Increase In Synaptic Transmission Research Articles

Brain-Derived Neurotrophic Factor Controls Activity-Dependent Maturation of CA1 Synapses by Downregulating Tonic Activationof Presynaptic Kainate Receptors

Immature hippocampal synapses express presynaptic kainate receptors (KARs), which tonically inhibit glutamate release. Presynaptic maturation involves activity-dependent downregulation of the tonic KAR activity and consequent increase in release probability; however, the molecular mechanisms underlying this developmental process are unknown. Here, we have investigated whether brain derived neurotrophic factor (BDNF), a secreted protein implicated in developmental plasticity in several areas of the brain, controls presynaptic maturation by regulating KARs. Application of BDNF in neonate hippocampal slices resulted in increase in synaptic transmission that fully occluded the immature-type KAR activity in area CA1. Conversely, genetic ablation of BDNF was associated with delayed synaptic maturation and persistent presynaptic KAR activity, suggesting a role for endogenous BDNF in the developmental regulation of KAR function. In addition, our data suggests a critical role for BDNF TrkB signaling in fast activity-dependent regulation of KARs. Selective acute inhibition of TrkB receptors using a chemical-genetic approach prevented rapid change in synapse dynamics and loss of tonic KAR activity that is typically seen in response to induction of LTP at immature synapses. Together, these data show that BDNF-TrkB-dependent maturation of glutamatergic synapses is tightly associated with a loss of endogenous KAR activity. The coordinated action of these two receptor mechanisms has immediate physiological relevance in controlling presynaptic efficacy and transmission dynamics at CA3-CA1 synapses at a stage of development when functional contact already exists but transmission is weak.

Alzheimer β-amyloid blocks epileptiform activity in hippocampal neurons

Several studies showed that hippocampal neurons respond with an increase in synaptic transmission after chronic blockade of GABA A receptors with bicuculline, a neuroplastic phenomenon likely associated to epileptiform states. Here, we tested the effect of Aβ 1–40 oligomers/aggregates, believed to be involved in Alzheimer's Disease (AD) genesis, on this type of synaptic plasticity. In the presence of bicuculline, the frequency of miniature currents increased from 1.2 ± 0.4 Hz to 3.1 ± 0.6 Hz ( n = 6, ⁎ p < 0.05). Similarly, current amplitude increased from 45 ± 3 pA to 81 ± 11 pA ( n = 5, ⁎ p < 0.05). These effects were completely inhibited in the presence of Aβ 1–40 aggregates. Data suggest that Aβ aggregates exert their influence principally by blocking synaptic transmission and altering the transcriptional pathway associated with CREB-p. In conclusion, neurons exposed to aggregated Aβ 1–40 showed a reduced level of neuronal plasticity and this suggests that they might be acting as anti-epileptiform modulators.

Retinoic acid regulates RARα-mediated control of translation in dendritic RNA granules during homeostatic synaptic plasticity

Homeostatic plasticity is thought to play an important role in maintaining the stability of neuronal circuits. During one form of homeostatic plasticity, referred to as synaptic scaling, activity blockade leads to a compensatory increase in synaptic transmission by stimulating in dendrites the local translation and synaptic insertion of the AMPA receptor subunit GluR1. We have previously shown that all-trans retinoic acid (RA) mediates activity blockade-induced synaptic scaling by activating dendritic GluR1 synthesis and that this process requires RARalpha, a member of the nuclear RA receptor family. This result raised the question of where RARalpha is localized in dendrites and whether its localization is regulated by RA and/or activity blockade. Here, we show that activity blockade or RA treatment in neurons enhances the concentration of RARalpha in the dendritic RNA granules and activates local GluR1 synthesis in these RNA granules. Importantly, the same RNA granules that contain RARalpha also exhibit an accumulation of GluR1 protein but with a much slower time course than that of RARalpha, suggesting that the former regulates the latter. Taken together, our results provide a direct link between dendritically localized RARalpha and local GluR1 synthesis in RNA granules during RA-mediated synaptic signaling in homeostatic synaptic plasticity.

Viral Vector–mediated Delivery of Estrogen Receptor-α to the Hippocampus Improves Spatial Learning in Estrogen Receptor-α Knockout Mice

Estrogen, which influences both classical genomic and rapid membrane-associated signaling cascades, has been implicated in the regulation of hippocampal function, including spatial learning. Gene mutation studies suggest that estrogen effects are mediated by estrogen receptor-α (ER-α); however, because gonadal steroids influence the organization of the hippocampus during development, it has been difficult to distinguish developmental effects from those specific to adults. In this study we show that lentiviral delivery of the gene encoding ER-α to the hippocampus of adult ER-α-knockout (ER-αKO) mice restores hippocampal responsiveness to estrogen and rescues spatial learning. We propose that constitutive estrogen receptor activity is important for maintaining hippocampus-dependent memory function in adults.

Endocytosis Is Required for Synaptic Activity-Dependent Release of Amyloid-β In Vivo

Aggregation of amyloid-beta (Abeta) peptide into soluble and insoluble forms within the brain extracellular space is central to the pathogenesis of Alzheimer's disease. Full-length amyloid precursor protein (APP) is endocytosed from the cell surface into endosomes where it is cleaved to produce Abeta. Abeta is subsequently released into the brain interstitial fluid (ISF). We hypothesized that synaptic transmission results in more APP endocytosis, thereby increasing Abeta generation and release into the ISF. We found that inhibition of clathrin-mediated endocytosis immediately lowers ISF Abeta levels in vivo. Two distinct methods that increased synaptic transmission resulted in an elevation of ISF Abeta levels. Inhibition of endocytosis, however, prevented the activity-dependent increase in Abeta. We estimate that approximately 70% of ISF Abeta arises from endocytosis-associated mechanisms, with the vast majority of this pool also dependent on synaptic activity. These findings have implications for AD pathogenesis and may provide insights into therapeutic intervention.

Regulation of glycinergic and GABAergic synaptogenesis by brain-derived neurotrophic factor in developing spinal neurons

Brain-derived neurotrophic factor (BDNF) effects on the establishment of glycinergic and GABAergic transmissions in mouse spinal neurons were examined using combined electrophysiological and calcium imaging techniques. BDNF (10 ng/ml) caused a significant acceleration in the onset of synaptogenesis without large effects on the survival of these neurons. Amplitude and frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) and miniature inhibitory postsynaptic currents (mIPSCs) associated to activation of glycine and GABA A receptors were augmented in neurons cultured with BDNF. The neurotrophin effect was blocked by long term tetrodotoxin (TTX) addition suggesting a dependence on neuronal activity. In addition, BDNF caused a significant increase in glycine- and GABA-evoked current densities that partly explains the increase in synaptic transmission. Presynaptic mechanisms were also involved in BDNF effects since triethylammonium(propyl)-4-(2-(4-dibutylamino-phenyl)vinyl)pyridinium (FM1-43) destaining with high K + was augmented in neurons incubated with the neurotrophin. The effects of BDNF were mediated by receptor tyrosine kinase B (TrkB) and mitogen-activated protein kinase kinase (MEK) activation since culturing neurons with either (9S,10R,12R)-2,3,9,10,11,12-hexahydro-10-hydroxy-9-methyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3′,2′,1′- kl]pyrrolo[3,4-i][1,6]benzodiazocine-10-carboxylic acid methyl ester (K252a) or 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one (PD98059) blocked the augmentation in synaptic activity induced by the neurotrophin.

Codificación y retención de la memoria: el factor neurotrófico derivado del cerebro (BDNF) en la plasticidad sináptica

It has been suggested that the long-term modifications that take place in synaptic transmission constitute the foundation of the processes by which information stored. The neurotrophin called brain-derived neurotrophic factor (BDNF) has recently emerged as a powerful molecular mediator in central synaptic plasticity. In this work we review the studies that have represented a significant step forward in explaining the role played by BDNF in long-term synaptic plasticity. The effects of BDNF on synaptic plasticity can be of a permissive nature, whereby it establishes the conditions under which plastic changes can take place, or it may be instructive. In this latter case it exerts direct effects that bring about changes in the communication and morphology of the synapses. The actions carried out by BDNF include its capacity to contribute to the stabilisation and maturation of already-existing synapses, as well as to generate new synaptic contacts. One important finding that highlights the participation of this neurotrophin in synaptic plasticity is the observation that adding BDNF gives rise to drastic long-term increases in synaptic transmission, similar to the long-term potentiation in the hippocampus and neocortex of mammals. Because BDNF modulates both the electrical properties and the structural organisation of the synapse, this neurotrophin has been considered to be an important marker during learning and memory processes.

Anti‐homeostatic synaptic plasticity of glycine receptor function after chronic strychnine in developing cultured mouse spinal neurons

In this study, we describe a novel form of anti-homeostatic plasticity produced after culturing spinal neurons with strychnine, but not bicuculline or 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). Strychnine caused a large increase in network excitability, detected as spontaneous synaptic currents and calcium transients. The calcium transients were associated with action potential firing and activation of gamma-aminobutyric acid (GABA(A)) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors as they were blocked by tetrodotoxin (TTX), bicuculline, and CNQX. After chronic blockade of glycine receptors (GlyRs), the frequency of synaptic transmission showed a significant enhancement demonstrating the phenomenon of anti-homeostatic plasticity. Spontaneous inhibitory glycinergic currents in treated cells showed a fourfold increase in frequency (from 0.55 to 2.4 Hz) and a 184% increase in average peak amplitude compared with control. Furthermore, the augmentation in excitability accelerated the decay time constant of miniature inhibitory post-synaptic currents. Strychnine caused an increase in GlyR current density, without changes in the apparent affinity. These findings support the idea of a post-synaptic action that partly explains the increase in synaptic transmission. This phenomenon of synaptic plasticity was blocked by TTX, an antibody against brain-derived neurotrophic factor (BDNF) and K252a suggesting the involvement of the neuronal activity-dependent BDNF-TrkB signaling pathway. These results show that the properties of GlyRs are regulated by the degree of neuronal activity in the developing network.

5‐HT4 receptor activation induces long‐lasting EPSP‐spike potentiation in CA1 pyramidal neurons

Recent studies implicated involvement of the 5-hydroxytryptamine4 (5-HT4) receptor in cognitive and emotional processes. The highest 5-HT4 receptor densities in the brain are found in the limbic system including the hippocampus. Here we used the selective 5-HT4 receptor full agonist, N-pentyl-N'-aminoguanidine carbazimidamide (SDZ-216454) to characterize effects of 5-HT4 receptor activation in whole-cell and field recordings in the area CA1 in hippocampal slices prepared from 3 to 4- and 6 to 9-week-old rats, respectively. Extracellular recordings showed that transient 5-HT4 receptor activation by 10-20 min application of SDZ-216454 induces field excitatory postsynaptic potential (fEPSP)-population spike potentiation (ESP(5-HT4)), which persisted for as long as we held the recordings (> 2 h). ESP(5-HT4) displayed characteristics different from EPSP-spike potentiation that accompanies long-term potentiation; it developed without an associated increase in synaptic transmission, was independent on afferent input, activity of postsynaptic neurons and N-methyl-d-aspartate receptor activation; and was expressed in the presence of GABA receptor antagonists. ESP(5-HT4) was also induced by transient application of the natural neurotransmitter, 5-HT. The increase in the evoked population spike (PS) induced by SDZ-216454 was not prevented by blockers of hyperpolarization-activated cation current (Ih), Cs+ and ZD-7288, but was mimicked and occluded by 150 microm Ba2+. Whole-cell voltage-clamp recordings from pyramidal neurons demonstrated that SDZ-216454 application increases membrane resistance with a concomitant decrease in a Ba2+-sensitive inwardly rectifying K+ current and the Ba2+-insensitive K+ current underlying slow afterhyperpolarization (I(sAHP)). We conclude that 5-HT4 receptor activation may cause a long-lasting excitability increase in CA1 pyramidal neurons by inhibition of a Ba2+-sensitive inwardly rectifying K+ current.

The acid nature of CO2‐evoked adenosine release in the CNS

The acid nature of CO₂‐evoked adenosine release in the CNS

Postsynaptic IP 3 receptor-mediated Ca 2+ release modulates synaptic transmission in hippocampal neurons

Ca 2+-dependent mechanisms are important in regulating synaptic transmission. The results herein indicate that whole-cell perfusion of inositol 1,4,5-trisphosphate receptor (IP 3R) agonists greatly enhanced excitatory postsynaptic current (EPSC) amplitudes in postsynaptic hippocampal CA1 neurons. IP 3R agonist-mediated increases in synaptic transmission changed during development and paralleled age-dependent increases in hippocampal type-1 IP 3Rs. IP 3R agonist-mediated increases in EPSC amplitudes were inhibited by postsynaptic perfusion of inhibitors of Ca 2+/calmodulin, PKC and Ca 2+/calmodulin-dependent protein kinase II. Postsynaptic perfusion of inhibitors of smooth endoplasmic reticulum (SER) Ca 2+-ATPases, which deplete intracellular Ca 2+ stores, also enhanced EPSC amplitudes. Postsynaptic perfusion of the IP 3R agonist adenophostin (AdA) during subthreshold stimulation appeared to convert silent to active synapses; synaptic transmission at these active synapses was completely blocked by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). Postsynaptic IP 3R-mediated Ca 2+ release also produced a significant increase in spontaneous EPSC frequency. These results indicate that Ca 2+ release from intracellular stores play a key role in regulating the function of postsynaptic AMPARs.

Norepinephrine Modulates Glutamatergic Transmission in the Bed Nucleus of the Stria Terminalis

The bed nucleus of the stria terminalis (BNST) and its adrenergic input are key components in stress-induced reinstatement and maintenance of drug use. Intra-BNST injections of either beta-adrenergic receptor (beta-AR) antagonists or alpha2-adrenergic receptor (alpha2-AR) agonists can inhibit footshock-induced reinstatement and maintenance of cocaine- and morphine-seeking. Using electrophysiological recording methods in an in vitro slice preparation from C57/Bl6j adult male mouse BNST, we have examined the effects of adrenergic receptor activation on excitatory synaptic transmission in the lateral dorsal supracommissural BNST (dBNST) and subcommissural BNST (vBNST). Alpha2-AR activation via UK-14,304 (10 microM) results in a decrease in excitatory transmission in both dBNST and vBNST, an effect predominantly dependent upon the alpha2A-AR subtype. Beta-AR activation via isoproterenol (1 microM) results in an increase in excitatory transmission in dBNST, but not in vBNST. Consistent with the work with receptor subtype specific agonists, application of the endogenous ligand norepinephrine (NE, 100 microM) elicits two distinct effects on glutamatergic transmission. In dBNST, NE elicits an increase in transmission (62% of dBNST NE experiments) or a decrease in transmission (38% of dBNST NE experiments). In vBNST, NE elicits a decrease in transmission in 100% of the experiments. In dBNST, the NE-induced increase in synaptic transmission is blocked by beta1/beta2- and beta2-, but not beta1-specific antagonists. In addition, this increase is also reduced by the alpha2-AR antagonist yohimbine and is absent in the alpha2A-AR knockout mouse. In vBNST, the NE-induced decrease in synaptic transmission is markedly reduced in the alpha2A-AR knockout mouse. Further experiments demonstrate that the actions of NE on glutamatergic transmission can be correlated with beta-AR function.

The role of c-Jun N-terminal kinase in the Aβ-mediated impairment of LTP and regulation of synaptic transmission in the hippocampus

The effects of the beta-amyloid peptide (Aβ) fragment 25–35 were investigated on hippocampal synaptic transmission and long-term potentiation (LTP) in vitro. Aβ [25–35] was found to impair both post-tetanic potentiation (PTP) and LTP in the hippocampal CA1. The anthra[1,9-cd]pyrazol-6(2H)-one, SP600125, was used to inhibit c-Jun N-terminal kinase (JNK) activity, which is believed to mediate cell death. Prior application of SP600125 attenuated the Aβ [25–35]-mediated impairment of PTP and LTP, when measured from the pre-drug baseline. In the presence of SP600125 alone, we observed an increase in baseline synaptic transmission and reduction in paired-pulse facilitation, consistent with an increase in synaptic transmission. There was no alteration in the level of PTP and LTP obtained, when measured from the pre-drug baseline. In the presence of both SP600125 and Aβ, however, PTP was greatly enhanced compared with controls. We therefore suggest that the activation of the JNK signalling pathway mediates the effects of Aβ on synaptic plasticity. Our data also indicate that endogenous JNK activity may regulate neurotransmitter release in the hippocampal CA1 in vitro.

Methods of detection of the transcription factor NF-κB in rat hippocampal slices

The hippocampus is one of the most studied sites for understanding the cellular and molecular mechanisms underlying long-term potentiation (LTP) and long-term depression (LTD), mechanisms believed to underlie the formation and storage of memories. The early-phases of LTP and LTD have been most intensively studied and have been shown to involve the activation of several kinases and phosphatases, respectively. The factors involved in the later stages have largely yet to be elucidated. We have focused our attention on the transcription factor NF-κB as a possible factor involved in such late-phase processes, and have developed both immunocytochemistry and electrophoretic mobility shift assay (EMSA) to measure the activated forms of this factor. This is important as many of the studies in this area are performed in vitro and to our knowledge quantitative assessment has not previously being deemed feasible in slice work. The pro-inflammatory cytokines TNF-α and IL-1β both led to pronounced nuclear activation of NF-κB in the dentate granule cells as demonstrated by immunostaining and EMSA, respectively. Electrophysiological measurements taken from slices treated with TNF-α showed that it inhibited LTP (field excitatory post-synaptic potentials (fEPSP) 116±10%, n=9, 60 min post-tetanus compared to control fEPSP 185±9%, n=6; P<0.001). The neurotransmitter l-glutamate also led to activation of NF-κB and electrophysiology recordings showed a small but sustained increase in synaptic transmission (fEPSP 106±12%, 30 min post-drug). These methods provide valuable tools to forward our understanding of the role of NF-κB in plasticity as well as in many neurological disorders being mimicked by in vitro studies.

Ionic mechanisms of GABA-induced long-term potentiation in the rat superior colliculus.

GABA-induced excitation and long-term potentiation (LTPG) have been demonstrated recently in the superficial layers of the superior colliculus (SC). In other regions of the nervous system, GABA elicits excitatory responses via ionotropic GABA receptors under certain conditions. This excitation is proposed to be due to either a high neuronal chloride concentration favouring a depolarising chloride efflux, or to a bicarbonate efflux coupled to a chloride influx. The aim of this study was to characterise the mechanisms underlying excitation and prolonged increase in synaptic transmission induced by GABA in the SC. Extracellular field potentials were recorded from 1-month-old rat SC slices, and LTPG of these responses was evoked by application of 3 mM GABA. GABA-induced excitation and LTPG were significantly reduced by lowering the extracellular calcium concentration, but not by a decreased potassium concentration. Replacing the extracellular bicarbonate-buffered perfusion medium with a HEPES-buffered solution had no effect on LTPG but blocking the bicarbonate-generating enzyme carbonic anhydrase both intra- and extracellularly with ethoxyzolamide (50 microM) prevented LTPG. The chloride transport inhibitor bumetanide (50 microM) reduced but did not block LTPG. We therefore suggest that the contribution of the chloride equilibrium to LTPG is only of minor importance. The intracellular bicarbonate pool and related efflux provides the basis for the excitatory action of GABA, leading to a subsequent depolarisation and calcium influx through voltage-dependent calcium channels, thus causing long-lasting changes in synaptic transmission.

The effects of angiotensin IV analogs on long-term potentiation within the CA1 region of the hippocampus in vitro

Within the brain-renin angiotensin system, it is generally assumed that angiotensin peptide fragments shorter than angiotensins II and III, including angiotensin IV (AngIV), are inactive. This belief has been challenged by the recent discovery that AngIV, and AngIV-like analogs, bind with high affinity and specificity to a putative angiotensin binding site termed AT 4. In the brain these sites include the hippocampus, cerebellum, and cerebral cortex, and influence associative and spatial learning tasks. The present study investigated the effects of two AngIV analogs, Nle 1-AngIV (an AT 4 receptor agonist) and Nle 1-Leual 3-AngIV (an AT 4 receptor antagonist), on long-term potentiation (LTP). Field excitatory postsynaptic potentials (fEPSPs) were recorded from the CA1 stratum radiatum following stimulation of the Schaffer collateral pathway. Activation of AT 4 receptors by Nle 1-AngIV enhanced synaptic transmission during low-frequency test pulses (0.1 Hz), and increased the level of tetanus-induced LTP by 63% over that measured under control conditions. Paired stimulation before and during infusion of Nle 1-AngIV indicated no change in paired-pulse facilitation (PPF) as a result of AT 4 receptor activation suggesting that the underlying mechanism(s) responsible for Nle 1-AngIV-induced increase in synaptic transmission and LTP is likely a postsynaptic event. Further, applications of Nle 1-Leual 3-AngIV prior to, but not 15 or 30 min after, tetanization prevented stabilization of LTP. These results extend previous findings from behavioral data in that AT 4 receptor agonists and antagonists are capable of activating, and inhibiting, learning and memory pathways in the hippocampus, and suggest that the AT 4 receptor subtype is involved in synaptic plasticity.

2-deoxyglucose induces LTP in layer I of rat somatosensory cortex in vitro

Temporary replacement of glucose by 2-deoxyglucose (2-DG) induces a long-term potentiation (2-DG-LTP) of excitatory synaptic transmission in hippocampal slices. We therefore examined the effects of 2-DG on monosynaptic field excitatory postsynaptic potentials (fEPSPs) in slices of somatosensory cortex from rats. Monosynaptic fEPSPs were elicited in layer I by stimulating horizontal projections in the same layer. Replacement of glucose (10 mM) in the artificial cerebrospinal fluid with 10 mM 2-DG for 15–17 min produced a minor reduction (by 10–30%), followed by a sustained increase (by≈150%) in synaptic responses that could last for over 2 hours. Equimolar replacement of glucose with sucrose did not induce potentiation. The addition of 5 or even 2.5 mM glucose to 10 mM 2-DG largely suppressed the effects of 2-DG; but topically-applied GABA antagonists bicuculline and CGP 35348 did not prevent 2-DG-LTP. Unlike hippocampal 2-DG-LTP, neocortical 2-DG-LTP was: (1) not sensitive to 2-amino-5-phosphonopentanoic acid (AP5); and (2) usually not depotentiated by stimulation at 1 Hz. We conclude that 2-DG produces a robust and sustained increase in synaptic transmission in the neocortex through mechanisms that are independent of NMDA receptor activation.

Spine changes associated with long-term potentiation.

High-frequency stimulation of excitatory synapses in many regions of the brain triggers a lasting increase in the efficacy of synaptic transmission referred to as long-term potentiation (LTP) and believed to contribute to learning and memory. One hypothesis proposed to account for the stability and properties of this functional plasticity is a structural remodeling of spine synapses. This possibility has recently received support from several studies. It has been found that spines are highly dynamic structures, that they can be formed very rapidly, and that synaptic activity and calcium modulate changes in spine shape and formation of new spines. Ultrastructural analyses bring additional support to these observations and suggest that LTP is associated with a remodeling of the postsynaptic density (PSD) and a process of spine duplication. This new information is reviewed and interpreted in light of other recent advances concerning the mechanisms of LTP and especially the role of postsynaptic glutamate receptor turnover in this form of plasticity. Taken together, a view is emerging that suggests that morphologic changes of spine synapses are associated with LTP and that they not only correlate with, but probably also contribute to the increase in synaptic transmission.

Spine changes associated with long‐term potentiation

High-frequency stimulation of excitatory synapses in many regions of the brain triggers a lasting increase in the efficacy of synaptic transmission referred to as long-term potentiation (LTP) and believed to contribute to learning and memory. One hypothesis proposed to account for the stability and properties of this functional plasticity is a structural remodeling of spine synapses. This possibility has recently received support from several studies. It has been found that spines are highly dynamic structures, that they can be formed very rapidly, and that synaptic activity and calcium modulate changes in spine shape and formation of new spines. Ultrastructural analyses bring additional support to these observations and suggest that LTP is associated with a remodeling of the postsynaptic density (PSD) and a process of spine duplication. This new information is reviewed and interpreted in light of other recent advances concerning the mechanisms of LTP and especially the role of postsynaptic glutamate receptor turnover in this form of plasticity. Taken together, a view is emerging that suggests that morphologic changes of spine synapses are associated with LTP and that they not only correlate with, but probably also contribute to the increase in synaptic transmission. Hippocampus 2000;10:596–604. © 2000 Wiley-Liss, Inc.

Cross-Modulation of Synaptic Plasticity by β-Adrenergic and 5-HT1AReceptors in the Rat Basolateral Amygdala

Neurotransmitter receptors are often colocalized in a neuron with other receptors, and activation of one receptor can either amplify or antagonize the response to a colocalized receptor. The aim of this study was to investigate the cross-regulation of synaptic transmission by beta-adrenergic and serotonin 1A (5-HT1A) receptors and to elucidate their underlying mechanisms. Stimulation of presynaptic beta-adrenergic receptors with isoproterenol (Iso) in the basolateral amygdala resulted in a long-lasting increase in synaptic transmission. This effect was mimicked by forskolin, an activator for adenylyl cyclase and a cAMP analog. In addition, the effect of forskolin was blocked by catalytic and regulatory site antagonists for cAMP-dependent protein kinase (PKA), indicating a PKA-mediated mechanism. Application of 5-HT depressed the synaptic transmission and blocked Iso- and forskolin-induced potentiation. The effect of 5-HT was mimicked by the selective 5-HT1A agonist 8-hydroxy-dipropylaminotetralin and was blocked by the selective 5-HT1A antagonist 1-(2-methoxyphenyl)-4[4-(2-phthalimido)butyl]piperazine, indicating its mediation by 5-HT1A receptors. To determine the locus of interaction, Sp-cAMPS, a membrane-permeable activator of PKA, was applied, and the potentiation produced by Sp-cAMPS was completely blocked in slices pretreated with 5-HT. These results suggest that the interaction between the intracellular signaling pathways activated by 5-HT1A and beta-adrenergic receptors occurs at a step downstream from cAMP production.