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D L Alkon

Publications and source records attributed to D L Alkon.

At least 19 recordsLinked to original sources
PubMed1992

Long-term transformation of an inhibitory into an excitatory GABAergic synaptic response.

For a constant membrane potential, a predominantly inhibitory GABAergic synaptic response is shown to undergo long-term transformation into an excitatory response after pairing of exogenous gamma-aminobutyric acid (GABA) with postsynaptic depolarization or pairing of pre- and postsynaptic stimulation. Current- and voltage-clamp experiments suggest that this synaptic transformation is due to a shift from a net increase of conductance to a net decrease of conductance in response to GABA. GABA-induced elevation of intracellular calcium is prolonged after the same stimulus pairing and may, therefore, contribute to this synaptic transformation via Ca(2+)-activated phosphorylation pathways. This synaptic transformation, which does not follow unpaired stimulus presentations, occurs in a neuronal compartment spatially separated from the soma, which also changes during stimulus pairing.

Animals↗
PubMed1992

GABA-induced responses in Purkinje cell dendrites of the rabbit cerebellar slice.

Pressure applications of GABA localized to Purkinje cell somas in a rabbit cerebellar slice produced uniphasic hyperpolarizing responses, whereas applications of GABA that were directed at the Purkinje cell dendrites produced complex, triphasic responses with hyperpolarizing and depolarizing components. Both somatic and dendritic application of GABA elicited fast hyperpolarization (GABAhf), but dendritic application also elicited a slower depolarization (GABAd) and a later, long-lasting hyperpolarization (GABAhl). All three types of responses were accompanied by increased conductance. Use of either GABA antagonist, bicuculline or picrotoxin, eliminated the GABAhf and GABAd responses but left the GABAhl response intact. Pressure delivery of the GABA agonist, baclofen, to the dendrites but not the soma elicited a GABAhl response. Application of baclofen paired with membrane depolarization sufficient to elicit local, calcium-dependent dendritic spiking produced a persistent reduction in the GABAhl response, whereas alternating presentations of baclofen and membrane depolarization or presentations of baclofen alone could not. The fact that GABA and baclofen inhibited Purkinje cell activity in the rabbit cerebellar slice and that picrotoxin and bicuculline eliminated some, but not all of the components of the GABA response suggests the presence of both GABAA and GABAB receptors. The ability of baclofen to inhibit Purkinje cells if it was applied to the dendrites but not if applied to the soma suggests that GABAB receptors are located predominantly on Purkinje cell dendrites. The pairing-specific change in the baclofen response suggests the existence of GABAB-mediated modifiability of Purkinje cell dendrites.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Classical conditioning and protein kinase C activation regulate the same single potassium channel in Hermissenda crassicornis photoreceptors.

The patch-clamp technique was used to study the effects of classical conditioning and protein kinase C (PKC) activation on K+ channels of identified neurons in the snail Hermissenda crassicornis. Here we present evidence that classical conditioning and PKC activation similarly modify the same K+ channel. K+ channels were recorded in cells from animals with different training experience. The 64-pS K+ channel appeared with significantly lower frequency in the conditioned group compared to the frequencies in control animals (naive and unpaired). In addition, when present, the 64-pS channel exhibited a lower percentage of open time and an increased interval between opening bursts in cells from conditioned animals. The 42-pS K+ channel was observed with about the same frequency in all three groups, and its percentage of open time was invariant, regardless of the animal's experience. Incubation of the photoreceptor with the PKC activator phorbol 12,13-dibutyrate (PDBu) led to a profound decrease in the percentage of open time of the 64-pS K+ channel, from 35.7% in the control group to 2.5% in the PDBu-treated group. The inactive phorbol 4 alpha-phorbol 12-myristate 13-acetate had no effect. The use of the PKC inhibitor H-7 significantly blocked the phorbol effect. Inside-out patches obtained from phorbol preincubated cells likewise showed the same effect of PDBu on K+ channels, but the effect was not observed when phorbol was added after the cell-free patches were obtained from nontreated cells. By contrast, the percentage of open time of the 42-pS K+ channel remained unchanged after phorbol treatment.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1992

Associative learning in a network model of Hermissenda crassicornis. I. Theory.

A time-varying Resistance-Capacitance (RC) circuit computer model was constructed based on known membrane and synaptic properties of the visual-vestibular network of the marine snail Hermissenda crassicornis. Specific biophysical properties and synaptic connections of identified neurons are represented as lumped parameters (circuit elements) in the model; in the computer simulation, differential equations are approximated by difference equations. The model's output, membrane potential, an indirect measure of firing frequency, closely parallels the behavioral and electrophysiologic outputs of Hermissenda in response to the same input stimuli presented during and after associative learning. The parallelism of the computer modeled and the biologic outputs suggests that the model captures the features necessary and sufficient for associative learning.

Animals↗
PubMed1992

The role of calcium in prolonged modification of a GABAergic synapse.

Caudal hair cell impulses cause postsynaptic inhibition of ipsilateral type B photoreceptors in the snail Hermissenda. This inhibition is shown to be GABAergic according to a number of criteria. HPLC, mass spectrophotometric, and immunocytochemical techniques demonstrated the presence of GABA in the hair cells and their axons. GABA agonists and antagonists mimic and block the synaptic effect in a manner consistent with endogenous GABAergic transmission. Other properties, including I-V relations, conductance changes and reversal potentials, are comparable for exogenous GABA responses and endogenous effects of the hair cell impulses. This inhibitory synapse has been found to undergo a long-lasting transformation into an excitatory synapse if GABA release is paired with post-synaptic depolarization. GABA, via GABAA and GABAB receptors in the B cell, causes the opening of calcium sensitive chloride and potassium channels that leads to the post-synaptic hyperpolarization. GABA also induces a long-lasting intracellular calcium elevation at the terminal branches of the B cell that greatly outlasts the voltage responses. Synaptic transformation induced by pairings is caused by a decrease in both GABA induced chloride and potassium conductances in the post-synaptic B cell, as well as a significant prolongation of the intracellular calcium accumulation in the B cell's terminal axonal branches.

Animals↗
PubMed1992

Biophysical and behavioral correlates of memory storage, degradation, and reactivation.

Neural correlates of associative memory and "forgetting" were observed 1, 6, and 14 days after acquisition of a conditioned response (CR) in the marine snail Hermissenda. Behavioral expression of a light-rotation association, as indexed by contraction of the animal's foot in response to light, dissipated throughout the 14-day interval such that a CR was observed 1 and 6 days after conditioning but was absent 14 days later. In relation to naive or pseudoconditioned animals, membrane resistance (inversely related to neuronal membrane conductance and directly related to excitability) of the isolated Type B photoreceptor (B cell) was elevated in conditioned animals on Days 1 and 6, whereas no elevation was detectable on Day 14. However, both the behavioral response and the elevated membrane resistance in conditioned animals were hypersensitive to light-rotation pairings (i.e., exhibited "savings") on Day 14, which is indicative of a latent memory trace. In a second experiment, a current-induced depolarization of the B cell after 14 retention days resulted in an increase in input resistance of the B cell membrane in previously conditioned animals but a weaker, transient rise in resistance in B cells from animals exposed to the nonassociative control procedure 14 days earlier. This effect was Ca(2+)-dependent because no rise in resistance was observed if Ca2+ was removed from the extracellular bath. These results indicate that modification of membrane conductance (i.e., elevated resistance), although apparently critical for the behavioral expression of the memory, is not essential for the maintenance of the latent memory trace, whereas Ca2+ hypersensitivity may be a principal contributor to the storage of a latent memory trace and memory reactivation.

Animals↗
PubMed1991

Arachidonic acid and diacylglycerol act synergistically to activate protein kinase C in vitro and in vivo.

Using a well-defined model membrane bilayer system, incorporation of both lipid second messengers, 1,2-diacylglycerol and arachidonic acid, at submaximal activating concentrations, resulted in a synergistic activation of protein kinase C in a Ca2+/phosphatidylserine-dependent manner as measured by monitoring phosphorylation of phosphoprotein substrates. The arachidonic acid appears to modulate membrane properties both at the hydrocarbon core and the membrane surface increasing the availability of the diacylglycerol which can bind to and subsequently activate the enzyme. Co-application of these two lipid activators to the Hermissenda photoreceptor reduced K+ channel conductance in a synergistic manner via a PKC-dependent pathway. Thus, these in vivo and in vitro studies suggest that the membrane bilayer properties of these PKC lipid activators interact to specifically regulate the cellular lipid microenvironment resulting in PKC activation.

Animals↗
PubMed1991

Protein kinase C redistribution within CA3 stratum oriens during acquisition of nictitating membrane conditioning in the rabbit.

This manuscript describes experiments designed to investigate protein kinase C redistribution occurring during acquisition of the rabbit nictitating membrane (NM) conditioned response (CR). The first experiment defined the acquisition phase of the NM response for our laboratory. A group of rabbits (n = 6) was given 2 days of paired NM training; a second group (n = 6) was given 2 days of unpaired NM training. The data document a variable level of responding on day 1 for rabbits given paired training (mean +/- SEM, 21 +/- 11% CRs) but show that on day 2 most rabbits reached the behavioral asymptote (five of six rabbits responding with greater than 85% CRs). Rabbits responding at the behavioral asymptote were defined as having acquired the NM conditioned response. These data were interpreted to indicate that 1 day of training initiated processes necessary for behavioral acquisition (i.e., responding at the behavioral asymptote). A quantitative film autoradiographic study of [3H]phorbol 12,13-dibutyrate binding was then used to determine the distribution of hippocampal protein kinase C in rabbits sacrificed after receiving either 1 day of paired stimuli (n = 10), 1 day of unpaired stimuli (n = 6), or no stimuli (n = 6). Autoradiograms were analyzed by measuring binding in strictly defined regions of interest and from transept profiles. A significant increase in binding of the phorbol ester was found in the CA3 stratum oriens in the paired group relative to unpaired and naive controls. No other significant differences were found.

Analysis of Variance↗
PubMed1991

GABA-induced potentiation of neuronal excitability occurs during contiguous pairings with intracellular calcium elevation.

The temporal convergence of neuronal signals is commonly considered as a likely prerequisite for enhanced neuronal excitability underlying the induction of associative memories. Here we report that transmitter application on presynaptic terminals of the Hermissenda Type B photoreceptors, when paired with depolarization, results in a potentiation of the excitability of the B-cell which derives from an increase in input resistance across the B-cell soma membrane. Pressure microapplication of gamma-aminobutyric acid (GABA) (12.5 microM) on the terminal branches of the Hermissenda Type B photoreceptors results in the fast (less than 1 s) activation of an inward Cl- conductance, characterized by a decrease in neuronal membrane resistance and an accompanying hyperpolarization (3-6 mV) of the B-cell. A slower effect of GABA, characterized by a slight depolarization (2-4 mV) and increase in resistance was observed approximately 2 min after GABA application. Following bath application of the Cl- channel blocker picrotoxin (100 microM), this increase in resistance was observed within 20 s of GABA application, suggesting that it was normally masked by the faster Cl- conductance. The magnitude of the resistance increase in response to GABA was enhanced when the B-cell was held at depolarized membrane potentials (-40 to -20 mV), but was eliminated if Ca2+ was removed from the extracellular bath, or if the non-specific protein kinase inhibitor H7 (100 microM) was added to the extracellular bath. In a final experiment, GABA application was paired with a transient (10 s) depolarization of the B-cell (to -20 mV).(ABSTRACT TRUNCATED AT 250 WORDS)

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1991

Learning-specific differences in Purkinje-cell dendrites of lobule HVI (Lobulus simplex): intracellular recording in a rabbit cerebellar slice.

The cerebellum has been directly implicated in the associative learning exemplified by classical conditioning of the rabbit nictitating membrane response. Lesions of cerebellar lobule HVI (Lobulus simplex) can disrupt or even abolish classical conditioning. Electrical stimulation of inputs that converge at cerebellar lobule HVI and the deep cerebellar nuclei has been shown to support classical conditioning of the responses elicited by such stimulation. Here we report that intracellular recording in a slice of rabbit cerebellar lobule HVI revealed a conditioning-specific increase in the excitability of Purkinje-cell dendrites without significant changes in dendritic membrane potential or input resistance. The finding of a conditioning-specific change in lobule HVI lends support to the theory that associative learning involves local dendritic modification and provides further evidence for the involvement of the cerebellar cortex in classical conditioning of the rabbit's nictitating membrane response.

Animals↗
PubMed1991

GTP-binding proteins and potassium channels involved in synaptic plasticity and learning.

Inhibition of potassium channels is possibly the first step in the sequence of biochemical events leading to memory formation. These channels appear to be regulated directly or indirectly by GTP-binding proteins (G proteins), which may themselves be affected by phosphorylation and dephosphorylation in response to elevated calcium levels or other phenomena resulting from the blockage of the potassium channels. A wide variety of cellular phenomena, from transcriptional changes to axonal transport, are thus capable of being initiated by these events.

Animals↗
PubMed1991

Classical conditioning-induced changes in low-molecular-weight GTP-binding proteins in rabbit hippocampus.

Classical conditioning of Hermissenda, involving paired light-rotation events, results in a 30-35% decrease in the levels of a 20-kDa G protein (cp20). To test whether a similar protein exists in vertebrates, rabbits were trained to associate a tone with periorbital electrical stimulation and G proteins were analyzed by photoaffinity labeling with [alpha-32P]GTP-azidoanilide. A 20-kDa G protein similar to cp20 decreased by 36% in the hippocampus of rabbits subjected to paired tone and electrical stimulation, but not in unpaired controls. Learning-specific decreases were also found in the amount of ras protein.

Acoustic Stimulation↗
PubMed1991

Voltage-clamp analysis of the effects of classical conditioning on the hippocampus.

1. Effects of nictitating membrane conditioning on K+ currents of CA1 pyramidal cells of rabbit hippocampus were studied by the use of the single-electrode voltage-clamp (SEVC) technique. 2. IQ, IM, IC, and IAHP were recorded in slices from control animals, showing behavior similar to that previously described for other preparations. IQ developed as an inward current during hyperpolarizing steps to potentials more negative than the K+ equilibrium potential. IM appeared as an inward inactivating relaxation during hyperpolarizing pulses, from potentials slightly more positive than the resting potential (approximately -40 mV). Such depolarization is thought to activate the IM, IC was recorded during long depolarizing pulses as a slow outward current. IAHP appeared during short depolarizing pulses as an outward current peaking at approximately 200 ms after the pulse. Progressively more positive pulses were accompanied by a linear increase of the peak IAHP value. The slope of the IAHP-voltage relation was used for comparison of cells between groups of animals that had different training experience. 3. Responses of control cells to cholinergic agents were similar to those previously characterized in other preparations. Specifically, cholinergic agonists blocked IM and IAHP, partially reduced IC, and did not affect IQ. 4. Conditioning did not affect IQ, IM, and IC but reduced the slope values of the IAHP-voltage relation. This change is consistent with the conditioning-specific afterhyperpolarization (AHP) reduction previously reported. 5. The effect of conditioning on the IAHP but not on the IC, both Ca(2+)-dependent K+ currents, suggests a direct effect on the former, rather than a reduction of ICa2+ or a change in the levels of Cai2+.

Animals↗
PubMed1991

Molecular mechanisms of memory and drug dependence.

Addiction has long been thought to include both metabolic and psychological dependence. Psychological dependence must involve long-term memory of behavioral patterns in response to specific experimental contexts. Mammalian memory, and more specifically, human memory, is largely associative. Animal models of associative memory have been provided by Pavlovian conditioning of the snail Hermissenda crassicornis and the rabbit. Striking parallels have been observed in the intrinsic molecular and biophysical transformations which accompany acquisition of the conditioned response in these different animals. In brief, associated stimuli cause elevation of Ca2+ and diacylglycerol, translocation of protein kinase C, phosphorylation of a membrane-associated G-protein, reduction of K+ currents, modification of axonal transport and structural alterations of neuronal branches. These changes can be understood and modelled as a plausible basis for memory acquisition during conditioning as well as more cognitively relevant learning such as spatial maze learning for which related neuronal alterations have recently been found. Identification of memory-specific molecular steps may help target pharmacologic agents for amelioration of learned aspects of psychiatric syndromes such as those of drug dependence.

Animals↗
PubMed1991

A role for protein kinase C in associative learning.

Recent work suggests that protein kinase C (PKC), an enzyme that has a critical role in the regulation of cell growth and differentiation, also participates in the sequence of molecular events that underlie learning and memory. By means of electrophysiological, biochemical, and neuro-imaging methods it has been demonstrated that, in the brain, the distribution of PKC changes as a result of memory storage. The changes in distribution occur within the same ensembles of nerve cells that are necessary for the acquisition and performance of various learning tasks in several species. Here we review the data pertaining to a model that has been proposed to account for the participation of PKC as a molecular signal for cotemporal synaptic input during associative learning.

Alzheimer Disease↗