The Balance Hypothesis for the Avian Lumbosacral Organ and an Exploration of Its Morphological Variation.

Birds (Aves) exhibit exceptional and diverse locomotor behaviors, including the exquisite ability to balance on two feet. How birds so precisely control their movements may be partly explained by a set of intriguing modifications in their lower spine. These modifications are collectively known as the lumbosacral organ (LSO) and are found in the fused lumbosacral vertebrae called the synsacrum. They include a set of transverse canal-like recesses in the synsacrum that align with lateral lobes of the spinal cord, as well as a dorsal groove in the spinal cord that houses an egg-shaped glycogen body. Based on compelling but primarily observational data, the most recent functional hypotheses for the LSO consider it to be a secondary balance organ, in which the transverse canals are analogous to the semicircular canals of the inner ear. If correct, this hypothesis would reshape our understanding of avian locomotion, yet the LSO has been largely overlooked in the recent literature. Here, we review the current evidence for this hypothesis and then explore a possible relationship between the LSO and balance-intensive locomotor ecologies. Our comparative morphological dataset consists of micro-computed tomography (µ-CT) scans of synsacra from ecologically diverse species. We find that birds that perch tend to have more prominent transverse canals, suggesting that the LSO is useful for balance-intensive behaviors. We then identify the crucial outstanding questions about LSO structure and function. The LSO may be a key innovation that allows independent but coordinated motion of the head and the body, and a full understanding of its function and evolution will require multiple interdisciplinary research efforts.

Validation Of The HAS-BLED Tool In Atrial Fibrillation Patients Receiving Rivaroxaban.

Background: Atrial fibrillation (Afib) patients are at an increased risk of stroke. Patients at moderate to high risk of stroke typically receive antithrombotics, placing them at an increased risk of bleeding. The HAS-BLED tool has been validated in Afib patients receiving warfarin for prediction of major bleeding events. Although HAS-BLED has been researched in patients receiving warfarin, this tool has not been validated with the novel anticoagulant rivaroxaban. Methods: The trial design was retrospective case-control approved by the Institutional Review Board at University of Tennessee Medical Center. Patients who were identified as having a bleeding event were cross-referenced with a list of patients receiving rivaroxaban. Inclusion criteria were adult patients with atrial fibrillation who were taking rivaroxaban for at least six months, with a CHA2DS2-VASc score greater than or equal to 2 OR CHADS2 score greater than or equal to 1. The primary endpoint is the predictive ability of HAS-BLED as measured through the c-statistic. Secondary endpoints include correlation of HAS-BLED and bleeding risk. Results: After reviewing 9621 medical records, 15 patients met the inclusion criteria for major bleeding. Ninety patients were randomly selected for inclusion as the matched control group. The predictive ability of HAS-BLED was not statistically significant (c statistic = 0.68; p = 0.07), but did show some diagnostic ability to predict major bleeding events. Patients with major bleeding were more likely to have a history of bleeding and use concomitant antiplatelet agents. There were significantly more patients with a HAS-BLED score greater than or equal to 3 in the patients that experienced a major bleeding event. Conclusion: HAS-BLED demonstrated some diagnostic ability to predict major bleeding events in patients receiving rivaroxaban but this was not statistically significant due to limited sample size.

Heart transplantation for end-stage heart failure due to cardiac sarcoidosis.

BACKGROUND: Cardiac sarcoidosis with end-stage heart failure has a poor prognosis without transplantation. The rates of sarcoid recurrence and rejection are not well established after heart transplantation. METHODS: A total of 19 heart transplant recipients with sarcoid of the explanted heart were compared with a contemporaneous control group of 1,050 heart transplant recipients without cardiac sarcoidosis. Assessed outcomes included 1st-year freedom from any treated rejection, 5-year actuarial survival, 5-year freedom from cardiac allograft vasculopathy (CAV), 5-year freedom from nonfatal major adverse cardiac events (NF-MACE), and recurrence of sarcoid in the allograft or other organs. Patients with sarcoidosis were maintained on low-dose corticosteroids after transplantation. RESULTS: There were no significant differences between the sarcoid and control groups in 1st-year freedom from any treated rejection (79% and 90%), 5-year posttransplantation survival (79% and 83%), 5-year freedom from CAV (68% and 78%), and 5-year freedom from NF-MACE (90% and 88%). Causes of death (n = 5) in the sarcoid group were coccidioidomycosis, pneumonia, rejection, hemorrhage, and CAV. No patient had recurrence of sarcoidosis in the cardiac allograft. Three of 19 patients (16%) experienced recurrence of extracardiac sarcoid, with no mortality. CONCLUSIONS: Patients with cardiac sarcoidosis undergoing heart transplantation have acceptable long-term outcomes without evidence of recurrence of sarcoidosis in the allograft when maintained on low-dose corticosteroids. Progression of extracardiac sarcoid was uncommon, possibly related to immunosuppression. In patients with cardiac sarcoidosis, heart transplantation is a viable treatment modality.

An avian basal ganglia pathway essential for vocal learning forms a closed topographic loop.

The mammalian basal ganglia-thalamocortical pathway is important for motor control, motor learning, and cognitive functions. It contains parallel, closed loops, at least some of which are organized topographically and in a modular manner. Songbirds have a circuit specialized for vocal learning, the anterior forebrain pathway (AFP), forming a basal ganglia loop with only three stations: the pallial ("cortex-like") lateral magnocellular nucleus of the anterior neostriatum (lMAN), the basal ganglia structure area X, and the medial portion of the dorsolateral thalamic nucleus (DLM). Several properties of this pathway resemble those of its mammalian counterpart, but it is unknown whether all projections in the loop are topographically organized, and if so, whether topography is maintained through the entire loop. After small single- or dual-tracer injections into area X and/or the lMAN of adult zebra finches, we found that the area X to DLM projection is topographically organized, and we confirmed the topography for all other AFP projections. Quantitative analysis suggests maintained topography throughout the loop. To test this directly, we injected different tracers into corresponding areas in lMAN and area X. We found somata retrogradely labeled from lMAN and terminals anterogradely labeled from area X occupying the same region of DLM. Many labeled somata were tightly surrounded by tracer-labeled terminals, indicating the microscopically closed nature of the AFP loop. Thus, like mammals, birds have at least one closed, topographic loop traversing the basal ganglia, thalamus, and pallium. Each such loop could serve as a computational unit for motor or cognitive functions.

Slow synaptic inhibition mediated by metabotropic glutamate receptor activation of GIRK channels.

Glutamate is the predominant excitatory neurotransmitter in the vertebrate CNS. Ionotropic glutamate receptors mediate fast excitatory actions whereas metabotropic glutamate receptors (mGluRs) mediate a variety of slower effects. For example, mGluRs can mediate presynaptic inhibition, postsynaptic excitation, or, more rarely, postsynaptic inhibition. We previously described an unusually slow form of postsynaptic inhibition in one class of projection neuron in the song-control nucleus HVc of the songbird forebrain. These neurons, which participate in a circuit that is essential for vocal learning, exhibit an inhibitory postsynaptic potential (IPSP) that lasts several seconds. Only a portion of this slow IPSP is mediated by GABA(B) receptors. Since these cells are strongly hyperpolarized by agonists of mGluRs, we used intracellular recording from brain slices to investigate the mechanism of this hyperpolarization and to determine whether mGluRs contribute to the slow synaptic inhibition. We report that mGluRs hyperpolarize these HVc neurons by activating G protein-coupled, inwardly-rectifying potassium (GIRK) channels. MGluR antagonists blocked this response and the slow synaptic inhibition. Thus, glutamate can combine with GABA to mediate slow synaptic inhibition by activating GIRK channels in the CNS.

Electrophysiological properties of avian basal ganglia neurons recorded in vitro.

The forebrains of mammals and birds appear quite different in their gross morphology, making it difficult to identify homologies between them and to assess how far they have diverged in organization. Nevertheless one set of forebrain structures, the basal ganglia, has been successfully compared in mammals and birds. Anatomical, histochemical, and molecular data have identified the avian homologues of the mammalian basal ganglia and indicate that they are very similar in organization, suggesting that they perform similar functions in the two classes. However, the physiological properties of the avian basal ganglia have not been studied, and these properties are critical for inferring functional similarity. We have used a zebra finch brain slice preparation to characterize the intrinsic physiological properties of neurons in the avian basal ganglia, particularly in the input structure of the basal ganglia, the striatum. We found that avian striatum contains a cell type that closely resembles the medium spiny neuron, the principal cell type of mammalian striatum. Avian striatum also contains a rare cell type that is very similar to an interneuron class found in mammalian striatum, the low-threshold spike cell. On the other hand, we found an aspiny, fast-firing cell type in avian striatum that is distinct from all known classes of mammalian striatal neuron. These neurons usually fired spontaneously at 10 Hz or more and were capable of sustained firing at very high rates when injected with depolarizing current. The existence of this cell type represents an important difference between avian striatum and mammalian dorsal striatum. Our data support the general idea that the organization and functional properties of the basal ganglia have been largely conserved in mammals and birds, but they imply that avian striatum is not identical to mammalian dorsal striatum.

Sexual dimorphism in the song system of the Carolina wren Thryothorus ludovicianus.

Sexual and interspecific differences in the size of passerine bird song repertoires are related to differences in the size of song-control regions (SCR) within the brain. Most species of Thryothorus wrens (family Certhiidae) are known to duet, and, in both sexes, song repertoire sizes are related to the size of the SCR. However, one member of this genus, the Carolina wren T. ludovicianus, is very sexually dimorphic in its singing behavior: Males develop large song repertoires, whereas females do not sing. In this study, Nissl staining was used to investigate whether the marked gender difference in the behavior of this species is related to sexual dimorphism of the SCR. Carolina wren males, as predicted, possess the largest premotor song nuclei within the genus; these nuclei could not be identified within Nissl-stained female tissue. The cellular bases for gender differences in SCR morphology also were examined: Males and females differed strongly in the size and density of neurons making up the regions in which SCRs exist in the male forebrain. Interspecific comparison provided no evidence for a decoupling of behavioral and neural evolution within this clade. Male Carolina wrens possess the largest song repertoires and SCRs within the genus, whereas females of this species represent the opposite behavioral and neural extremes of this songbird group. These results are consistent with the hypothesis that the size of the passerine song repertoire is limited by the amount of neural tissue devoted to singing.

Disparity in neurotransmitter release probability among competing inputs during neuromuscular synapse elimination.

Competition among the several motor axons transiently innervating neonatal muscle fibers results in an increasing disparity in the quantal content and synaptic territory of each competitor, culminating in the permanent loss of all but one axon from neuromuscular junctions. We asked whether differences in the probability of neurotransmitter release also contribute to the increasing disparity in quantal content among competing inputs, and when in the process of competition changes in release probability become apparent. To address these questions, intracellular recordings were made from dually innervated neonatal mouse soleus muscle fibers, and quantal content and paired-pulse facilitation were evaluated for each input. At short interpulse intervals, paired-pulse facilitation was significantly higher for the weaker input with the smaller quantal content than the stronger input with the larger quantal content. Because neurotransmitter release probability across all release sites is inversely related to the extent of facilitation observed after paired-pulse stimulation, this result suggests that release probability is lower for weak compared with strong inputs innervating the same junction. A disparity in the probability of neurotransmitter release thus contributes to the disparity in quantal content that occurs during synaptic competition. Together, this work suggests that an input incapable of sustaining a high release probability may be at a competitive disadvantage for synaptic maintenance.

Complementary 'bottom-up' and 'top-down' approaches to basal ganglia function.

Recently, two quite different approaches exemplifying 'bottom-up' and 'top-down' philosophies have shed new light on basal ganglia function. In vitro work using organotypic co-cultures has implicated the subthalamic nucleus (STN) and the external segment of the globus pallidus (GP(e)) as pacemakers for low-frequency bursting that is reminiscent of the activity produced in Parkinsonian tremor. A circuit essential for avian song learning has been identified as part of the basal ganglia with surprisingly well conserved cellular details; investigation of this system may help to address general issues of basal ganglia function.

Two-stage, input-specific synaptic maturation in a nucleus essential for vocal production in the zebra finch.

In most songbirds, vocal learning occurs through two experience-dependent phases, culminating in a reduction of behavioral plasticity called song crystallization. At ends of developmentally plastic periods in other systems, synaptic properties change in a fashion appropriate to limit plasticity. Maturation of glutamatergic synapses often involves a reduction in duration of NMDA receptor (NMDAR)-mediated synaptic responses and a coincident reduction in the contribution of NMDARs to synaptic transmission. We hypothesized that similar changes in the zebra finch song system help limit behavioral plasticity during song development. Nucleus robustus archistriatalis (RA) is a key nucleus in the forebrain song motor pathway and receives glutamatergic input from the motor nucleus HVc. RA also receives glutamatergic input, mediated primarily by NMDARs, from the lateral magnocellular nucleus of the anterior neostriatum, which is part of a circuit essential for learning but not song production. We examined whether synaptic maturation occurs in either input to RA by recording synaptic currents in brain slices prepared from zebra finches of different ages. We find the motor input from HVc to RA uses both AMPA receptors (AMPARs) and NMDARs, and synaptic maturation occurs in two phases: an early reduction in duration of NMDAR-mediated synaptic currents in both inputs, and a later reduction in the NMDAR contribution to synaptic responses in the motor pathway. Although NMDAR kinetics change too early to account for crystallization, the reduction of the relative NMDAR contribution to synaptic transmission could contribute to the onset of crystallization. Thus, synaptic maturation events can be temporally distinct and input-specific and may play different roles in behavioral plasticity.

A GABAergic, strongly inhibitory projection to a thalamic nucleus in the zebra finch song system.

The anterior forebrain pathway (AFP) of the oscine song system is essential for song learning but not song production. Most cells recorded in this serially connected pathway show increased firing in response to song playback, suggesting largely excitatory connections among AFP nuclei. However, the neurons forming a key projection in this pathway, from area X to the medial nucleus of the dorsolateral thalamus (DLM), express glutamic acid decarboxylase in their somata and terminals, suggesting an inhibitory connection. To investigate the firing properties of DLM neurons and the functional influence of area X afferents in DLM, we made whole-cell recordings from DLM neurons in brain slices from adult male zebra finches. Most cells had intrinsic properties closely resembling those of mammalian thalamocortical cells, including a low-threshold Ca(2+) spike and time-dependent, hyperpolarization-activated inward rectification. Activation of afferents from area X evoked a strong, all-or-none IPSP whose amplitude and latency were unchanged by application of glutamate antagonists, consistent with a monosynaptic contact. The IPSP had a reversal potential near -70 mV and was blocked by the GABA(A) receptor antagonist bicuculline methiodide. Post-inhibitory rebound firing occurred in DLM neurons with a delay near 50 msec. Strong inhibition can combine with the intrinsic properties of DLM neurons to allow signaling on disinhibition. Our data are consistent with the hypothesis that the AFP corresponds to the mammalian corticobasal ganglia-thalamocortical loop. The similar functional properties of avian and mammalian thalamic neurons suggest conserved forebrain mechanisms of sensorimotor information processing across vertebrate taxa.

Pharmacological characterization of an unusual mGluR-evoked neuronal hyperpolarization mediated by activation of GIRK channels.

The metabotropic glutamate receptor (mGluR) agonist ACPD exerts an unusual inhibitory effect on a population of neurons of the song-control nucleus HVc of the zebra finch via activation of the GIRK channel. We report in the present study the pharmacology of this response. ACPD directly hyperpolarized the neurons by a mechanism independent of GABA(B) receptors. The group I mGluR agonist DHPG had no effect on membrane properties and the group I mGluR antagonist 4-CPG did not affect the ACPD-induced hyperpolarization. In contrast, the ACPD response was mimicked by the group II mGluR agonist LY314593 and the group II and III agonist L-CCG-I. The group II mGluR antagonist LY307452 fully antagonized the ACPD response and reduced the response induced by L-CCG-I. The group III mGluR agonist L-AP4 induced a small hyperpolarization, which was antagonized by the group III mGluR antagonist MAP-4. These data indicate that group II and group III mGluRs are present and functional in the postsynaptic membrane of these HVc neurons, and mediate the hyperpolarizing action of mGluR agonists. In contrast, group I mGluRs are absent from these neurons, nonfunctional, or coupled to different effector systems that do not influence membrane potential or input resistance.

Long-range GABAergic projection in a circuit essential for vocal learning.

The anterior forebrain pathway (AFP) in the passerine song system is essential for song learning but not for song production. Several lines of evidence suggest that area X, a major nucleus in the AFP, forms part of the avian striatum. A key feature of striatal projection neurons is that they use the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). Some area X neurons express GABA-like immunoreactivity, but the neurotransmitter phenotype of the projection neurons is largely unknown. To determine whether area X projection neurons are GABAergic, we used immunocytochemistry and confocal microscopy to examine whether these neurons in adult male zebra finches express the GABA synthetic enzyme glutamic acid decarboxylase (GAD). We observed numerous large and small GAD+ somata in area X, and dense GAD+ terminals, but no GAD+ somata in the target of area X, the medial nucleus of the dorsolateral thalamus (DLM). The density of GAD+ terminals in DLM was strongly reduced by ibotenic acid lesions of area X. After tracer injection into the DLM, all of the retrogradely labeled neurons in area X were GAD+. After tracer injection into area X, the vast majority of anterogradely labeled terminals in DLM were GAD+. We conclude that area X neurons projecting to DLM express GAD and are thus likely GABAergic. If this projection is indeed inhibitory, information processing in the AFP is substantially more complicated than previously realized. Moreover, because a GABAergic projection to a thalamic target is reminiscent of pallidal rather than of striatal circuitry, area X may contain both striatal and pallidal components.

Multiple cell types distinguished by physiological, pharmacological, and anatomic properties in nucleus HVc of the adult zebra finch.

Nucleus HVc of the songbird is a distinct forebrain region that is essential for song production and shows selective responses to complex auditory stimuli. Two neuronal populations within HVc give rise to its efferent projections. One projection, to the robust nucleus of the archistriatum (RA), serves as the primary motor pathway for song production, and can also carry auditory information to RA. The other projection of HVc begins a pathway through the anterior forebrain, (area X --> medial portion of the dorsolateral nucleus of the thalamus (DLM) --> lateral portion of the magnocellular nucleus of the anterior neostriatum (L-MAN) --> RA) that is crucial for song learning but, although active during singing, is not essential for adult song production. To test whether these different projection neuron classes have different functional properties, we recorded intracellularly from neurons in nucleus HVc in brain slices. We observed at least three classes of neuron based on intrinsic physiological and pharmacological properties as well as on synaptic inputs. We also examined the morphological properties of the cells by filling recorded neurons with neurobiotin. The different physiological cell types correspond to separate populations based on their soma size, dendritic extent, and axonal projection. Thus HVc neurons projecting to area X have large somata, show little spike-frequency adaptation, a hyperpolarizing response to the metabotropic glutamate receptor (mGluR) agonist (1S,3R)-trans-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD), and exhibit a slow inhibitory postsynaptic potential (IPSP) following tetanic stimulation. Those HVc neurons projecting to motor nucleus RA have smaller somata, show strong accommodation, are not consistently hyperpolarized by ACPD, and exhibit no slow IPSP. A third, rarely recorded class of neurons fire in a sustained fashion at very high-frequency and may be interneurons. Thus the neuronal classes within HVc have different functional properties, which may be important for carrying specific information to their postsynaptic targets.

Slow synaptic inhibition in nucleus HVc of the adult zebra finch.

Nervous systems process information over a broad range of time scales and thus need corresponding cellular mechanisms spanning that range. In the avian song system, long integration times are likely necessary to process auditory feedback of the bird's own vocalizations. For example, in nucleus HVc, a center that contains both auditory and premotor neurons and that is thought to act as a gateway for auditory information into the song system, slow inhibitory mechanisms appear to play an important role in the processing of auditory information. These long-lasting processes include inhibitory potentials thought to shape auditory selectivity and a vocalization-induced inhibition of auditory responses lasting several seconds. To investigate the possible cellular mechanisms of these long-lasting inhibitory processes, we have made intracellular recordings from HVc neurons in slices of adult zebra finch brains and have stimulated extracellularly within HVc. A brief, high-frequency train of stimuli (50 pulses at 100 Hz) could elicit a hyperpolarizing response that lasted 2-20 sec. The slow hyperpolarization (SH) could still be elicited in the presence of glutamate receptor blockers, suggesting that it does not require polysynaptic excitation. Three major components contribute to this activity-induced SH: a long-lasting GABAB receptor-mediated IPSP, a slow afterhyperpolarization requiring action potentials but not Ca2+ influx, and a long-lasting IPSP, the neurotransmitter and receptor of which remain unidentified. These three slow hyperpolarizing events are well placed to contribute to the observed inhibition of HVc neurons after singing and could shape auditory feedback during song learning.

The role of Ca2+ entry via synaptically activated NMDA receptors in the induction of long-term potentiation.

Influx of Ca2+ through the NMDA subtype of glutamate receptor is widely accepted as a trigger for many forms of neural plasticity. However, direct support for this model has been elusive, since indirect activation of dendritic voltage-sensitive Ca2+ channels is difficult to exclude. We have optically measured synaptically induced changes in cytoplasmic free Ca2+ concentration in pyramidal cell dendrites in hippocampal slices. Steady postsynaptic depolarization to the synaptic reversal potential eliminated the effect of voltage-sensitive Ca2+ channels. Under these conditions, synaptically induced Ca2+ transients were observed, which were blocked by the NMDA receptor antagonist APV. In addition, the magnitude of LTP was diminished when induced with the postsynaptic membrane held at progressively more positive potentials. LTP could be completely suppressed at potentials near +100 mV. These results provide important experimental support for a role for Ca2+ influx through NMDA receptors in synaptic plasticity.

Evidence for all-or-none regulation of neurotransmitter release: implications for long-term potentiation.

1. We have used the whole-cell patch-clamp recording technique to examine the modulation of dual-component excitatory postsynaptic currents (EPSCs) in CA1 pyramidal cells in guinea-pig hippocampal slices. 2. The dramatic difference in the reported sensitivities of the N-methyl-D-aspartate (NMDA) and non-NMDA glutamate receptors to glutamate suggests that changes in transmitter concentration in the synaptic cleft would result in differential modulation of the two components of the EPSC. 3. To test whether presynaptic manipulations change transmitter concentration in the synaptic cleft, pharmacological modulation of transmitter release by the GABAB agonist baclofen or by the adenosine antagonist theophylline was used. These manipulations resulted in parallel changes of NMDA and non-NMDA receptor-mediated components of EPSCs over a sixteen-fold range. 4. Stimuli that induce long-term potentiation (LTP) did not cause a sustained enhancement of isolated NMDA receptor-mediated EPSCs evoked in the presence of the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). 5. To compare directly the effect of LTP on the components of the EPSC, dual-component EPSCs were elicited while the postsynaptic membrane potential was held at +30 mV. Induction of long-term potentiation by delivering low-frequency synaptic stimulation in conjunction with such depolarization led to differential enhancement of the non-NMDA receptor-mediated component of the EPSC. 6. These data support the notion that synaptic transmission at individual boutons occurs in an all-or-none fashion, without changing peak transmitter concentration in the synaptic cleft. Long-term potentiation could occur through a postsynaptic modification of receptors or through a presynaptic change involving increased transmitter concentration in the synaptic cleft, but is difficult to explain by a generalized increase in release probability.

Modulation of synaptic transmission and long-term potentiation: effects on paired pulse facilitation and EPSC variance in the CA1 region of the hippocampus.

1. Whole-cell patch-clamp recordings of excitatory postsynaptic currents (EPSCs) were made from guinea pig hippocampal CA1 pyramidal cells. The sensitivity of paired pulse facilitation (PPF) and EPSC variance to changes in synaptic transmission was investigated and the results were compared with the changes in these parameters evoked by long-term potentiation (LTP). 2. Presynaptic manipulations, such as activation of presynaptic gamma-aminobutyric acid-B receptors by baclofen, blockade of presynaptic adenosine receptors by theophylline, blockade of presynaptic potassium channels by cesium, and increasing the Ca(2+)-Mg2+ ratio in the external recording solution, each reliably changed PPF in a fashion reciprocal to the change in the EPSC amplitude. However, recruitment of additional synaptic release sites by increasing stimulus strength and antagonism of non-N-methyl-D-aspartate (NMDA) glutamate receptors by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) failed to alter PPF. 3. Presynaptic manipulations including increased stimulus strength gave the predicted changes in the value of mean 2/variance (M2/sigma 2). Moreover, postsynaptic manipulations that altered EPSC amplitude, including blockade of non-NMDA receptors by CNQX, or changing the holding potential of the postsynaptic cell, gave little change in M2/sigma 2, as would be predicted for manipulations resulting in a uniform postsynaptic change. 4. LTP caused no change in PPF, whereas the presynaptic manipulations, which caused a similar amount of potentiation to that induced by LTP, significantly decreased PPF. On the other hand, LTP did increase M2/sigma 2, although the increase was less than that predicted for a purely presynaptic mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)

Ca2+ entry via postsynaptic voltage-sensitive Ca2+ channels can transiently potentiate excitatory synaptic transmission in the hippocampus.

We have studied the role of Ca2+ entry via voltage-sensitive Ca2+ channels in long-term potentiation (LTP) in the CA1 region of the hippocampus. Repeated depolarizing pulses, in the presence of the NMDA receptor antagonist D-APV and without synaptic stimulation, resulted in a potentiation of excitatory postsynaptic potentials (EPSPs) or currents (EPSCs). This depolarization-induced potentiation was augmented in raised extracellular Ca2+ and was blocked by intracellular BAPTA, a Ca2+ chelator, or by nifedipine, a Ca2+ channel antagonist, indicating that the effect was mediated by Ca2+ entry via voltage-sensitive Ca2+ channels. Although the peak potentiation could be as large as 3-fold, the EPSP(C)s decayed back to baseline values within approximately 30 min. However, synaptic activation paired with depolarizing pulses in the presence of D-APV converted the transient potentiation into a sustained form. These results indicate that a rise in postsynaptic Ca2+ via voltage-sensitive Ca2+ channels can transiently potentiate synaptic transmission, but that another factor associated with synaptic transmission may be required for LTP.

Calcium activates two types of potassium channels in rat hippocampal neurons in culture.

Several calcium-dependent potassium currents can contribute to the electrophysiological properties of neurons. In hippocampal pyramidal cells, 2 afterhyperpolarizations (AHPs) are mediated by different calcium-activated potassium currents. First, a rapidly activated current contributes to action-potential repolarization and the fast AHP following individual action potentials. In addition, a slowly developing current underlies the slow AHP, which occurs after a burst of action potentials and contributes substantially to the spike-frequency accommodation observed in these cells during a prolonged depolarizing current pulse. In order to investigate the single Ca2(+)-dependent channels that might underlie these currents, we performed patch-clamp experiments on hippocampal neurons in primary culture. When excised inside-out patches were exposed to 1 microM Ca2+, 2 types of channel activity were observed. In symmetrical bathing solutions containing 140 mM K+, the channels had conductances of 19 pS and 220 pS, and both were permeable mainly to potassium ions. The properties of these 2 channels differed in a number of ways. At negative membrane potentials, the small-conductance channels were more sensitive to Ca2+ than the large channels. At positive potentials, the small-conductance channels displayed a flickery block by Mg2+ ions on the cytoplasmic face of the membrane. Low concentrations of tetraethylammonium (TEA) on the extracellular face of the membrane specifically caused an apparent reduction of the large-channel conductance. The properties of the large- and small-conductance channels are in accord with those of the fast and slow AHP, respectively.