Biomedical subjects

P F Chapman

Publications and source records attributed to P F Chapman.

14 recordsLinked to original sources

PubMed1995

The alpha-Ca2+/calmodulin kinase II: a bidirectional modulator of presynaptic plasticity.

The alpha-Ca2+/calmodulin kinase II (alpha CaMKII) is required for long-term potentiation in the CA1 region of the hippocampus. Here, we report that this kinase also has a crucial role in presynaptic plasticity. Paired-pulse facilitation is blunted in the CA1 region of mice heterozygous for a targeted mutation of alpha CaMKII, confirming that this kinase can promote neurotransmitter release. Unexpectedly, field and whole-cell recordings of posttetanic potentiation show that the synaptic responses of mutants are larger than those of controls, indicating that alpha CaMKII can also inhibit transmitter release immediately after tetanic stimulation. Thus, alpha CaMKII has the capacity either to potentiate or to depress excitatory synaptic transmission depending on the pattern of presynaptic activation.

Animals↗

PubMed1994

Inhibition of nitric oxide synthase does not impair spatial learning.

Nitric oxide (NO), a putative intercellular messenger in the CNS, may be involved in certain forms of synaptic plasticity and learning. This article reports a series of experiments investigating the effects of N omega-nitro-L-arginine methyl ester (L-NAME) upon various forms of learning and memory in the watermaze. L-NAME (75 mg/kg, i.p., sufficient to bring about > 90% inhibition of NO synthesis in brain) produced an apparent impairment in spatial learning when given to naive rats during acquisition (3 d, six training trials per day). This impairment was dose related, stereoselective, and attenuated by coadministration of L-arginine. A second study showed that L-NAME did not affect the retention of a previously learned spatial task. In addition, in a visual discrimination task, the rate at which criterion levels of performance were reached was unaffected by L-NAME. Thus, inhibition of NO synthase may cause a selective impairment of spatial learning without effect upon retention. However, analysis of the early training trials of the visual discrimination task revealed significantly elevated escape latencies in the L-NAME-treated rats, suggesting that inhibition of NO synthase may have more general effects. As normal rats learn the spatial task very rapidly, the possibility arises that the apparent deficit in learning is due to a disruption of some process other than learning per se. A further series of experiments investigated this possibility. L-NAME was found not to impair the learning of a new platform position in the same spatial environment. Surprisingly, L-NAME also had no effect on spatial learning in a second watermaze located in a novel spatial environment by rats well practiced with all aspects of watermaze training. Finally, L-NAME had no effect on spatial learning in naive rats trained with just one trial per day. Thus, systemic injection of an NO synthase inhibitor impairs behavioral performance in two tasks during their initial acquisition, but the basis of this functional disruption is unlikely to be due to any direct effect upon the mechanisms of spatial learning.

Amino Acid Oxidoreductases↗

PubMed1994

Inhibition of nitric oxide synthase does not prevent the induction of long-term potentiation in vivo.

Nitric oxide (NO), a putative intercellular messenger in the CNS, may be involved in certain forms of synaptic plasticity and learning. This article reports a series of experiments investigating whether an inhibitor of NO synthase, N omega-nitro-L-arginine methyl ester (L-NAME), affects long-term potentiation (LTP) in vivo, as the results of recent in vitro experiments would predict. L-NAME, given as an acute injection at a dose sufficient to inhibit hippocampal NO synthase (> 90%), had no effect on perforant path-dentate gyrus LTP induced by a strongly suprathreshold tetanus, but appeared to impair LTP induced by a weak near-threshold tetanus that may be more physiologically relevant. However, subsequent studies revealed that chronic L-NAME treatment (> 95% inhibition of NO synthase) had no effect upon LTP induction, and that acute (but not chronic) treatment resulted in a gradual but significant reduction in nontetanized baseline field potentials. The baseline shift appeared to be of a magnitude sufficient to account for the apparent impairment of weak tetanus-induced LTP. This possibility was further examined in a two-hemisphere experiment in which the time course of changes in the field EPSP of the nontetanized pathway served as the within-subject control for the tetanized pathway. No impairment of LTP induction was observed; indeed, if anything, there was a trend for greater potentiation with L-NAME. Because NO has also been implicated in the control of vasodilation, the effect of L-NAME on cerebrovascular function was also investigated. Peripheral blood pressure was significantly increased by L-NAME at the same dose that affected the field EPSP. Local cerebral glucose utilization was unchanged, while local cerebral blood flow decreased significantly in various brain regions, including the hippocampus, indicating an uncoupling of cerebral metabolism and blood flow. Thus, while NO synthase inhibition does not appear to limit the induction of LTP in vivo, it does reduce the size of baseline field EPSPs and affect local cerebrovascular function.

Amino Acid Oxidoreductases↗

PubMed1993

Nitric oxide synthase inhibitors block long-term potentiation induced by weak but not strong tetanic stimulation at physiological brain temperatures in rat hippocampal slices.

Nitric oxide synthase (NOS) inhibitors have been shown to block long-term synaptic enhancements in the mammalian hippocampus. This effect has been somewhat controversial, however, showing sensitivity to both temperature and stimulus strength. We have demonstrated a differential effect of the NOS inhibitor L-NG-nitroarginine (NOArg) on long-term potentiation (LTP) induced by weak and strong tetanic stimulation in slices of rat hippocampus. NOArg prevented LTP induction by a weak tetanus that produced stable potentiation in control slices, while the NOS inhibitor was without effect when strong tetani were used. These results suggest that nitric oxide (NO) produced as a result of tetanic stimulation plays a role in adjusting the threshold of LTP induction, but is not necessary for establishing synaptic enhancement under conditions of strong synaptic activation.

Amino Acid Oxidoreductases↗

PubMed1992

Induction of long-term potentiation in the basolateral amygdala does not depend on NMDA receptor activation.

Long-term potentiation (LTP) can be induced in the lateral and basolateral amygdala by stimulating synaptic afferents in the external capsule (EC). We examined the sensitivity of amygdaloid LTP to the NMDA receptor antagonist 2-amino-5-phosphonopentanoate (AP5), which is known to block LTP induction in the Schaffer collateral/CA1 synapses in the hippocampus. While relatively high concentrations (100 microM) of DL-AP5 were effective in preventing LTP induction in the lateral and basolateral amygdala in vitro, the same concentrations also significantly depressed synaptic responses to low-frequency stimulation. Furthermore, at 50 microM, a concentration sufficient to block both synaptic responses mediated by NMDA receptors and LTP induction in the hippocampus and neocortex, AP5 did not affect the probability of inducing LTP in the amygdala. Application of 10 microM 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), which blocks non-NMDA excitatory amino acid receptors, reduced the monosynaptic response to EC stimulation by 85%. The remaining CNQX-insensitive response did not appear to be mediated by NMDA-type receptors, since it was not reduced by 50 or 100 microM AP5, and showed none of the voltage sensitivity characteristic of NMDA responses. These data suggest that while the induction of LTP in the amygdala produced by EC stimulation is blocked by high doses of AP5, plasticity at these synapses probably does not require activation of NMDA receptors.

2-Amino-5-phosphonovalerate↗

PubMed1992

The role of nitric oxide in hippocampal long-term potentiation.

Long-term potentiation is a long-lasting, use-dependent increase in the strength of synaptic connections. We investigated the role of nitric oxide (NO) in determining the duration of potentiation induced by high frequency stimulation of afferents in the CA1 region of the rat hippocampus. The calcium/calmodulin-dependent production of NO can be initiated by activation of excitatory amino acid receptors and results in increased levels of cGMP in target cells. Here we report that only a relatively short-term potentiation can be induced in the presence of nitro-L-arginine methyl ester (L-NAME), an NO synthase inhibitor. The effects of L-NAME on the duration of potentiation are partially reversed by coadministration of L-arginine, a precursor of neuronal NO, and by dibutyryl cGMP. Hemoglobin, which binds extracellular NO, also shortens the duration of stimulus-induced potentiation. The results suggest a role for NO in the maintenance of activity-dependent synaptic enhancements, possibly via the generation of cGMP.

Amino Acid Oxidoreductases↗

PubMed1992

Inhibition of nitric oxide synthesis impairs two different forms of learning.

Nitric oxide (NO), an intercellular messenger in the central nervous system of vertebrates, plays an important role in the establishment of synaptic plasticity. In order to investigate the role of NO and synaptic plasticity in learning, we injected rats and rabbits with the NO synthase inhibitor nitro-L-arginine methyl ester (L-NAME) prior to training on two tests of learning. Rats treated with L-NAME were impaired in learning a spatial learning task, while rabbits given the NO synthase inhibitor demonstrated learning deficits in the conditioned eyeblink response. The results support the hypothesis that NO plays a critical role in acquisition of two different forms of learning.

Animals↗

PubMed1991

Isolation and phenotypic characterization of an oxidase-negative Aeromonas salmonicida causing furunculosis in coho salmon (Oncorhynchus kisutch).

An oxidase-negative Aeromonas salmonicida was isolated from coho salmon (Oncorhynchus) kisutch) suffering from an epizootic of furunculosis at the state hatchery near Belfair, Washington. Typical, oxidase-positive A. salmonicida was isolated concurrently from the same population of fish. Mortality was controlled with medicated feed treatments. Evidence supporting the identification of the two types of A. salmonicida is presented. Methods for the proper identification of oxidase-negative A. salmonicida isolates are evaluated.

Aeromonas↗

PubMed1990

Effects of lidocaine injection in the interpositus nucleus and red nucleus on conditioned behavioral and neuronal responses.

The role of the cerebellum and the red nucleus in the conditioned eyeblink response was assessed, using a combination of reversible lesions and multiple-unit extracellular recording in the awake, behaving rabbit. Lesion, recording, and stimulation experiments have indicated that both of these structures are involved in the performance of learned skeletal muscle responses. The present study sought to distinguish the relative contributions of the interpositus nucleus and the red nucleus to the expression of the learned response by recording behavior-related multiple unit activity in one structure while reversibly inactivating the other via injections of local anesthetic. Results indicate that inactivating either the interpositus or the red nucleus temporarily abolishes the learned eyeblink response. Injection of lidocaine into the interpositus also abolishes the neuronal unit model of the conditioned response in the red nucleus, while injection into the red nucleus does not affect the model in the interpositus. These results are consistent with the hypothesis that the red nucleus acts as a relay for motor commands from the cerebellum, and that the plasticity that generates conditioned responses occurs in the cerebellum or an afferent structure.

Animals↗

PubMed1990

Long-term synaptic potentiation in the amygdala.

The manner in which the circuitry of the amygdala computes its suspected mnemonic functions has been a mystery, partly because the cytoarchitectual complexity of this nuclear group has impeded the necessary cellular analysis. Here we report in vitro methods and results that may help elucidate cellular learning mechanisms in amygdala neurons. The amygdala brain slice preparation was combined with the single-electrode clamp (SEC) technique for intracellular analysis of membrane properties and synaptic responses. With respect to the active and passive membrane properties, we found considerable diversity among the population of cells that were sampled in the lateral and basolateral nuclei (n = 85). Synaptic inputs to these neurons were studied by stimulating the external capsule (EC), which was shown to produce a complex response that typically consisted of an excitatory followed by an inhibitory component. Based on several criteria, the excitatory component appeared to reflect a monosynaptic connection from the EC. One immediate goal was to discover whether the excitatory component displays the phenomenon of long-term potentiation (LTP)--a persistent increase in synaptic strength that can be induced by brief periods of the appropriate synaptic stimulation. Indeed, we found that high-frequency (100 Hz) stimulation of the EC induced LTP in 80% of the cells from which suitable recordings were obtained (n = 20). This finding of LTP in the amygdala is significant in regard to current efforts to explore linkages between this use-dependent form of synaptic plasticity and rapid kinds of associative learning.

Amygdala↗

PubMed1988

Long-term synaptic potentiation.

Long-term synaptic potentiation (LTP) is a leading candidate for a synaptic mechanism of rapid learning in mammals. LTP is a persistent increase in synaptic efficacy that can be quickly induced. The biophysical process that controls one type of LTP is formally similar to a synaptic memory mechanism postulated decades ago by the psychologist Donald Hebb. A key aspect of the modification process involves the N-methyl-D-aspartate (NMDA) receptor-ionophore complex. This ionophore allows calcium influx only if the endogenous ligand glutamate binds to the NMDA receptor and if the voltage across the associated channel is also sufficiently depolarized to relieve a magnesium block. According to one popular hypothesis, the resulting increase in the intracellular calcium concentration activates protein kinases that enhance the postsynaptic conductance. Further biophysical and molecular understanding of the modification process should facilitate detailed explorations of the mnemonic functions of LTP.

Animals↗

PubMed1988

Classical conditioning does not occur when direct stimulation of the red nucleus or cerebellar nuclei is the unconditioned stimulus.

The involvement of the cerebellum and the red nucleus in the classically conditioned nictitating membrane/eyeblink response in the rabbit is investigated using direct stimulation of the interpositus or the red nucleus as the unconditioned stimulus. Stimulation of either of these structures produced eye closure in naive animals, and this eye closure was paired with a tone in the standard Pavlovian conditioning paradigm. The results indicate that eyelid closure due to stimulation of either the red nucleus or the interpositus nucleus is not sufficient for the development of conditioned responses to the tone. Animals which had received interpositus stimulation as the unconditioned stimulus acquired the conditioned response to tone significantly faster following the substitution of air puff for stimulation than did those animals that had received red nucleus stimulation, or controls that did not receive any stimulation. However, animals that had been trained to tone-air puff could not retain the conditioned response after being switched to tone-interpositus stimulation. Lesions of the interpositus and the red nucleus through the stimulating electrodes were effective in impairing or abolishing conditioned responses. The results are interpreted to indicate that the red nucleus and interpositus are elements of the circuit that carries out the expression of the conditioned response. In addition the interpositus, but not the red nucleus, may be critical in the formation of the memory trace for the conditioned stimulus-unconditioned stimulus association, by virtue of the greatly accelerated learning that results from its stimulation.

Animals↗

PubMed1988

Videomicroscopy of acute brain slices from amygdala and hippocampus.

Video-enhanced contrast, differential-interference contrast microscopy (VEC-DICM) was used to visualize the cytoarchitecture and subcellular neuronal structure of acute brain slices from rat hippocampus and amygdala. Even at low-power magnification, the VEC-DICM system vastly improved our ability to visualize and examine the gross organization of the tissue. With medium-power magnification, the neuronal somata and proximal dendrites were clearly visible. With high-power magnification, some of the subcellular details could be clearly discerned--including cell nuclei, cell nucleoli, fine dendritic processes, and varicosities that may be synaptic expansions. We conclude that improved optical techniques should be valuable to cellular neurobiologists interested in structure-function relationships in brain slices.

Aging↗

PubMed1986

Classical conditioning of the rabbit eyelid response with a mossy-fiber stimulation CS: I. Pontine nuclei and middle cerebellar peduncle stimulation.

The nictitating membrane/eyelid responses of 18 rabbits were classically conditioned using cerebellar mossy-fiber stimulation as a conditioned stimulus (CS) and air puff as an unconditioned stimulus (US). The dorsolateral, lateral, and medial pontine nuclei and the middle cerebellar peduncle were effective stimulation-CS sites for training. In one group of rabbits, robust conditioned eyelid responses were produced with paired trials and subsequently extinguished with CS-alone and explicitly unpaired presentation of the CS and US. In a second group of rabbits, no conditioned responses were evident for 4 days of unpaired CS and US presentations. Conditioned responses did develop, however, after paired training was begun. Lesions of the interpositus nucleus of the cerebellum completely abolished the conditioned responses of a third group of rabbits overtrained with the mossy-fiber CS and air-puff US. These results support previous studies which have demonstrated that the cerebellum is critically involved in acquisition and retention of simple learned responses. In addition, the present results support previous theories of cerebellar function which have proposed that mossy fibers supply critical "learning" input to the cerebellum for acquisition and retention of motor skills.

Animals↗