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D L Alkon

Publications and source records attributed to D L Alkon.

At least 91 records · Page 5Linked to original sources
PubMed1993

Rabbit cerebellar slice analysis of long-term depression and its role in classical conditioning.

Cerebellar long-term depression (LTD) has been proposed as a mechanism underlying classical conditioning of the rabbit nictitating membrane/eyelid response (NMR). However, LTD has only been obtained reliably when (1) cerebellar slices are bathed in GABA antagonists which abolish disynaptic inhibitory post synaptic potentials, and (2) the temporal sequence of stimulation used in slice or intact preparations is the opposite of that used in classical conditioning. Based on intradendritic Purkinje cell recordings obtained from rabbit cerebellar slices, we report that stimulation of climbing fibers and then parallel fibers in the presence of the GABA antagonist, bicuculline, produced significant depression of parallel fiber excitatory post synaptic potential (epsp) amplitude that continued to increase for at least 20 min after stimulation. However, application of the same stimulation protocol without GABA antagonists produced a brief depression of parallel fiber epsps that disappeared within minutes. Activation of parallel fibers and then climbing fibers in an order opposite to the LTD-producing sequence (i.e. a classical conditioning-like order) produced a brief depression that dissipated quickly. Stimulation of parallel fibers alone produced a small, slowly developing potentiation, but stimulation of parallel fibers during depolarization-induced local dendritic calcium spikes produced significant depression almost immediately which then declined slowly to more modest levels. Finally, stimulation of parallel fibers at frequencies used in in vivo parallel fiber-climbing fiber stimulation experiments (e.g. 100 Hz) produced an immediate and profound long-lasting epsp depression. The depression occurred, however, whether parallel and climbing fibers were stimulated separately (unpaired) or in a classical conditioning-like protocol (paired) where parallel fiber stimulation coterminated with climbing fiber stimulation (10 Hz).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Potassium channel dysfunction in fibroblasts identifies patients with Alzheimer disease.

Since memory loss is characteristic of Alzheimer disease (AD), and since K+ channels change during acquisition of memory in both molluscs and mammals, we investigated K+ channel function as a possible site of AD pathology and, therefore, as a possible diagnostic index as well. A 113-pS tetraethylammonium (TEA)-sensitive K+ channel was consistently absent from AD fibroblasts, while it was often present in young and aged control fibroblasts. A second (166-pS) K+ channel was present in all three groups. Elevated external potassium raised intracellular Ca2+ in all cases. TEA depolarized and caused intracellular Ca2+ elevation in young and aged control fibroblasts but not AD fibroblasts. The invariable absence of a 113-pS TEA-sensitive K+ channel and TEA-induced Ca2+ signal indicate K+ channel dysfunction in AD fibroblasts. These results suggest the possibility of a laboratory method that would diagnostically distinguish AD patients, with or without a family history of AD, from normal age-matched controls and also from patients with non-AD neurological and psychiatric disorders.

Adult↗
PubMed1993

Associative learning potentiates protein kinase C activation in synaptosomes of the rabbit hippocampus.

Using electrophysiological, biochemical, and autoradiographic techniques, changes in protein kinase C (PKC) activity in specific regions of the hippocampus have been previously implicated in classical conditioning of the nictitating membrane response of the rabbit. Here we report that activation of PKC is potentiated 2- to 3-fold in synaptosomes of the hippocampal CA1 and CA2 to -3 regions in rabbits that have undergone classical conditioning of the nictitating membrane response. This potentiation is apparently due to a change in the biochemical properties of PKC within the synaptosomes and is not a result of an increase in total PKC activity. This observation correlates a subcellular biochemical change with classical conditioning of a mammal.

Animals↗
PubMed1993

Gated informational transfer within the mammalian hippocampus: a new hypothesis.

Presented here is a position paper that advocates a novel and testable hypothesis concerning the role and function of the mammalian hippocampal formation especially with regards to neonatal neural development. The present paper is based upon recent electrophysiological and biochemical studies of the developing rabbit hippocampus and proposes that by gating the transfer of sensory information through the trisynaptic circuit, the hippocampus allows, in a permissive sense, the buildup of cognitive maps, either in the hippocampus itself, or in other brain loci such as the neocortex. The model makes certain predictions that can be experimentally tested and therefore may prove useful for organizing future data in research into hippocampal function.

Aging↗
PubMed1993

G-protein effects on retrograde axonal transport.

Movements of medium and large sized membranous organelles (0.5-1 microns in diameter) were visualized within segments of the crab walking leg nerve with Nomarski differential interference contrast optics and subjected to video contrast enhancement. Accessibility to the axoplasm was demonstrated by intra-axonal fluorescence following addition of rhodamine conjugated to 40 kDa dextran to the external medium. Perfusion of the axons with a 1 microM solution of the 20 kDa G-protein, cp20, but not control solutions, reduced the number of organelles moving in the retrograde direction per unit time, but not the number of organelles moving in the anterograde direction. Such alteration of organelle movement may contribute to memory-specific changes of neuronal morphology.

Animals↗
PubMed1993

Associative learning in a network model of Hermissenda crassicornis. II. Experiments.

A companion paper in a previous issue of this journal presented a resistance-capacitance circuit computer model of the four-neuron visual-vestibular network of the invertebrate marine mollusk Hermissenda crassicornis. In the present paper, we demonstrate that changes in the model's output in response to simulated associative training is quantitatively similar to behavioral and electrophysiological changes in response to associative training of Hermissenda crassicornis. Specifically, the model demonstrates many characteristics of conditioning: sensitivity to stimulus contingency, stimulus specificity, extinction, and savings. The model's learning features also are shown to be devoid of non-associative components. Thus, this computational model is an excellent tool for examining the information flow and dynamics of biological associative learning and for uncovering insights concerning associative learning, memory, and recall that can be applied to the development of artificial neural networks.

Animals↗
PubMed1993

Different ionic conductances are modulated during the late receptor potential and the prolonged depolarizing afterpotential in Hermissenda type A photoreceptors.

Wavelength-dependent, bistable phenomena were found in the receptor potential of Hermissenda crassicornis type A photoreceptors. Short exposure to blue light induced a prolonged depolarizing afterpotential (PDA) following the cessation of the light stimulus. Stronger adaptation to blue light, as caused by prolonged exposure and/or high intensity stimulation, effected a reduction in the early depolarizing transient of the late receptor potential (LRP) as elicited by subsequent stimuli. Vast separation of LRP emergence and PDA emergence could be obtained in photoreceptors in which a strong cancellation of the LRP was accomplished but a PDA still emerged after cessation of the light stimulus. Short exposure to yellow light cancelled the PDA, and stronger adaptation restored the LRP (opposite effect to blue light). The initial depolarizing part of the LRP had earlier been demonstrated to be mediated by the light-dependent increase of an inward conductance. In contrast, in this study the PDA was found to be accompanied by the reduction of an outward conductance, most likely a K+ conductance. A bistable photopigment system is thought to control the bistable receptor potential phenomenology by regulating the different membrane conductances during the LRP and the PDA.

Animals↗
PubMed1993

Quantitative distribution of protein kinase C alpha, beta, gamma, and epsilon mRNAs in the hippocampus of control and nictitating membrane conditioned rabbits.

We used oligonucleotide in situ hybridization and film autoradiography to quantitate the distributions of protein kinase C (PKC) alpha, beta, gamma, and epsilon mRNAs in subregions of rabbit hippocampus. Levels of each of the hippocampal PKC isozyme mRNAs and patterns of their regional distributions were remarkably invariant between individuals. Within stratum pyramidale, the highest levels of PKC alpha mRNA were in the CA2 region, while PKC beta mRNA was maximally expressed in CA1, and PKC epsilon mRNA in CA3; PKC gamma mRNA was abundantly expressed throughout Ammon's horn. Previous experiments employing quantitative autoradiography for [3H]PDBU (Olds et al., Science, 245 (1989) 866-869) revealed an increase in membrane-bound PKC in the CA1 region of rabbit hippocampus up to 3 days following classical conditioning of the nictitating membrane response. We report here that there were no differences in levels of PKC alpha, beta, gamma, or epsilon mRNA between conditioned and control rabbits in any hippocampal region one day after training. These data are consistent with the hypothesis that PKC is post-translationally activated and translocated to the membrane during memory storage.

Acoustic Stimulation↗
PubMed1993

Reconstruction of ionic currents in a molluscan photoreceptor.

Two-microelectrode voltage-clamp measurements were made to determine the kinetics and voltage dependence of ionic currents across the soma membrane of the Hermissenda type B photoreceptor. The voltage-dependent outward potassium currents, IA and ICa(2+)-K+, the inward voltage-dependent calcium current, ICa2+ and the light-induced current, IIgt, were then described with Hodgkin-Huxley-type equations. The fast-activating and inactivating potassium current, IA, was described by the equation; IA(t) = gA(max)(ma infinity[1-exp(-t/tau ma)])3 x (ha infinity [1-exp(-t/tau ha)] + exp(-t/tau ha)) (Vm-EK), where the parameters ma infinity, ha infinity, tau ma, and tau ha are functions of membrane potential, Vm, and ma infinity and ha infinity are steady-state activation and inactivation parameters. Similarly, the calcium-dependent outward potassium current, ICa(2+)-K+, was described by the equation, ICa(2+)-K+ (t) = gc(max)(mc infinity(VC)(1-exp[-t/tau mc (VC)]))pc (hc infinity(VC) [1-exp(-t/tau hc)] + exp(-t/tau hc(VC)])pc(VC-EK). In high external potassium, ICa(2+)-K+ could be measured in approximate isolation from other currents as a voltage-dependent inward tail current following a depolarizing command pulse from a holding potential of -60 mV. A voltage-dependent inward calcium current across the type B soma membrane, ICa2+, activated rapidly, showed little inactivation, and was described by the equation: ICa2+ = gCa(max) [1 + exp](-Vm-5)/7]-1 (Vm-ECa), where gCa(max) was 0.5 microS. The light-induced current with both fast and slow phases was described by: IIgt(t) = IIgt1 + IIgt2 + IIgt3, IIgti = gIgti [1-exp(- ton/tau mi)] exp(-ton/tau hi)(Vm-EIgti) (i = 1, 2). For i = 3, /Igt(t) = gigt3m33h3(Vm - Eigt3)exp(-ton/Ton) x exp(-tfoff/t Off). Based on these reconstructions of ionic currents, learning-induced enhancement of the long lasting depolarization (LLD) of the photoreceptor'slight response was shown to arise from progressive inactivation of /A, lca2+ -K+, and lCa2+.

Animals↗
PubMed1993

GABA-mediated synaptic interaction between the visual and vestibular pathways of Hermissenda.

The synaptic convergence of the eyes and the vestibular hair cells in the nudibranch mollusc Hermissenda has been shown previously to mediate the learning of simple visual-vestibular associations. The neurotransmitter mediating this interaction between the visual and vestibular organs was characterized. HPLC chromatography, confirmed by mass spectroscopic analysis, demonstrated endogenous GABA in the statocysts, in a concentration approximately 150 times greater than in the whole CNS. Additional confirmation was provided by immunocytochemical localization of GABA in hair cell axons and branches that converge with photoreceptor terminal branches. Depolarization of the hair cells in the caudal region of the statocyst in response to positive current injection or vibratory stimulation caused a hyperpolarization and a cessation of the type B photoreceptor impulse activity. The inhibition of the B cell was unaffected by addition to the artificial sea water bath of the adrenergic antagonist yohimbine (250 microM), the cholinergic antagonist atropine (250 microM), and the serotonergic antagonist imipramine (50 microM). In contrast, the GABAA antagonist bicuculline (250 microM) significantly reduced the inhibitory interaction. Moreover, the GABA reuptake inhibitor guvisine (250 microM) increased the hyperpolarization. Pressure microapplication of GABA (12.5 or 25 microM) onto the terminal branches of the B cell resulted in a concentration-dependent hyperpolarization and cessation of spikes in the B cell. Depolarization of the caudal hair cell, or direct GABA application, decreased input resistance across the B cell soma membrane. Moreover, removal of chloride from the extracellular solution reduced inhibition of the B cell induced by GABA application or hair cell stimulation. Furthermore, application of the GABAB agonist baclofen hyperpolarized the type B cell and reduced or eliminated spontaneous impulse activity at the resting membrane potential. The reversal potentials for inhibition induced in all three procedures ranged from -70 to -80 mV and were consistent with mixed Cl- and K+ conductances. These results implicate GABA as the endogenous neurotransmitter mediating visual-vestibular interactions in this animal, and suggest a possible role of GABA in visual-vestibular associative learning.

Animals↗
PubMed1993

Cell specificity of molecular changes during memory storage.

The aeolid nudibranch, Hermissenda crassicornis, exhibits Pavlovian conditioning to paired light and rotational stimuli and it has been suggested that protein kinase C(PKC) may play a critical role in the cellular mechanism for this conditioned behavioral response in the B-cell photoreceptor. The present study was designed to further examine learning-specific PKC involvement in identified cellular areas, particularly those in the visual-vestibular network, of the Hermissenda nervous system after Pavlovian conditioning. As used in previous vertebrate studies, the highly specific PKC radioligand, [3H]phorbol-12,13-dibutyrate ([3H]-PDBU), was used to determine the binding characteristics of the molluscan protein receptor considered to be PKC. The binding was specific, saturable, and could be displaced by a soluble diacylglycerol analogue. The binding activity was distributed evenly between the cytosol and the membrane. All of these analyses suggest that [3H]PDBU binds primarily to PKC in Hermissenda as it does in many other systems. Computerized grain image analysis was then used to determine the cellular localization of PKC as a function of Pavlovian conditioning. The medial and intermediate B photoreceptor and the optic ganglion showed significantly increased [3H]PDBU binding in conditioned animals. The present results provide the first report of an associative learning change of a key signal transduction component in identified neurons.

Animals↗
PubMed1993

Protein kinase C: a nexus in the biochemical events that underlie associative learning.

We have proposed that protein kinase C, an enzyme critical to cell regulation of growth, secretion and differentiation, is a part of a sequence of molecular events that underlie learning and memory. Electrophysiological, biochemical and neuro-imaging methods have been employed to show that the enzyme changes its distribution as a result of memory storage within the neural networks that are necessary for the acquisition and performance of various learning tasks in several species. We propose here, a model of protein kinase C as a molecular signal for the association of synaptic input that is parsimonious with the recent data, mainly from our laboratory, concerning its function in memory formation.

Animals↗
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↗