identified various parallel loops linking the hippocampus with neocortical areas, enabling the acquisition of spatial and episodic memories. Especially the hippocampal trisynaptic circuit [entorhinal cortex layer II → dentate gyrus (DG) → cornu ammonis (CA)-3 → CA1] was studied in great detail because of its seemingly simple connectivity and characteristic structures that are experimentally well accessible. While numerous researchers focused on functional aspects, obtained from a limited number of cells in distinct hippocampal subregions, little is known about the neuronal network dynamics which drive information across multiple synapses for subsequent long-term storage. Fast voltage-sensitive dye imaging in vitro allows real-time recording of activity patterns in large/meso-scale neuronal networks with high spatial resolution. In this way, we recently found that entorhinal theta-frequency input to the DG most effectively passes filter mechanisms of the trisynaptic circuit network, generating activity waves which propagate across the entire DG-CA axis. These “trisynaptic circuit waves” involve high-frequency firing of CA3 pyramidal neurons, leading to a rapid induction of classical NMDA receptor-dependent long-term potentiation (LTP) at CA3-CA1 synapses (CA1 LTP). CA1 LTP has been substantially evidenced to be essential for some forms of explicit learning in mammals. Here, we review data with particular reference to whole network-level approaches, illustrating how activity propagation can take place within the trisynaptic circuit to drive formation of CA1 LTP.