Long-term Changes In Synaptic Transmission Research Articles

General Anesthesia During Neurodevelopment Reduces Autistic Behavior in Adult BTBR Mice, a Murine Model of Autism.

Preclinical studies suggest that repeated exposure to anesthetics during a critical period of neurodevelopment induces long-term changes in synaptic transmission, plasticity, and behavior. Such changes are of great concern, as similar changes have also been identified in animal models of neurodevelopmental disorders (NDDs) such as autism. Because of overlapping synaptic changes, it is also possible that anesthetic exposures have a more significant effect in individuals diagnosed with NDDs. Thus, we evaluated the effects of early, multiple anesthetic exposures in BTBR mice, an inbred strain that displays autistic behavior. We discovered that three cycles of sevoflurane anesthesia (2.5%, 1 h) with 2-h intervals between each exposure in late postnatal BTBR mice did not aggravate, but instead improved pathophysiological mechanisms involved with autistic behavior. Sevoflurane exposures restored E/I balance (by increasing inhibitory synaptic transmission), and increased mitochondrial respiration and BDNF signaling in BTBR mice. Most importantly, such changes were associated with reduced autistic behavior in BTBR mice, as sociability was increased in the three-chamber test and repetitive behavior was reduced in the self-grooming test. Our results suggest that anesthetic exposures during neurodevelopment may affect individuals diagnosed with NDDs differently.

SCRAPPER Selectively Contributes to Spontaneous Release and Presynaptic Long-Term Potentiation in the Anterior Cingulate Cortex

SCRAPPER is an E3 ubiquitin ligase expressed in presynaptic terminals, neural cell body, and dendrites of the hippocampus and cortex, which is coded by the FBXL20 gene. SCRAPPER is known to regulate synaptic transmissions and long-term potentiation (LTP) in the hippocampus, but no report is available for the cortex. Here we show genetic evidence for critical roles of SCRAPPER in excitatory transmission and presynaptic LTP (pre-LTP) of the anterior cingulate cortex (ACC), a critical cortical region for pain, anxiety, and fear. Miniature and spontaneous releases, but not evoked release, of glutamate were significantly increased in SCRAPPER knock-out (SCR-KO) mice. Interestingly, SCRAPPER selectively contributes to the increases of frequency and amplitude. The pre-LTP in the ACC was completely blocked in SCR-KO mice. Our results thus provide direct evidence for SCRAPPER in both spontaneous release and pre-LTP in the ACC and reveal a potential novel target for treating anxiety-related disease.SIGNIFICANCE STATEMENT The anterior cingulate cortex (ACC) plays critical roles in pain, anxiety, and fear. Peripheral injury induces long-term changes in synaptic transmission in the ACC. Our recent study found that a presynaptic form of LTP (pre-LTP) in the ACC contributes to chronic pain-induced anxiety. Here, we show that SCRAPPER plays a critical role in ACC pre-LTP as well as synaptic transmission.

Mechanisms of Long-Term Plasticity of Hippocampal GABAergic Synapses.

Long-term potentiation and depression of synaptic transmission have been considered as cellular mechanisms of memory in studies conducted in recent decades. These studies were predominantly focused on mechanisms underlying plasticity at excitatory synapses. Nevertheless, normal central nervous system functioning requires maintenance of a balance between inhibition and excitation, suggesting existence of similar modulation of glutamatergic and GABAergic synapses. Here we review the involvement of G-protein-coupled receptors in the generation of long-term changes in synaptic transmission of inhibitory synapses. We considered the role of endocannabinoid and glutamate systems, GABAB and opioid receptors in the induction of long-term potentiation and long-term depression in inhibitory synapses. The pre- and postsynaptic effects of activation of these receptors are also discussed.

Unlocking the secrets of the δ2 glutamate receptor

Long-term changes in synaptic transmission in the central nervous system, such as long-term potentiation and long-term depression (LTD), are believed to underlie learning and memory in vivo. Despite intensive research, the precise molecular mechanisms underlying these phenomena have remained unclear. LTD is most commonly caused by the endocytosis of postsynaptic AMPA-type glutamate receptors, triggered by activity-induced serine phosphorylation of the GluA2 subunit. Interestingly, cerebellar LTD, which occurs at synapses between parallel fibers (PFs; axons of granule cells) and Purkinje cells, is unique in requiring an additional type of glutamate receptor, the δ2 receptor (GluD2). Cbln1 was recently identified as a GluD2 ligand that regulates PF synapse formation and maintenance. However, how GluD2 induces downstream signaling in Purkinje cells to regulate LTD induction is unknown. We here present evidence that GluD2 reduces the tyrosine phosphorylation level of the GluA2 subunit via PTPMEG, a protein tyrosine phosphatase that binds to GluD2's C-terminus. We also found that the serine phosphorylation of GluA2, a crucial step for AMPA-receptor endocytosis, requires prior tyrosine dephosphorylation. Thus, GluD2 may serve as a gatekeeper for LTD induction by coordinating interactions between GluA2's 2 phosphorylation sites.

Area-Specific Alterations of Synaptic Plasticity in the 5XFAD Mouse Model of Alzheimer’s Disease: Dissociation between Somatosensory Cortex and Hippocampus

Transgenic mouse models of Alzheimer’s disease (AD) that overproduce the amyloid beta peptide (Aβ) have highlighted impairments of hippocampal long-term synaptic plasticity associated with the progression of the disease. Here we examined whether the characteristics of one of the hallmarks of AD, i.e. Aβ deposition, in both the somatosensory cortex and the hippocampus, correlated with specific losses of synaptic plasticity in these areas. For this, we evaluated the occurrence of long-term potentiation (LTP) in the cortex and the hippocampus of 6-month old 5xFAD transgenic mice that exhibited massive Aβ deposition in both regions but with different features: in cortical areas a majority of Aβ deposits comprised a dense core surrounded by a diffuse corona while such kind of Aβ deposition was less frequently observed in the hippocampus. In order to simultaneously monitor synaptic changes in both areas, we developed a method based on the use of Multi-Electrode Arrays (MEA). When compared with wild-type (WT) mice, basal transmission was significantly reduced in both areas in 5xFAD mice, while short-term synaptic plasticity was unaffected. The induction of long-term changes of synaptic transmission by different protocols revealed that in 5xFAD mice, LTP in the layer 5 of the somatosensory cortex was more severely impaired than LTP triggered in the CA1 area of the hippocampus. We conclude that cortical plasticity is deficient in the 5xFAD model and that this deficit could be correlated with the proportion of diffuse plaques in 5xFAD mice.

Heterosynaptic plasticity induced by intracellular tetanization in layer 2/3 pyramidal neurons in rat auditory cortex

Associative Hebbian-type synaptic plasticity underlies the mechanisms of learning and memory; however, Hebbian learning rules lead to runaway dynamics of synaptic weights and lack mechanisms for synaptic competition.Heterosynaptic plasticity may solve these problems by complementing plasticity at synapses that were active during the induction, with opposite-sign changes at non-activated synapses. In visual cortex, a potential candidate mechanism for normalization is plasticity induced by a purely postsynaptic protocol, intracellular tetanization. Here we asked if intracellular tetanization can induce long-term plasticity in auditory cortex. We recorded excitatory postsynaptic potentials (EPSPs) of regular (n =76) and all-or-none (n =24) type in layer 2/3 pyramidal cells in slices from rat auditory cortex. After intracellular tetanization, 32 of 76 regular inputs (42%) showed long-term depression, 21 inputs (28%) showed potentiation and 23 inputs (30%) did not change. The direction of plasticity correlated with the initial release probability: inputs with initially low release probability tended to be potentiated, while inputs with high release probability tended to be depressed. Thus, intracellular tetanization had a normalizing effect on synaptic efficacy. Induction of plasticity by intracellular tetanization required a rise of intracellular [Ca(2+)], because it was impaired by chelating intracellular calcium with EGTA. The long-term changes induced by intracellular tetanization involved both pre and postsynaptic mechanisms. EPSP amplitude changes were correlated with changes of release indices: paired-pulse ratio and the inverse of the coefficient of variation (CV(-2)). Furthermore at some all-or-none synapses, changes of averaged response amplitude were correlated with a change of the failure rate, without a change of the synaptic potency, measured as averaged amplitude of successful responses. Presynaptic components of plastic changes were abolished in experiments with blockade of NO-synthesis and spread, indicating involvement of NO signalling. These results demonstrate that the ability of purely postsynaptic challenges to induce plasticity is a general property of pyramidal neurons of both auditory and visual cortices.

Methamphetamine-Evoked Depression of GABAB Receptor Signaling in GABA Neurons of the VTA

Psychostimulants induce neuroadaptations in excitatory and fast inhibitory transmission in the ventral tegmental area (VTA). Mechanisms underlying drug-evoked synaptic plasticity of slow inhibitory transmission mediated by GABA(B) receptors and G protein-gated inwardly rectifying potassium (GIRK/Kir(3)) channels, however, are poorly understood. Here, we show that 1 day after methamphetamine (METH) or cocaine exposure both synaptically evoked and baclofen-activated GABA(B)R-GIRK currents were significantly depressed in VTA GABA neurons and remained depressed for 7 days. Presynaptic inhibition mediated by GABA(B)Rs on GABA terminals was also weakened. Quantitative immunoelectron microscopy revealed internalization of GABA(B1) and GIRK2, which occurred coincident with dephosphorylation of serine 783 (S783) in GABA(B2), a site implicated in regulating GABA(B)R surface expression. Inhibition of protein phosphatases recovered GABA(B)R-GIRK currents in VTA GABA neurons of METH-injected mice. This psychostimulant-evoked impairment in GABA(B)R signaling removes an intrinsic brake on GABA neuron spiking, which may augment GABA transmission in the mesocorticolimbic system.

Endocannabinoids mediate synaptic plasticity at glutamatergic synapses on spiny neurons within a basal ganglia nucleus necessary for song learning

Activation of type 1 cannabinoid receptors (CB(1)R) in many central nervous system structures induces both short- and long-term changes in synaptic transmission. Within mammalian striatum, endocannabinoids (eCB) are one of several mechanisms that induce synaptic plasticity at glutamatergic terminals onto medium spiny neurons. Striatal synaptic plasticity may contribute a critical component of adaptive motor coordination and procedural learning. Songbirds are advantageous for studying the neural mechanisms of motor learning because they possess a neural pathway necessary for song learning and adult song plasticity that includes a striato-pallidal nucleus, area X (homologous to a portion of mammalian basal ganglia). Recent findings suggest that eCBs contribute to vocal development. For example, dense CB(1)R expression in song control nuclei peaks around the closure of the sensori-motor integration phase of song development. Also, systemic administration of a CB(1)R agonist during vocal development impairs song learning. Here we test whether activation of CB(1)R alters excitatory synaptic input on spiny neurons in area X of adult male zebra finches. Application of the CB(1)R agonist WIN55212-2 decreased excitatory postsynaptic current (EPSC) amplitude; that decrease was blocked by the CB(1)R antagonist AM251. Guided by eCB experiments in mammalian striatum, we tested and verified that at least two mechanisms indirectly activate CB(1)Rs through eCBs in area X. First, activation of group I metabotropic glutamate receptors with the agonist 3,5-dihydroxyphenylglycine (DHPG) induced a CB(1)R-mediated reduction in EPSC amplitude. Second, we observed that a 10 s postsynaptic depolarization induced a calcium-mediated, eCB-dependent decrease in synaptic strength that resisted rescue with late CB(1)R blockade. Together, these results show that eCB modulation occurs at inputs to area X spiny neurons and could influence motor learning and production.

Regulation of synaptic transmission and plasticity by neuronal nicotinic acetylcholine receptors

Nicotinic acetylcholine receptors (nAChRs) are widely expressed throughout the central nervous system and participate in a variety of physiological functions. Recent advances have revealed roles of nAChRs in the regulation of synaptic transmission and synaptic plasticity, particularly in the hippocampus and midbrain dopamine centers. In general, activation of nAChRs causes membrane depolarization and directly and indirectly increases the intracellular calcium concentration. Thus, when nAChRs are expressed on presynaptic membranes their activation generally increases the probability of neurotransmitter release. When expressed on postsynaptic membranes, nAChR-initiated calcium signals and depolarization activate intracellular signaling mechanisms and gene transcription. Together, the presynaptic and postsynaptic effects of nAChRs generate and facilitate the induction of long-term changes in synaptic transmission. The direction of hippocampal nAChR-mediated synaptic plasticity – either potentiation or depression – depends on the timing of nAChR activation relative to coincident presynaptic and postsynaptic electrical activity, and also depends on the location of cholinergic stimulation within the local network. Therapeutic activation of nAChRs may prove efficacious in the treatment of neuropathologies where synaptic transmission is compromised, as in Alzheimer's or Parkinson's disease.

Ageing, hippocampal synaptic activity and magnesium.

Ageing is associated with a general decline in physiological functions. Amongst the different aspects of body deterioration, cognitive impairments, and particularly defects in learning and memory, represent one of the most frequent features in the elderly. However, a great variability exists among aged subjects. Clinical reports and experimental data in animal models of ageing have shown that age-associated memory deficits are broadly identical to those induced by damage to the hippocampus. It is therefore not surprising that many functional properties of hippocampal neuronal networks are particularly altered with ageing. Whereas passive membrane properties of neurons are conserved with age, neuronal excitability is altered, in keeping with weaker performances of aged subjects in memory tasks. Synaptic transmission within hippocampal networks also decreases in brain ageing. Deficits concern both glutamatergic and cholinergic pathways, which represent the main excitatory neurotransmitter systems responsible for neuronal communication in the hippocampus. In addition, long-term changes in synaptic transmission, possible cellular substrates for learning and memory, are also impaired in ageing in correlation with cognitive impairments. Neuronal properties and synaptic plasticity closely depend on ion exchanges between intra- and extracellular compartments. Changes in ion regulation during ageing may therefore participate in altering functional properties of neuronal networks. Calcium dysregulation has been extensively investigated in brain ageing but the role of magnesium has received less attention though ageing constitutes a risk factor for magnesium deficit. One of general properties of magnesium at presynaptic fibre terminals is to reduce transmitter release. At the postsynaptic level, it closely controls the activation of the N-methyl-D-aspartate receptor, a subtype of glutamate receptor, which is critical for the expression of long-term changes in synaptic transmission. In addition, magnesium is a cofactor of many enzymes localized either in neurons or in glial cells that control neuronal properties and synaptic plasticity such as protein-kinase C, calcium/calmodulin-dependent protein kinase II and serine racemase. It is therefore likely that a change in magnesium concentration would significantly impair synaptic functions in the aged hippocampus. Experiments addressing this question remain too scarce but recent data indicate that magnesium is involved in age-related deficits in transmitter release, neuronal excitability and in some forms of synaptic plasticity such as long-term depression of synaptic transmission. Further studies are still necessary to better delineate to what extent magnesium contributes to the impaired cellular mechanisms of cognitive functions in the elderly which will help to develop new strategies to minimize age-related memory declines.

Long-term potentiation of evoked presynaptic response at CA3–CA1 synapses by transient oxygen-glucose deprivation in rat brain slices

Physiological activity-dependent long-term changes in synaptic transmission, as long-term potentiation (LTP) are thought to be the substrate of learning and memory. However, a form of postsynaptic pathological LTP at the CA3-CA1 synapses has been demonstrated following few minutes of anoxia and aglycemia in vitro. The ischemia LTP shared many molecular mechanisms with the physiological LTP, and was believed to be involved in the delayed neuronal death following ischemia. However, the role of the presynaptic component in this regard is not known. Here we show that a short period of oxygen-glucose deprivation can induce a form of LTP (lasting for hours) of the presynaptic response at the CA3-CA1 synapses. This form of LTP is independent of postsynaptic alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors, but Ca(2+) dependent. This presynaptic LTP may represent a presynaptic hyperexcitability of the afferent fibers following ischemia, and responsible for the excitotoxicity to the CA1 neurons (ischemia-induced increases of glutamate release that kills neurons) and the postsynaptic pathological ischemic LTP.

Long‐term in vivo modulation of synaptic efficacy at the neuromuscular junction of Rana pipiens frogs

Prolonged changes in motor neurone activity can result in long-term changes in synaptic transmission. We investigated whether mechanisms commonly thought to be involved in determining synaptic efficacy of vertebrate motor neurones are involved in these long-term changes. The nerve supplying the cutaneous pectoris muscle was chronically stimulated via skin surface electrodes in freely moving frogs for 5-7 days. Chronic stimulation induced a 50% reduction in evoked endplate potential (EPP) amplitude at stimulated neuromuscular junctions (NMJs). These changes appear to be presynaptic since miniature EPP (mEPP) amplitude was unchanged while mEPP frequency was decreased by 46% and paired-pulse facilitation was increased by 26%. High frequency facilitation (40 Hz, 2 s) was also increased by 89%. Moreover, stimulated NMJs presented a 92% decrease in synaptic depression (40 Hz, 2 s). An increase in mitochondrial metabolism was observed as indicated by a more pronounced labelling of active mitochondria (Mitotracker) in stimulated nerve terminals, which could account for their greater resistance to synaptic depression. NMJ length visualized by alpha-bungarotoxin staining of nAChRs was not affected. Presynaptic calcium signals measured with Calcium Green-1 were larger in stimulated NMJs at low frequency (0.2 Hz) and not different from control NMJs at higher frequency (40 Hz, 2 s and 30 s). These results suggest that some mechanisms downstream of calcium entry are responsible for the determination of synaptic output, such as a down-regulation of some calcium-binding proteins, which could explain the observed results. The possibility of a change in frequenin expression, a calcium-binding protein that is more prominently expressed in phasic synapses, was, however, refuted by our results.

Prepulse inhibition and fear-potentiated startle are altered in tissue inhibitor of metalloproteinase-2 (TIMP-2) knockout mice

The ability to discriminate between potential dangers and recall those stimuli is essential for survival. This emotional learning requires the involvement of higher brain structures, including the amygdala, hippocampus and related cortical structures. Long-term changes in synaptic transmission and structure are important for the establishment and consolidation of fear memory. The structural changes associated with this synaptic plasticity likely require alterations in the composition of the extracellular matrix (ECM). ECM integrity is maintained by the opposing action of matrix metalloproteinases (MMPs) and their specific inhibitors, tissue inhibitors of metalloproteinases (TIMPs). To date, no studies have examined the role of MMPs or TIMPs in conditioned fear. Here, we show that neither male nor female mice deficient in TIMP-2 (knockout) exhibit prepulse inhibition of the startle reflex, suggesting deficits in pre-attentional sensorimotor gating. In addition, knockout mice and mice expressing a mutant truncated TIMP-2 (knock-down) show deficits in fear-potentiated startle. This is the first report of a phenotype for the TIMP-2 −/− mice and suggests that TIMP-2 may play a role in the synaptic plasticity underlying learning and memory.

Retrograde signalling with nitric oxide at neocortical synapses.

Long-term changes of synaptic transmission in slices of rat visual cortex were induced by intracellular tetanization: bursts of short depolarizing pulses applied through the intracellular electrode without concomitant presynaptic stimulation. Long-term synaptic changes after this purely postsynaptic induction were associated with alterations of release indices, thus providing a case for retrograde signalling at neocortical synapses. Both long-term potentiation and long-term depression were accompanied by presynaptic changes, indicating that retrograde signalling can achieve both up- and down-regulation of transmitter release. The direction and the magnitude of the amplitude changes induced by a prolonged intracellular tetanization depended on the initial properties of the input. The inputs with initially high paired-pulse facilitation (PPF) ratio, indicative of low release probability, were most often potentiated. The inputs with initially low PPF ratio, indicative of high release probability, were usually depressed or did not change. Thus, prolonged postsynaptic activity can lead to normalization of the weights of nonactivated synapses. The dependence of polarity of synaptic modifications on initial PPF disappeared when plastic changes were induced with a shorter intracellular tetanization, or when the NO signalling pathway was interrupted by inhibition of NO synthase activity or by application of NO scavengers. This indicates that the NO-dependent retrograde signalling system has a relatively high activation threshold. Long-term synaptic modifications, induced by a weak postsynaptic challenge or under blockade of NO signalling, were nevertheless associated with presynaptic changes. This suggests the existence of another retrograde signalling system, additional to the high threshold, NO-dependent system. Therefore, our data provide a clear case for retrograde signalling at neocortical synapses and indicate that multiple retrograde signalling systems, part of which are NO-dependent, are involved.

Apoptotic and anti-apoptotic synaptic signaling mechanisms.

Although several prominent morphological features of apoptosis are evident in the cell body (e.g., cell shrinkage, membrane blebbing, and nuclear DNA condensation and fragmentation) the biochemical and molecular cascades that constitute the cell death machinery can be engaged in synaptic terminals and neurites. Initiating events such as oxyradical production and calcium influx, and effector processes such as Par-4 production, mitochondrial alterations and caspase activation, can be induced in synapses and neurites. Several prominent signal transduction pathways in synaptic terminals play important roles in either promoting or preventing neuronal death in physiological and pathological conditions. For example, activation of glutamate receptors in postsynaptic spines can induce neuronal apoptosis, whereas local activation of neurotrophic factor receptors in presynaptic terminals can prevent neuronal death. Factors capable of inducing nuclear chromatin condensation and fragmentation can be produced locally in synaptic terminals and neurites, and may propogate to the cell body. Recent findings suggest that, beyond their roles in inducing or preventing cell death, apoptotic and anti-apoptotic cascades play roles in synaptic plasticity (structural remodelling and long-term functional changes). For example, caspase activation results in proteolysis of glutamate receptor (AMPA) subunits, which results in altered neuronal responsivity to glutamate. Activation of neurotrophic factor receptors in synaptic terminals can result in local changes in energy metabolism and calcium homeostasis, and can induce long-term changes in synaptic transmission. The emerging data therefore suggest that synapses can be considered as autonomous compartments in which both pro- and anti-apoptotic signaling pathways are activated resulting in structural and functional changes in neuronal circuits. A better understanding of such synaptic signaling mechanisms may reveal novel approaches for preventing and treating an array of neurodegenerative conditions that are initiated by perturbed synaptic homeostasis.

Kainate receptors are involved in synaptic plasticity.

The ability of synapses to modify their synaptic strength in response to activity is a fundamental property of the nervous system and may be an essential component of learning and memory. There are three classes of ionotropic glutamate receptor, namely NMDA (N-methyl-D-aspartate), AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole-4-propionic acid) and kainate receptors; critical roles in synaptic plasticity have been identified for two of these. Thus, at many synapses in the brain, transient activation of NMDA receptors leads to a persistent modification in the strength of synaptic transmission mediated by AMPA receptors. Here, to determine whether kainate receptors are involved in synaptic plasticity, we have used a new antagonist, LY382884 ((3S, 4aR, 6S, 8aR)-6-((4-carboxyphenyl)methyl-1,2,3,4,4a,5,6,7,8,8a-decahydro isoquinoline-3-carboxylic acid), which antagonizes kainate receptors at concentrations that do not affect AMPA or NMDA receptors. We find that LY382884 is a selective antagonist at neuronal kainate receptors containing the GluR5 subunit. It has no effect on long-term potentiation (LTP) that is dependent on NMDA receptors but prevents the induction of mossy fibre LTP, which is independent of NMDA receptors. Thus, kainate receptors can act as the induction trigger for long-term changes in synaptic transmission.

Interaction between intracellular tetanization and pairing-induced long-term synaptic plasticity in the rat visual cortex

Long-term changes in synaptic transmission in slices of rat visual cortex were induced either by pairing the excitatory postsynaptic potentials with postsynaptic depolarization or by intracellular tetanization without synaptic stimulation. Changes in the excitatory postsynaptic potential amplitude induced by any of the protocols applied in isolation persisted for longer than 1 h. Pairing-induced long-term potentiation was input specific. We studied the interaction between intracellular tetanization and pairing-induced plasticity by applying the two protocols one after the other at 10-min intervals. The pairing procedure applied after intracellular tetanization did not lead to any further potentiation, but to a depotentiation of the potentiated inputs. A second pairing protocol applied 10 min later led to further depotentiation, while previously unaffected inputs became weakly depressed. If intracellular tetanization was applied after the pairing procedure, the synaptic responses did not change immediately, but a slow return of the excitatory postsynaptic potential amplitude to the control level could be observed. Therefore, intracellular tetanization is not capable of inducing further potentiation after pairing, and pairing cannot further potentiate the inputs which have already been potentiated by intracellular tetanization. The maintenance of long-term potentiation induced by any of the protocols was impaired by successive application of another procedure. These results suggest a similarity of the mechanisms of synaptic changes induced by the two protocols and demonstrate that the direction of synaptic gain change depends on the history of the synapse.

Synaptic depression induced by pharmacological activation of metabotropic glutamate receptors in the perirhinal cortex in vitro

The perirhinal cortex is crucially involved in various forms of learning and memory. Decrements in neuronal responsiveness occur in the perirhinal cortex with stimulus repetition during visual recognition performance. However, very little is known concerning the underlying mechanisms of synaptic transmission and plasticity in this cortical region. In this study, we provide evidence demonstrating the presence of functional group I, II and III metabotropic glutamate receptors in the rat perirhinal cortex in vitro. Furthermore, the results demonstrate long-lasting synaptic depression in the perirhinal cortex. Extracellular synaptic responses were recorded from superficial layers of the perirhinal cortex directly below the rhinal sulcus, in response to electrical stimuli delivered in the superficial or intermediate layers to the entorhinal or temporal cortex sides of the rhinal sulcus. Evoked synaptic potentials were depressed during bath perfusion of each of the following: the broad-spectrum metabotropic glutamate receptor agonist (1 S,3 R)-1-aminocyclopentane-1,3-dicarboxylic acid, the selective group I agonist ( R, S)-3,5-dihydroxyphenylglycine, the group II agonist (2 S,1′ R,2′ R,3′ R)-(2′,3′-dicarboxycyclopropyl)glycine and the group III agonist ( S)-2-amino-4-phosphonobutanoate. Furthermore, there was a long-lasting depression of synaptic transmission following washout of (1 S,3 R)-1-aminocyclopentane-1,3-dicarboxylic acid, ( R, S)-3,5-dihydroxyphenylglycine or (2 S,1′ R,2′ R,3′ R)-(2′,3′-dicarboxycyclopropyl)glycine. Activation of group III metabotropic glutamate receptors by ( S)-2-amino-4-phosphonobutanoate did not result in long-lasting changes in synaptic transmission. Thus, the pharmacological activation of metabotropic glutamate receptors can produce short- or long-term changes in synaptic transmission in the perirhinal cortex. It is possible therefore, that metabotropic glutamate receptors are involved in the decrement in neuronal responsiveness associated with visual recognition in the perirhinal cortex.

Long-term changes of synaptic transmission: A topic of long-term interest

Long-term modifications of synaptic efficacy at excitatory synapses are considered as a putative cellular substrate for learning and memory processes. Cerebellar long-term depression (LTD) occurring at parallel fibers (PF)-Purkinje neurons (PN) synapses is thought to repre-sent a cellular model of motor learning. Crépel et al. and Linden describe this phenomenon by utilizing different tissue preparations. [CRÉPEL et al., LINDEN]

Shared calcium signaling pathways in the induction of long-term potentiation and synaptic disinhibition in CA1 pyramidal cell dendrites

1. Calcium signaling pathways were examined in the induction of long-term synaptic disinhibition following tetanization. Effects of tetanization on gamma-aminobutyric acid-A (GABAA receptor-mediated inhibitory responses were measured and compared with excitatory responses under experimental conditions previously used for examining induction mechanisms of N-methyl-D-aspartate (NMDA)-dependent long-term potentiation (LTP). Intracellular recordings were performed in current-clamp and discontinuous single-electrode voltage-clamp (dSEVC) modes in CA1 pyramidal cell apical dendrites in hippocampal slices of adult guinea pigs with the use of sharp electrodes. Test pulses and tetanic stimuli were applied to the Schaffer collateral fibers in stratum radiatum. 2. Under standard control conditions [3 M K Ac in the recording pipette and artificial cerebrospinal fluid as extracellular solution], tetanization-induced sustained increases of excitatory responses were accompanied by marked decreases of parameters of GABAA-mediated synaptic inhibition: at 40 min after tetanization [posttetanus 40 (PT 40)], orthodromically evoked excitatory postsynaptic potential (EPSP) peak amplitudes were on average 195 +/- 15% (mean +/- SE) and excitatory postsynaptic currents (IPSPs) were 166 +/- 10% of pretetanus controls. Peak amplitudes of orthodromically evoked inhibitory postsynaptic potentials (IPSPs) were 30 +/- 5% and inhibitory postsynaptic currents (IPSCs) were 21 +/- 4% at PT 40. Synaptic GABAA conductances (measured as chord conductances) were reduced to 22 +/- 4% at PT 40. Iontophoretic GABAA responses measured as conductance changes were 28 +/- 4% of pretetanus controls at PT 40. 3. A role of NMDA receptors in induction of long-term synaptic disinhibition was tested by preventing NMDA receptor activation 1) by pharmacological means and 2) by holding the membrane clamped at -80 mV (in dSEVC) during tetanization. In the presence of the NMDA-receptor antagonist D-2-amino5-phosphonopentanoic acid (D-AP5) 10-40 microM), orthodromically evoked EPSP amplitudes were 107 +/- 9%, EPSCs were 104 +/- 6%, GABAA-mediated IPSPs were 88 +/- 8%, IPSCs were 97 +/- 8%, synaptic GABAA conductances were 84 +/- 9%, and iontophoretic GABAA conductances were 102 +/- 13% at PT 40. In recordings in which the dendritic membrane potential was clamped at -80 mV during tetanization, orthodromically evoked peak amplitudes of EPSPs were 105 +/- 11%, EPSCs were 102 +/- 8, IPSPs were 103 +/- 4%, IPSCs were 102 +/- 5%, GABAA chord conductances were 101 +/- 9%, and iontophoretically evoked GABAA conductances were 105 +/- 5% at PT 40. 4. In recordings in which the intracellular pipette was preloaded with the Ca2+ chelator 1,2-bis(2-aminophenoxy) ethane-N,N,N'N"-tetraacetic acid (BAPTA) (5mM), long-term changes of synaptic transmission (increases of excitation, decreases of synaptic inhibition) were prevented. At PT 40, EPSP peak amplitudes were 93 +/- 7%, EPSCs were 115 +/- 6%, IPSPs were 115 +/- 9%, IPSCs were 117 +/- 8%, and synaptic GABAA conductances were 108 +/- 17%. Iontophoretic conductances at PT 40 were 109 +/- 9% over pretetanus controls when recorded with BAPTA-containing electrodes. 5. In recordings in which the intracellular pipette was preloaded with cypermethrin, a potent and selective inhibitor of phosphatase 2B, respective long-term changes of synaptic transmission (increases of excitation, decreases of synaptic inhibition) were prevented. At PT 40, EPSP peak amplitudes were 98 +/- 6%, EPSCs were 105 +/- 10%, IPSPs were 99 +/- 5%, IPSCs were 104 +/- 7%, synaptic GABAA conductances were 97 +/- 6% and iontophoretic GABAA conductances were 113 +/- 18% over pretetanus controls in cypermethrin-containing recordings. 6. In conclusion, the data presented demonstrate shared cellular pathways in the induction of both LTP and long-term synaptic disinhibition in apical dendrites of CA1 pyramidal cells after tetanization of the Schaffer collaterals.