Biomedical subjects

L D Matzel

Publications and source records attributed to L D Matzel.

At least 19 recordsLinked to original sources

PubMed2001

The role of the hippocampus in trace conditioning: temporal discontinuity or task difficulty?

It is well established that the hippocampal formation is critically involved in the acquisition of trace memories, a paradigm in which the conditioned (CS) and unconditioned stimuli (US) are separated by a temporal gap (Solomon et al., 1986). The structure is reportedly not critical for the acquisition of delay memories, where the CS and the US overlap in time (Berger & Orr, 1983; Schmaltz & Theios, 1972). Based on these results, it is often stated that the hippocampus is involved in "filling the gap" or otherwise associating the two stimuli in time. However, in addition to the presence of a temporal gap, there are other differences between trace and delay conditioning. The most apparent difference is that animals require many more trials to learn the trace task, and thus it is inherently more difficult than the delay task. Here, we tested whether the hippocampus was critically involved in delay conditioning, if it was rendered more difficult such that the rate of acquisition was shifted to be analogous to trace conditioning. Groups of rats received excitotoxic lesions to the hippocampus, sham lesions or were left intact. Using the same interstimulus intervals (ISI), control animals required more trials to acquire the trace than the delay task. As predicted, animals with hippocampal lesions were impaired during trace conditioning but not delay conditioning. However, when the delay task was rendered more difficult by extending the ISI (a long delay task), animals with hippocampal lesions were impaired. In addition, once the lesioned animal learned the association between the CS and the US during delay conditioning, it could learn and perform the trace CR. Thus, the role of the hippocampus in classical conditioning is not limited to learning about discontiguous events in time and space; rather the structure can become engaged simply as a function of task difficulty.

Animals↗

PubMed2001

Receptor-stimulated phospholipase A(2) liberates arachidonic acid and regulates neuronal excitability through protein kinase C.

Type B photoreceptors in Hermissenda exhibit increased excitability (e.g., elevated membrane resistance and lowered spike thresholds) consequent to the temporal coincidence of a light-induced intracellular Ca(2+) increase and the release of GABA from presynaptic vestibular hair cells. Convergence of these pre- and postsynaptically stimulated biochemical cascades culminates in the activation of protein kinase C (PKC). Paradoxically, exposure of the B cell to light alone generates an inositol triphosphate-regulated rise in diacylglycerol and intracellular Ca(2+), co-factors sufficient to stimulate conventional PKC isoforms, raising questions as to the unique role of synaptic stimulation in the activation of PKC. GABA receptors on the B cell are coupled to G proteins that stimulate phospholipase A(2) (PLA(2)), which is thought to regulate the liberation of arachidonic acid (AA), an "atypical" activator of PKC. Here, we directly assess whether GABA binding or PLA(2) stimulation liberates AA in these cells and whether free AA potentiates the stimulation of PKC. Free fatty-acid was estimated in isolated photoreceptors with the fluorescent indicator acrylodan-derivatized intestinal fatty acid-binding protein (ADIFAB). In response to 5 microM GABA, a fast and persistent increase in ADIFAB emission was observed, and this increase was blocked by the PLA(2) inhibitor arachidonyltrifluoromethyl ketone (50 microM). Furthermore, direct stimulation of PLA(2) by melittin (10 microM) increased ADIFAB emission in a manner that was kinetically analogous to GABA. In response to simultaneous exposure to the stable AA analogue oleic acid (OA, 20 microM) and light (to elevate intracellular Ca(2+)), B photoreceptors exhibited a sustained (>45 min) increase in excitability (membrane resistance and evoked spike rate). The excitability increase was blocked by the PKC inhibitor chelerythrine (20 microM) and was not induced by exposure of the cells to light alone. The increase in excitability in the B cell that followed exposure to light and OA persisted for > or =90 min when the pairing was conducted in the presence of the protein synthesis inhibitor anisomycin (1 microm), suggesting that the synergistic influence of these signaling agents on neuronal excitability did not require new protein synthesis. These results indicate that GABA binding to G-protein-coupled receptors on Hermissenda B cells stimulates a PLA(2) signaling cascade that liberates AA, and that this free AA interacts with postsynaptic Ca(2+) to synergistically stimulate PKC and enhance neuronal excitability. In this manner, the interaction of postsynaptic metabotropic receptors and intracellular Ca(2+) may serve as the catalyst for some forms of associative neuronal/synaptic plasticity.

Animals↗

PubMed2000

The tractable contribution of synapses and their component molecules to individual differences in learning.

Though once of central importance to psychologists and neurophysiologists alike, the elucidation of neural substrates for individual differences in learning no longer attracts a broad research effort and occupies a place of largely historical interest to the contemporary disciplines. The decline in interest in this subject ensued in part from the perception, arrived at decades ago, that individual differences in learning were not quantified as easily as had once been presumed. Furthermore, the dominant hypotheses in the field defied testing within the constraints imposed by the complex and largely inaccessible vertebrate nervous system. Using a 'model systems' approach where the individual cells and synaptic interactions that comprise a neural network can be identified, we have returned to this question and have established a framework by which we can begin to discern the basis for much of the variability between individuals in their capacity to learn. In the marine mollusc Hermissenda, we have found that a common influence on transmitter exocytosis is expressed homogeneously throughout the nervous system regardless of transmitter system or receptor class. Though uniformly expressed within an individual, this influence on synaptic efficacy is differentially expressed between animals. Importantly, the basal efficiency of exocytosis expressed in an individual nervous system is strongly correlated with the degree to which activity-dependent forms of neuronal/synaptic facilitation can be induced in that nervous system, and predicts the capacity for the intact animal to learn a Pavlovian association. Furthermore, we have established that a decline in basal synaptic efficacy in aged animals, arising from chronic presynaptic Ca(2+) 'leak', may contribute to age-related learning impairments. Because certain fundamental components of the exocytotic cascade are conserved widely across cell types, transmitter systems and species, the principles that we describe may have broad implications for understanding normal variability in learning, but also, in the development of specific strategies to compensate for mild learning deficits and age-related cognitive decline.

Animals↗

PubMed2000

Synaptic efficacy is commonly regulated within a nervous system and predicts individual differences in learning.

The hypothesis that an individual's capacity for learning might be predicted or influenced by basal levels of synaptic efficacy has eluded empirical tests, owing in part to the inability to compare between animals single identified synaptic responses in the mammalian brain. To overcome this limitation, we have focused our analysis on the invertebrate Hermissenda, whose nervous system is composed of identifiable cells and synaptic interactions. Hermissenda were exposed to paired presentations of light and rotation such that the light came to elicit a learned defensive motor response. An animal's rate of learning was strongly correlated with the amplitude of the synaptic potential evoked in that animal's visual (light sensitive) receptors in response to stimulation of presynaptic vestibular (rotation sensitive) hair cells. In naive animals, strong correlations between the amplitude of both inhibitory and excitatory synaptic potentials were observed between synapses distributed throughout an animal's nervous system, and this conservation of synaptic efficacy was largely attributable to a common influence on transmitter release. These observations suggest that basal synaptic efficacy may be uniformly regulated throughout a nervous system, and provide direct evidence that the basal efficacy of synaptic transmission predicts, and possibly contributes to, individual differences between animals in their capacity to learn.

Action Potentials↗

PubMed2000

Modulation of presynaptic action potential kinetics underlies synaptic facilitation of type B photoreceptors after associative conditioning in Hermissenda.

Descriptions of conditioned response generation in Hermissenda stipulate that the synaptic interaction between type B and A photoreceptors should be enhanced after associative pairings of light and rotation. Although evidence from several laboratories has confirmed this assumption, the mechanism underlying this synaptic facilitation has not been elucidated. Here we report that in vitro conditioning (i.e., light paired with stimulation of vestibular hair cells) modifies the kinetics of presynaptic action potentials in the B photoreceptor in a manner sufficient to account for this synaptic facilitation. After paired training, we observed an increase in the duration of evoked action potentials and a decrease in the amplitude of the spike afterhyperpolarization in the B-cell. As previously reported, paired training also enhanced the excitability (i.e., input resistance and evoked spike rate) of the B photoreceptor. In a second experiment, simultaneous recordings were made in type B and A photoreceptors, and paired training was found to produce an increase in the amplitude of the IPSP in the A photoreceptor in response to an evoked spike in the B-cell. Importantly, there was no change in the initial slope of the postsynaptic IPSP in the A photoreceptor, suggesting that spike duration-independent mechanisms of neurotransmitter exocytosis or postsynaptic receptor sensitivity did not contribute to the observed synaptic facilitation. Perfusion of 4-aminopyridine (4-AP) mimicked a known effect of behavioral conditioning in that it specifically reduced the amplitude of the transient voltage-dependent K(+) current (I(A)) in the B-cell, but in addition, produced action potential broadening and synaptic facilitation that was analogous to that observed after in vitro conditioning. Finally, the effect of 4-AP on B-cell action potentials and on the postsynaptic IPSP in the A-cell was occluded by previous paired (but not unpaired) training, suggesting that the prolongation of the B-cell action potential by a reduction of I(A) was sufficient to account for the observed synaptic facilitation. The occlusion of the effects of 4-AP by paired training was not attributable to a saturation of the capacity of the B-cell for transmitter exocytosis, because it was observed that tetraethylammonium (TEA)-induced inhibition of the delayed voltage-dependent K(+) current induced both spike broadening and synaptic facilitation regardless of training history. Collectively, these results demonstrate that training-induced facilitation at B-cell synapses is attributable to the effects of a reduction of a presynaptic K(+) conductance on action potential kinetics and suggest another critical similarity between the cellular basis for learning in Hermissenda and other invertebrate systems.

4-Aminopyridine↗

PubMed2000

Memory involves far more than 'consolidation'.

The observation that retrieval returns a stable memory into a labile state cannot be readily explained by any simple version of consolidation theory. This finding has been interpreted as evidence for the need to reconsolidate a memory after reactivating it. However, as we discuss in this commentary, other behavioural observations indicate that even this modification to consolidation theory may be insufficient to describe the dynamic properties of memory.

Amnesia↗

PubMed1999

Neurophysiological substrates of context conditioning in Hermissenda suggest a temporally invariant form of activity-dependent neuronal facilitation.

The neurophysiological basis for context conditioning is conceptually problematic because neurophysiological descriptions of activity-dependent (associative) forms of neuronal plasticity uniformly assume that a specific temporal relationship between signals is necessary for memory induction. In the present experiments, this problem is addressed empirically by presenting, as a temporally diffuse contextual signal, a stimulus that results in known neural modifications following punctate (temporally contiguous) pairings with an aversive unconditioned stimulus. Hermissenda were trained to discriminate between adjoining contexts that were distinguished only in that one was lit and one was dark. Thirty unsignaled rotations were presented during each of three 15-min sessions in one of the two (lit or dark) contexts. Prior to training, animals displayed a slight preference for the lit context. After exposure to unsignaled rotation, animal's preferences shifted strongly to the dark context if unsignaled rotations were presented in the light, and tended (nonsignificantly) to the lit context if unsignaled rotations were presented in the dark. The B photoreceptors of the Hermissenda eye undergo several forms of activity-dependent facilitation (e.g., an increase in neuronal input resistance and evoked spike frequency) following pairings of punctate light (CS) and presynaptic vestibular stimulation (US). Similar facilitation in the B photoreceptor was observed following in vitro training that mimicked context conditioning in which presynaptic vestibular stimulation was presented repetitively during a continuous 7.5-min light. Subsequently, Ca(2+)-imaging experiments were conducted with Fura-2AM. It was determined that intracellular Ca(2+), the CS-induced second messenger critical for the induction of activity-dependent facilitation, was elevated in the B photoreceptor throughout the 7.5-min light presentation. These results indicate that activity-dependent facilitation within similar neural structures can underlie learning about both temporally diffuse contextual stimuli and temporally punctate CS-US pairings. These results suggest that a common mechanism may underlie learning about diffuse contextual stimuli as well as punctate-conditioned stimuli, provided that the stimuli are processed similarly in each type of conditioning arrangement. Consequently, the expression of different responses to contextual and discrete stimuli are likely to reflect a higher property of the neural network, and do not necessarily arise from unique underlying mechanisms.

Animals↗

PubMed1999

Interactive contributions of intracellular calcium and protein phosphatases to massed-trials learning deficits in Hermissenda.

Using Hermissenda as subjects, massed-trials training deficits were examined. Associative pairings of light and rotation induced a progressively greater conditioned foot contraction in response to light as the intertrial interval (ITI) was extended (up to 8 min). In contrast, a short ITI (30 s) produced no evidence of learning. In a corresponding in vitro conditioning experiment that mimicked training of the intact animal, facilitation of neuronal excitability in the animal's B photoreceptors paralleled the results obtained in vivo. Imaging of intracellular Ca2+ using Fura-2 indicated that Ca2+ levels remained elevated during short ITIs. This Ca2+ accumulation appears to induce activation of protein phosphatases because normal facilitation of the B photoreceptors was induced with a short ITI if training occurred in the presence of a phosphatase inhibitor. These results suggest that intracellular Ca2+ and protein phosphatases contribute interactively to the kinetics of memory formation and provide evidence that an accumulation of intracellular Ca2+ across training trials may impede memory formation.

Animals↗

PubMed1998

Intracellular Ca2+ and adaptation of voltage responses to light in Hermissenda photoreceptors.

Fluorescent imaging of Ca2+ and intracellular recordings were used to assess Ca2+ increases and voltage responses during light presentations in Hermissenda B photoreceptors. Ca2+ levels increased and were sustained during a relatively long exposure to light. Repeated presentations of a brief light induced an elevation of intracellular Ca2+ that persisted throughout short interlight intervals, but which dissipated during long interlight intervals. In all instances, the magnitude of the intracellular Ca2+ signal was inversely related to the amplitude of the light-induced generator potential. Blocking of voltage-dependent Ca2+ channels did not significantly affect the magnitude of the Ca2+ signal, suggesting that the intracellular Ca2+ response arises primarily from release from intracellular stores. These results indicate that Ca2+ plays an important role in the modulation of the voltage responses to light, acting to suppress the response during repetitive or prolonged stimulation.

Adaptation, Ocular↗

PubMed1997

Phospholipases and arachidonic acid contribute independently to sensory transduction and associative neuronal facilitation in Hermissenda type B photoreceptors.

During contiguous pairings of light and rotation, B photoreceptors in the Hermissenda eye undergo an increase in excitability that contributes to a modification of several light-elicited behaviors. This excitability increase requires a light-induced rise in intracellular Ca2+ in the photoreceptor concomitant with transmitter binding to G protein-coupled receptors as a result of presynaptic vestibular hair cell stimulation. Phospholipases and arachidonic acid (ArA) are here reported to be involved in independent signal transduction pathways that underlie both receptor function and activity-dependent facilitation of the B photoreceptor. 4-Bromophenacyl bromide (BPB), an inhibitor of phospholipases A2 (PLA2) and C (PLC), blocked the generation of light-induced depolarizing generator potentials, but had no affect on the inhibitory postsynaptic potential (IPSP) in the B cell that results from hair cell stimulation. Quinacrine, which predominantly blocks the activity of PLA2 in neurons, had no affect on either the light response or the IPSP, but did block increases in excitability (i.e. increased input resistance and elicited spike rate) of the B cell that results from pairings of light and presynaptic vestibular stimulation (i.e., in vitro associative conditioning). Neither nordihydroquararetic acid (NDGA), which inhibits metabolism of ArA by cyclooxygenase, nor indomethacin, which inhibits lipoxygenase metabolism of ArA, affected the light response or IPSP, but both blocked the increases in excitability in the B cell that accompanied in vitro conditioning. In combination with earlier results, these data suggest that ArA activates PKC in a synergistic fashion with Ca2+ and diacylglycerol in the B cell, and suggest that PLA2-induced ArA release, though not necessary for transduction of light or the hair cell-induced IPSP in the B cell, is a critical component of the convergence of signals that precipitates associative facilitation in this system.

Acetophenones↗

PubMed1997

Long-term potentiation: what's learning got to do with it?

Long-term potentiation (LTP) is operationally defined as a long-lasting increase in synaptic efficacy following high-frequency stimulation of afferent fibers. Since the first full description of the phenomenon in 1973, exploration of the mechanisms underlying LTP induction has been one of the most active areas of research in neuroscience. Of principal interest to those who study LTP, particularly in the mammalian hippocampus, is its presumed role in the establishment of stable memories, a role consistent with "Hebbian" descriptions of memory formation. Other characteristics of LTP, including its rapid induction, persistence, and correlation with natural brain rhythms. provide circumstantial support for this connection to memory storage. Nonetheless, there is little empirical evidence that directly links LTP to the storage of memories. In this target article we review a range of cellular and behavioral characteristics of LTP and evaluate whether they are consistent with the purported role of hippocampal LTP in memory formation. We suggest that much of the present focus on LTP reflects a preconception that LTP is a learning mechanism, although the empirical evidence often suggests that LTP is unsuitable for such a role. As an alternative to serving as a memory storage device, we propose that LTP may serve as a neural equivalent to an arousal or attention device in the brain. Accordingly, LTP may increase in a nonspecific way the effective salience of discrete external stimuli and may thereby facilitate the induction of memories at distant synapses. Other hypotheses regarding the functional utility of this intensely studied mechanism are conceivable; the intent of this target article is not to promote a single hypothesis but rather to stimulate discussion about the neural mechanisms underlying memory storage and to appraise whether LTP can be considered a viable candidate for such a mechanism.

Attention↗

PubMed1997

Incremental redistribution of protein kinase C underlies the acquisition curve during in vitro associative conditioning in Hermissenda.

An incremental increase in the excitability (i.e., input resistance, evoked spike frequency) of B photoreceptors in Hermissenda accompanied successive pairings of light and presynaptic stimulation of vestibular hair cells (simulating light-rotation pairings in an intact animal). Analysis of protein kinase C (PKC) in the Hermissenda's photoreceptors indicated a training-induced incremental reduction of PKC in cytosolic compartments, a tendency toward an increase in membrane compartments, and a small decrease in total enzyme activity (possibly owing to a downregulation or conversion of PKC to a calcium-independent state). Neither the biophysical or biochemical effects were observed in Hermissenda exposed to unpaired light and rotation or in those trained in the presence of the selective PKC inhibitor NPC-15437 (which had no effect on synaptic interactions or light-induced generator potentials). These results suggest that the intracellular redistribution of a protein kinase contributes critically to the kinetics of new learning.

Animals↗

PubMed1996

Calcium influx and release from intracellular stores contribute differentially to activity-dependent neuronal facilitation in Hermissenda photoreceptors.

A series of experiments is described that elucidates the sources of Ca2+ that contribute to activity-dependent neuronal facilitation in Hermissenda B photoreceptors during associative conditioning. In an in vitro preparation, pairings of a 4-s light with a 3-s mechanical stimulation of presynaptic hair cells increased the input resistance and elicited spike rate (i.e., excitability) of the B photoreceptors in the Hermissenda eye, indicative of a Ca(2+)-dependent process that is analogous to associative conditioning in the intact animal. This increase in excitability was reduced but not eliminated when hyperpolarizing current was applied to the B cell during the pairings, suggesting that voltage-dependent influx of Ca2+ contributed only a portion of the total calcium signal necessary for facilitation. Moreover, no increase in excitability was observed when a comparable current-induced depolarization of the photoreceptor was substituted for light-induced depolarization. In other experiments, Ca(2+)-dependent inactivation of a light-induced Na+ current was used as an index of intracellular Ca2+ concentration. It was determined that light caused a large increase in intracellular Ca2+ concentration regardless of whether the photoreceptor was allowed to freely depolarize in response to light or was voltage clamped at its resting membrane potential. Current-induced depolarization produced a smaller increase, while presynaptic stimulation had no measurable effect. Intracellular injections of either heparin, an antagonist of intracellular Ca2+ release, or EGTA, a general Ca2+ chelator, induced comparable reductions of light-induced Ca2+ accumulation. Finally, intracellular injections of heparin blocked the pairing-induced increases in B cell excitability as effectively as injections of EGTA. Taken as a whole, these data suggest that Ca2+ release from intracellular stores may be sufficient for the induction of facilitation in this preparation, while Ca2+ influx through voltage-dependent channels may have an additive effect and provide further evidence for the ubiquitous role of Ca2+ in learning-related forms of neuronal plasticity.

Animals↗

PubMed1996

Bidirectional regulation of neuronal potassium currents by the G-protein activator aluminum fluoride as a function of intracellular calcium concentration.

Hydrolysis-resistant activation of G-proteins by extracellular perfusion of fluoride ions was examined in Type B cells isolated from the cerebral ganglion of the marine mollusc Hermissenda. Under single-electrode voltage-clamp, modulation by aluminum fluoride ions of several classes of outward K+ currents as well as an inward Ca2+ current was observed. Following injection of the Ca2+ chelator EGTA, aluminum fluoride ions selectively increased a slow, voltage-dependent K+ current (IK) within 5 min of application, while in the absence of EGTA, aluminum fluoride ions induced a small, transient reduction of IK. Neither the magnitude nor steady-state inactivation of a fast, voltage-dependent K+ current (IA), nor a slow, Ca2+-dependent K+ current (IK-Ca), were affected by aluminum fluoride ions. In contrast, when perfusion of aluminum fluoride ions was accompanied by a repetitive depolarization and a concomitant increase in intracellular Ca2+, both IA and the combined late currents (IK and IK-Ca) were markedly reduced, a reduction which was not observed following depolarization alone or if the pairing of aluminum fluoride ions and depolarization was preceded by an injection of EGTA. The reduction of membrane conductance by the pairing of aluminum fluoride ions with depolarization could not be accounted for by an increased Ca2+ conductance, as aluminum fluoride ions produced only a small decrease in the voltage-dependent Ca2+ current. In total, these results indicate that regulatory G-proteins may bidirectionally modulate neuronal K+ currents, the direction of which is dependent on intracellular Ca2+ concentration. Such a dual regulatory mechanism may contribute to the modulation of membrane excitability observed when presynaptic activity is paired with postsynaptic depolarization, and thus may contribute to some forms of activity-dependent plasticity involving metabatropic receptors.

Aluminum Compounds↗

PubMed1996

Variations in learning reflect individual differences in sensory function and synaptic integration.

With the invertebrate Hermissenda as subjects, variability in acquisition of a learned association between light and rotation was correlated with the magnitude of the unconditioned responses elicited by these stimuli. Moreover, learning was facilitated by increasing stimulus intensity. In the isolated nervous system, pairings of light and mechanical stimulation of the animal's vestibular hair cells resulted in an increase in the excitability of B photoreceptors (an in vitro index of learning) that was strongly correlated with the strength of the synaptic interaction between the hair cells and the photoreceptors and weakly correlated with the magnitude of the light response in the photoreceptors. Because these in vitro results are not attributable to motor or motivational variables, they suggest that the efficacy of synaptic integration between sensory systems and sensory transduction is the primary determinant of the variability in learning.

Animals↗

PubMed1995

G-protein mediated responses to localized serotonin application in an invertebrate photoreceptor.

A G-protein dependent serotonin (5-HT) receptor on B photoreceptors of Hermissenda crassicornis was investigated. Microapplication of 5-HT to the soma region, but not to the terminal branches, resulted in a rapid, biphasic depolarization with a slow time course of dissipation. The 5-HT-induced depolarization increased at hyperpolarized potentials, and exhibited a strong and complex sensitivity to external K+, but not Na+ or Ca2+. The 5-HT response, but not a cholinergically mediated intraphotoreceptor interaction, was abolished by intracellular injection of the G protein antagonist, GDP[beta S], although the response was unaffected by pretreatment with pertussis toxin. These results are discussed in terms of known 5-HT receptor subtypes, and the potential role of this receptor in activity-dependent forms of plasticity exhibited by these cells.

Action Potentials↗

PubMed1995

Diverse current and voltage responses to baclofen in an identified molluscan photoreceptor.

1. gamma-Aminobuturic acid-B (GABAB) receptors play a role in the mediation of slow inhibitory postsynaptic potentials in mammalian as well as some nonmammalian species. In identified photoreceptors from the marine mollusc Hermissenda, recent evidence has suggested that GABA, as well as the GABAB receptor agonist baclofen, might simultaneously modulate multiple conductances on the postsynaptic membrane. Here, using intracellular current-clamp and single-electrode voltage-clamp techniques, we have characterized responses to baclofen in the B photoreceptors of the Hermissenda eye. 2. Microapplication of baclofen (12.5-62.5 microM) to the terminal branches of the B photoreceptors induced a slow, concentration-dependent hyperpolarization (approximately 3-8 mV) that was accompanied by a cessation of spontaneous action potentials and a positive shift in firing threshold. Both the hyperpolarization and the shift in spike threshold in response to baclofen were attenuated largely by the K+ channel blocker tetraethylammonium chloride (TEA; 50 mM). 3. Bath application of baclofen (100 microM) decreased the amplitude, duration, and the afterhyperpolarization (AHP) of evoked action potentials. Although baclofen's effect on spike duration and amplitude persisted in the absence of extracellular Ca2+, the reduction of the AHP by baclofen was eliminated, suggesting that multiple conductances mediated the baclofen-induced modification of the action potential. 4. Using a single-electrode voltage-clamp technique, microapplication of baclofen to the terminal branches of the B photoreceptor produced a slow, net outward current (< 0.5 nA) that reversed near the equilibrium potential for K+ and shifted to more positive potentials when extracellular K+ was increased, in approximate agreement with the Nernst equation for K+. 5. Baclofen induced an increase in amplitude of the nonvoltage dependent leak conductance (IL), and the increase was blocked by TEA. The baclofen-induced increase of IL was accompanied by an increase in amplitude and a negative shift in the voltage dependence of a slow, steeply voltage-dependent K+ current (IK), which displays selective sensitivity to TEA but does not normally contribute to leak conductance. The amplitude and steady-state inactivation of a fast, transient K+ current, as well as the amplitude of an inwardly rectifying K+ current were unaffected by baclofen. 6. Both the rate of activation as well as the amplitude of a voltage-dependent Ca2+ current (ICa) were reduced by baclofen. The reduction of ICa resulted in a concomitant suppression of a Ca(2+)-dependent K+ current (IK-Ca) that was sufficient to account for the reduction of the AHP after evoked action potentials.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1994

Current, voltage and pharmacological substrates of a novel GABA receptor in the visual-vestibular system of Hermissenda.

In the marine mollusc, Hermissenda crassicornis, Type B photoreceptors exhibit an IPSP to both presynaptic hair cell stimulation and microapplication of gamma-aminobutyric acid (GABA) to the terminal branches. It was found that both the endogenous IPSP and the response to exogenously applied GABA were mediated to a large part by an outward current which reversed at approximately -80 mV. Additionally, these hyperpolarizing responses were found to mask a smaller depolarization that was mediated by the reduction of a basal outward current. Both the IPSP and the hyperpolarizing response to GABA, as well as the sublimated depolarizing response to GABA, were attenuated by the K+ channel blocker tetraethylammonium chloride (TEA) and displayed a strong sensitivity to [K+]o, while showing no sensitivity to [Cl-]o or the Cl- channel blocker picrotoxin. Moreover, iontophoretic injections of stable guanine analogues, GTP[gamma S] and GDP[beta S], into B photoreceptors eliminated both the IPSP and the GABA-induced hyperpolarization, while cholinergically mediated, interphotoreceptor interactions were unaffected. These results suggest that the endogenous receptor is at least partially homologous to the mammalian GABAB class receptor. Consistent with this classification, microapplication of selective GABAB receptor agonist baclofen onto the terminal region of the B photoreceptor resulted in a hyperpolarizing response that was qualitatively similar to that of GABA, although the GABAA agonist muscimol was also active, but less so than either GABA or baclofen. Attempts to block the endogenous IPSP or GABA-induced hyperpolarization by bath application of the GABAA receptor subtype antagonist bicuculline was ineffective and the GABAB receptor subtype antagonist saclofen was only weakly effective. These data demonstrate that the presynaptic hair cell's influence on postsynaptic B photoreceptors is in many respects similar to GABAB mediated responses in the mammalian CNS. This receptor is in some respects unique, however, in terms of its cross-sensitivity to both GABAA and GABAB agonists, its weak sensitivity to saclofen, and its apparent anomalous modulation of multiple K+ conductances.

Animals↗