In appetitive Pavlovian conditioning, experience with a conditional relationship between a cue [c... more In appetitive Pavlovian conditioning, experience with a conditional relationship between a cue [conditioned stimulus (CS)] and a reward [unconditioned stimulus (US)] bestows CS with the ability to promote adaptive behavior patterns. Different features of US (e.g., identity-specific sensory, general motivational) can be encoded by CS based on the nature of the CS-US relationship experienced (e.g., temporal factors such as training amount) and the content of association may determine the influence of CS over behavior (e.g., mediated learning, conditioned reinforcement). The content of association changed with varying conditioning factors, thereby altering behavioral consequences, however, has never been addressed in relevant brain signals evoked by CS. Our previous study found that phospholipase C β1-knockout (PLCβ1-KO) mice display persistent mediated learning over the extended course of odor-sugar conditioning, and that wild-type (WT) mice lose mediated learning sensitivity after ex...
The basal ganglia network has been implicated in the control of adaptive behavior, possibly by in... more The basal ganglia network has been implicated in the control of adaptive behavior, possibly by integrating motor learning and motivational processes. Both positive and negative reinforcement appear to shape our behavioral adaptation by modulating the function of the basal ganglia. Here, we examined a transgenic mouse line (G2CT) in which synaptic transmissions onto the medium spiny neurons (MSNs) of the basal ganglia are depressed. We found that the level of collaterals from direct pathway MSNs in the external segment of the globus pallidus (GPe) (‘bridging collaterals’) was decreased in these mice, and this was accompanied by behavioral inhibition under stress. Furthermore, additional manipulations that could further decrease or restore the level of the bridging collaterals resulted in an increase in behavioral inhibition or active behavior in the G2CT mice, respectively. Collectively, our data indicate that the striatum of the basal ganglia network integrates negative emotions and...
Cyclin Y (CCNY) is a member of cyclin superfamily proteins involved in the regulation of the cell... more Cyclin Y (CCNY) is a member of cyclin superfamily proteins involved in the regulation of the cell cycle in proliferating cells. Intriguingly, CCNY is highly expressed in terminally differentiated neuronal cells of multiple brain regions and acts as a postsynaptic protein, which plays an inhibitory role in long-term potentiation. However, the pathophysiological significance of CCNY in the nervous system remains largely unexplored. In this study, we revisited our RNA-sequencing (RNA-seq) data obtained from cultured hippocampal neurons virally overexpressing or depleting CCNY. Using RNA-seq-based bioinformatic disease analysis and synaptic gene ontology analysis, we identified that numerous genes associated with epilepsy (e.g. Chrna4, Gabrd, Nhlrc1, Reln, Samd12, Slc6a1, etc.) or neurodegenerative diseases (e.g. Psen1, Pdyn, Ndrg1, etc.) are affected by the level of CCNY expression. In agreement with the RNA-seq-based disease analysis, we found that Ccny knockout (KO) mice are more susceptible to kainic acid-induced epilepsy than wild-type mice. In addition, some epilepsy-associated genes that are regulated by CCNY levels were further validated in the brain of Ccny KO mice at the mRNA and protein levels. Collectively, our findings indicate that CCNY shifts the expression profile of epilepsyassociated genes and exerts a protective effect against kainic acid-induced epilepsy, suggesting CCNY as a potential pharmaceutical candidate for the treatment of epilepsy.
Nitric oxide (NO) acts as a neurotransmitter and neuromodulator in the nervous systems of many ve... more Nitric oxide (NO) acts as a neurotransmitter and neuromodulator in the nervous systems of many vertebrates and invertebrates. We investigated the mechanism of NO action at an identified synapse between a mechanoafferent neuron, C2, and the serotonergic metacerebral cell (MCC) in the cerebral ganglion of the molluscAplysia californica. Stimulation of C2 produces a decreasing conductance, very slow EPSP in the MCC. C2 is thought to use histamine and NO as cotransmitters at this synapse, because both agents mimic the membrane responses. Now we provide evidence that treatment with NO donors stimulates soluble guanylyl cyclase (sGC) in the MCC, and as a result cGMP increases.S-Nitrosocysteine (SNC, an NO donor) and 8-bromo-cGMP (8-Br-cGMP) both induced the membrane depolarization and increase in input resistance that are characteristic of the very slow EPSP. Two inhibitors of sGC, 6-anilino-5,8-quinolinequinone (LY83583) and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one (ODQ), suppressed ...
Hallucinations and delusions are the most prominent symptoms of schizophrenia and characterized b... more Hallucinations and delusions are the most prominent symptoms of schizophrenia and characterized by impaired reality testing. Representation-mediated taste aversion (RMTA) has been proposed as a potential behavioral assessment of reality testing and has been applied to a neurodevelopmental rat model of schizophrenia. However, the theory underlying this approach has not been generalized yet with any demonstration of impaired reality testing in other animal models of schizophrenia, such as genetically-modified mice. We devised a RMTA procedure for mice that combines a Pavlovian association protocol pairing odor conditioned stimulus (CS) with sugar reward unconditioned stimulus (US), and a conditioned taste aversion (CTA) method. In this RMTA paradigm, we compared performances of wildtype (PLCβ1 +/+) mice and phospholipase C β1 knockout (PLCβ1-/-) mice which are known as one of the genetic models for schizophrenia. With a minimal amount of initial odor-sugar associative training, both PLCβ1 +/+ and PLCβ1-/mice were able to form an aversion to the sugar reward when the odor CS predicting sugar was paired with nausea. With an extended initial training, however, only PLCβ1-/mice could form a RMTA. This persistent RMTA displayed by PLCβ1-/mice shows their inability to distinguish real sugar from the CS-evoked representation of sugar at a stage in associative learning where wild-type mice normally could differentiate the two. These results demonstrate an impaired reality testing first observed in a genetic mouse model of schizophrenia, and suggest that RMTA paradigm may, with general applicability, allow diverse biological approaches to impaired reality testing.
Abnormal expression patterns of phospholipase C-β1(PLC-β1) in specific brain areas of patients wi... more Abnormal expression patterns of phospholipase C-β1(PLC-β1) in specific brain areas of patients with schizophrenia, and its high genetic linkage to the disorder implicated a pathogenetical involvement of PLC-β1 signaling system. The schizophrenia-related behavioral phenotypes displayed in the mutant mice lacking PLC-β1 (PLC-β1 KO) suggested that PLCβ1-linked signaling pathways may be involved in the neural system whose function is disrupted in the pathogenesis of schizophrenia. In the brain, PLC-β1 is known to be linked to muscarinic acetylcholine receptors, metabotropic glutamatergic, serotonergic, and oxytocinergic systems. The objective of this review is to provide an overview of the current knowledge regarding these schizophrenia-related behaviors and discuss the probable ways in which PLC-β1signalling can be involved in the neural mechanisms for each behavior, which may help suggest future directions for research in this area.
European journal of medicinal chemistry, Jan 6, 2014
There has been much attention to discover mGluR1 antagonists for treating various central nervous... more There has been much attention to discover mGluR1 antagonists for treating various central nervous system diseases such as seizures and neuropathic pain. Thienopyrimidinone derivatives were designed, synthesized, and biologically evaluated against mGluR1. Among the synthesized compounds, 3-(4-methoxyphenyl)-7-(o-tolyl)thienopyrimidin-4-one 30 exhibited the most potent inhibitory activity with an IC50 value of 45 nM and good selectivity over mGluR5. Also, the selective mGluR1 antagonist 30 showed marginal hERG channel activity (IC50 = 9.87 μM), good profiles to CYP isozymes, and a good pharmacokinetic profile. Overall, the compound 30 was identified as a selective mGluR1 antagonist with a good pharmacokinetic profile, which is probably devoid of cardiac side effect and drug-drug interactions. Therefore, the compound 30 can be expected to be broadly used as mGluR1 antagonistic chemical probe in in vitro and in vivo study for investigating CNS diseases.
Many behaviors display various forms of activity-dependent plasticity. An example of such plastic... more Many behaviors display various forms of activity-dependent plasticity. An example of such plasticity is the progressive shortening of the duration of protraction phase of feeding responses of Aplysia that occurs when feeding responses are repeatedly elicited. A similar protraction-duration shortening is observed in isolated ganglia of Aplysia when feeding-like motor programs are elicited through a prolonged stimulation of the command-like neuron CBI-2. Here, we investigate a cellular mechanism that may underlie this activity-dependent shortening of protraction duration of feeding motor programs. CBI-2 contains two neuropeptides, CP2 and FCAP. Previous work showed that CP2 shortens protraction duration of CBI-2 elicited programs. We show here that the same is true for FCAP. We also show that both CP2 and FCAP modulated the biophysical properties of a plateau-generating neuron, B64, that plays an important role in terminating the protraction phase of feeding motor programs. We find th...
Posttetanic potentiation (PTP)-like phenomena appear to be mediated by a variety of mechanisms. A... more Posttetanic potentiation (PTP)-like phenomena appear to be mediated by a variety of mechanisms. Although neuropeptides are located in a large number of neurons and many neuropeptides, like PTP, can enhance synaptic transmission, there is a paucity of studies indicating that peptides may actually participate in PTP. Here, we utilize a single central synapse in the feeding circuit of Aplysia to investigate a possible peptidergic contribution to PTP in the CNS. The cholinergic command-like interneuron, cerebral-buccal interneuron 2 (CBI-2), contains two neuropeptides, feeding circuit activating peptide (FCAP) and cerebral peptide 2 (CP2). Previous studies showed that tetanic prestimulation or repeated stimulation of CBI-2, as well as perfusion of FCAP and CP2, increase the size of the cholinergic excitatory postsynaptic potentials (EPSPs) that CBI-2 evokes in the motoneurons B61/62 and shorten the latency to initiate B61/62 firing in response to CBI-2 stimulation. We used temperature-d...
In many neurons more than one peptide is colocalized with a classical neurotransmitter. The funct... more In many neurons more than one peptide is colocalized with a classical neurotransmitter. The functional consequence of such an arrangement has been rarely investigated. Here, within the feeding circuit of Aplysia, we investigate at a single synapse the actions of two modulatory neuropeptides that are present in a cholinergic interneuron. In combination with previous work, our study shows that the command-like neuron for feeding, CBI-2, contains two neuropeptides, feeding circuit activating peptide (FCAP) and cerebral peptide 2 (CP2). Previous studies showed that high-frequency prestimulation or repeated stimulation of CBI-2 increases the size of CBI-2 to B61/62 excitatory postsynaptic potentials (EPSPs) and shortens the latency of firing of neuron B61/62 in response to CBI-2 stimulation. We find that both FCAP and CP2 mimic these two effects. The variance method of quantal analysis indicates that FCAP increases the calculated quantal size ( q) and CP2 increases the calculated quantal...
Abnormal phospholipid metabolism has been implicated in the pathogenesis of schizophrenia, and it... more Abnormal phospholipid metabolism has been implicated in the pathogenesis of schizophrenia, and it was reported that phospholipase C (PLC) β1 is reduced in specific brain areas of patients with schizophrenia. However, the causal relationship of the PLCβ1 gene with behavioral symptoms of schizophrenia remains unclear. To address this issue, we have examined the mutant mice lacking PLCβ1 for schizophrenia‐related phenotypes by performing various behavioral tests, including general locomotor activity, sensorimotor gating, social behaviors, and learning and memory. Phospholipase C β1 knockout mice showed hyperactivities in an open field. They showed impaired prepulse inhibition of acoustic startle response, which was ameliorated by a systemic administration of an antipsychotic D2‐receptor antagonist, haloperidol. In addition, they showed abnormal social behaviors, such as lack of barbering behavior, socially recessive trait and lack of nesting behavior. Furthermore, they showed impaired ...
Nitric oxide (NO) acts as an orthograde neurotransmitter in the central nervous system by stimula... more Nitric oxide (NO) acts as an orthograde neurotransmitter in the central nervous system by stimulating guanylyl cyclase and increasing cGMP. We previously demonstrated this pathway for an identified synaptic follower neuron in the cerebral ganglion of the mollusc Aplysia californica. Here, we investigated the NO–cGMP pathway in other Aplysia central neurons using cGMP immunocytochemistry and intracellular recordings. NO‐induced cGMP immunoreactivity in a few neurons in the abdominal, pleural and buccal ganglia, including identified neurons L11 and R15 in the abdominal ganglion and neuron Bng in the buccal ganglion. NO depolarized all these neurons but none of the four nonimmunoreactive neurons tested. In neuron L11, NO‐induced depolarization, tonic spiking and a reduction in membrane conductance at resting potential. The NO effect was mimicked by applying the membrane permeable analogue, 8‐Br‐cGMP in L11. Neuron R15 was depolarized and its activity shifted from spike/bursts to tonic ...
Biochemical and Biophysical Research Communications, 1989
Bleomycin-induced DNA repair synthesis in the permeabilized HeLa cells was sensitive to aphidicol... more Bleomycin-induced DNA repair synthesis in the permeabilized HeLa cells was sensitive to aphidicolin, an inhibitor of DNA polymerase a and 6, and to dideoxythymidine triphosphate (ddTTP), a specific inhibitor of DNA polymerase P. Upon combined treatment with these inhibitors, the DNA repair synthesis was inhibited to an even higher degree. This indicated that the aphidicolin-and ddTTP-sensitive DNA repair syntheses may occur by independent mechanisms. The structure of incomplete repair patches being accumulated in the presence of these inhibitors was investigated by digestion of DNA with exonuclease III after incubation with Klenow fragment and T4 DNA ligase. The results have suggested that the patch accumulating in the presence of aphidicolin is a single-stranded gap made by excision enzyme(s), whereas that accumulating in the presence of ddTTP may be generated by strand displacement.
Background: Decreased expression of phospholipase C-β1 (PLC-β1) has been observed in the brains o... more Background: Decreased expression of phospholipase C-β1 (PLC-β1) has been observed in the brains of patients with schizophrenia, but, to our knowledge, no studies have shown a possible association between this altered PLC-β1 expression and the pathogenesis of schizophrenia. Although PLC-β1-null (PLC-β1 −/−) mice exhibit multiple endophenotypes of schizophrenia, it remains unclear how regional decreases in PLC-β1 expression in the brain contribute to specific behavioural defects. Methods: We selectively knocked down PLC-β1 in the medial prefrontal cortex (mPFC) using a small hairpin RNA strategy in mice. Results: Silencing PLC-β1 in the mPFC resulted in working memory deficits, as assayed using the delayed non-match-to-sample T-maze task. Notably, however, other schizophreniarelated behaviours observed in PLC-β1 −/− mice, including phenotypes related to locomotor activity, sociability and sensorimotor gating, were normal in PLC-β1 knockdown mice. Limitations: Phenotypes of PLC-β1 knockdown mice, such as locomotion, anxiety and sensorimotor gating, have already been published in our previous studies. Further, the neural mechanisms underlying the working memory deficit in mice may be different from those in human schizophrenia. Conclusion: These results indicate that PLC-β1 signalling in the mPFC is required for working memory. Importantly, these results support the notion that the decrease in PLC-β1 expression in the brains of patients with schizophrenia is a pathogenically relevant molecular marker of the disorder.
In appetitive Pavlovian conditioning, experience with a conditional relationship between a cue [c... more In appetitive Pavlovian conditioning, experience with a conditional relationship between a cue [conditioned stimulus (CS)] and a reward [unconditioned stimulus (US)] bestows CS with the ability to promote adaptive behavior patterns. Different features of US (e.g., identity-specific sensory, general motivational) can be encoded by CS based on the nature of the CS-US relationship experienced (e.g., temporal factors such as training amount) and the content of association may determine the influence of CS over behavior (e.g., mediated learning, conditioned reinforcement). The content of association changed with varying conditioning factors, thereby altering behavioral consequences, however, has never been addressed in relevant brain signals evoked by CS. Our previous study found that phospholipase C β1-knockout (PLCβ1-KO) mice display persistent mediated learning over the extended course of odor-sugar conditioning, and that wild-type (WT) mice lose mediated learning sensitivity after ex...
The basal ganglia network has been implicated in the control of adaptive behavior, possibly by in... more The basal ganglia network has been implicated in the control of adaptive behavior, possibly by integrating motor learning and motivational processes. Both positive and negative reinforcement appear to shape our behavioral adaptation by modulating the function of the basal ganglia. Here, we examined a transgenic mouse line (G2CT) in which synaptic transmissions onto the medium spiny neurons (MSNs) of the basal ganglia are depressed. We found that the level of collaterals from direct pathway MSNs in the external segment of the globus pallidus (GPe) (‘bridging collaterals’) was decreased in these mice, and this was accompanied by behavioral inhibition under stress. Furthermore, additional manipulations that could further decrease or restore the level of the bridging collaterals resulted in an increase in behavioral inhibition or active behavior in the G2CT mice, respectively. Collectively, our data indicate that the striatum of the basal ganglia network integrates negative emotions and...
Cyclin Y (CCNY) is a member of cyclin superfamily proteins involved in the regulation of the cell... more Cyclin Y (CCNY) is a member of cyclin superfamily proteins involved in the regulation of the cell cycle in proliferating cells. Intriguingly, CCNY is highly expressed in terminally differentiated neuronal cells of multiple brain regions and acts as a postsynaptic protein, which plays an inhibitory role in long-term potentiation. However, the pathophysiological significance of CCNY in the nervous system remains largely unexplored. In this study, we revisited our RNA-sequencing (RNA-seq) data obtained from cultured hippocampal neurons virally overexpressing or depleting CCNY. Using RNA-seq-based bioinformatic disease analysis and synaptic gene ontology analysis, we identified that numerous genes associated with epilepsy (e.g. Chrna4, Gabrd, Nhlrc1, Reln, Samd12, Slc6a1, etc.) or neurodegenerative diseases (e.g. Psen1, Pdyn, Ndrg1, etc.) are affected by the level of CCNY expression. In agreement with the RNA-seq-based disease analysis, we found that Ccny knockout (KO) mice are more susceptible to kainic acid-induced epilepsy than wild-type mice. In addition, some epilepsy-associated genes that are regulated by CCNY levels were further validated in the brain of Ccny KO mice at the mRNA and protein levels. Collectively, our findings indicate that CCNY shifts the expression profile of epilepsyassociated genes and exerts a protective effect against kainic acid-induced epilepsy, suggesting CCNY as a potential pharmaceutical candidate for the treatment of epilepsy.
Nitric oxide (NO) acts as a neurotransmitter and neuromodulator in the nervous systems of many ve... more Nitric oxide (NO) acts as a neurotransmitter and neuromodulator in the nervous systems of many vertebrates and invertebrates. We investigated the mechanism of NO action at an identified synapse between a mechanoafferent neuron, C2, and the serotonergic metacerebral cell (MCC) in the cerebral ganglion of the molluscAplysia californica. Stimulation of C2 produces a decreasing conductance, very slow EPSP in the MCC. C2 is thought to use histamine and NO as cotransmitters at this synapse, because both agents mimic the membrane responses. Now we provide evidence that treatment with NO donors stimulates soluble guanylyl cyclase (sGC) in the MCC, and as a result cGMP increases.S-Nitrosocysteine (SNC, an NO donor) and 8-bromo-cGMP (8-Br-cGMP) both induced the membrane depolarization and increase in input resistance that are characteristic of the very slow EPSP. Two inhibitors of sGC, 6-anilino-5,8-quinolinequinone (LY83583) and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one (ODQ), suppressed ...
Hallucinations and delusions are the most prominent symptoms of schizophrenia and characterized b... more Hallucinations and delusions are the most prominent symptoms of schizophrenia and characterized by impaired reality testing. Representation-mediated taste aversion (RMTA) has been proposed as a potential behavioral assessment of reality testing and has been applied to a neurodevelopmental rat model of schizophrenia. However, the theory underlying this approach has not been generalized yet with any demonstration of impaired reality testing in other animal models of schizophrenia, such as genetically-modified mice. We devised a RMTA procedure for mice that combines a Pavlovian association protocol pairing odor conditioned stimulus (CS) with sugar reward unconditioned stimulus (US), and a conditioned taste aversion (CTA) method. In this RMTA paradigm, we compared performances of wildtype (PLCβ1 +/+) mice and phospholipase C β1 knockout (PLCβ1-/-) mice which are known as one of the genetic models for schizophrenia. With a minimal amount of initial odor-sugar associative training, both PLCβ1 +/+ and PLCβ1-/mice were able to form an aversion to the sugar reward when the odor CS predicting sugar was paired with nausea. With an extended initial training, however, only PLCβ1-/mice could form a RMTA. This persistent RMTA displayed by PLCβ1-/mice shows their inability to distinguish real sugar from the CS-evoked representation of sugar at a stage in associative learning where wild-type mice normally could differentiate the two. These results demonstrate an impaired reality testing first observed in a genetic mouse model of schizophrenia, and suggest that RMTA paradigm may, with general applicability, allow diverse biological approaches to impaired reality testing.
Abnormal expression patterns of phospholipase C-β1(PLC-β1) in specific brain areas of patients wi... more Abnormal expression patterns of phospholipase C-β1(PLC-β1) in specific brain areas of patients with schizophrenia, and its high genetic linkage to the disorder implicated a pathogenetical involvement of PLC-β1 signaling system. The schizophrenia-related behavioral phenotypes displayed in the mutant mice lacking PLC-β1 (PLC-β1 KO) suggested that PLCβ1-linked signaling pathways may be involved in the neural system whose function is disrupted in the pathogenesis of schizophrenia. In the brain, PLC-β1 is known to be linked to muscarinic acetylcholine receptors, metabotropic glutamatergic, serotonergic, and oxytocinergic systems. The objective of this review is to provide an overview of the current knowledge regarding these schizophrenia-related behaviors and discuss the probable ways in which PLC-β1signalling can be involved in the neural mechanisms for each behavior, which may help suggest future directions for research in this area.
European journal of medicinal chemistry, Jan 6, 2014
There has been much attention to discover mGluR1 antagonists for treating various central nervous... more There has been much attention to discover mGluR1 antagonists for treating various central nervous system diseases such as seizures and neuropathic pain. Thienopyrimidinone derivatives were designed, synthesized, and biologically evaluated against mGluR1. Among the synthesized compounds, 3-(4-methoxyphenyl)-7-(o-tolyl)thienopyrimidin-4-one 30 exhibited the most potent inhibitory activity with an IC50 value of 45 nM and good selectivity over mGluR5. Also, the selective mGluR1 antagonist 30 showed marginal hERG channel activity (IC50 = 9.87 μM), good profiles to CYP isozymes, and a good pharmacokinetic profile. Overall, the compound 30 was identified as a selective mGluR1 antagonist with a good pharmacokinetic profile, which is probably devoid of cardiac side effect and drug-drug interactions. Therefore, the compound 30 can be expected to be broadly used as mGluR1 antagonistic chemical probe in in vitro and in vivo study for investigating CNS diseases.
Many behaviors display various forms of activity-dependent plasticity. An example of such plastic... more Many behaviors display various forms of activity-dependent plasticity. An example of such plasticity is the progressive shortening of the duration of protraction phase of feeding responses of Aplysia that occurs when feeding responses are repeatedly elicited. A similar protraction-duration shortening is observed in isolated ganglia of Aplysia when feeding-like motor programs are elicited through a prolonged stimulation of the command-like neuron CBI-2. Here, we investigate a cellular mechanism that may underlie this activity-dependent shortening of protraction duration of feeding motor programs. CBI-2 contains two neuropeptides, CP2 and FCAP. Previous work showed that CP2 shortens protraction duration of CBI-2 elicited programs. We show here that the same is true for FCAP. We also show that both CP2 and FCAP modulated the biophysical properties of a plateau-generating neuron, B64, that plays an important role in terminating the protraction phase of feeding motor programs. We find th...
Posttetanic potentiation (PTP)-like phenomena appear to be mediated by a variety of mechanisms. A... more Posttetanic potentiation (PTP)-like phenomena appear to be mediated by a variety of mechanisms. Although neuropeptides are located in a large number of neurons and many neuropeptides, like PTP, can enhance synaptic transmission, there is a paucity of studies indicating that peptides may actually participate in PTP. Here, we utilize a single central synapse in the feeding circuit of Aplysia to investigate a possible peptidergic contribution to PTP in the CNS. The cholinergic command-like interneuron, cerebral-buccal interneuron 2 (CBI-2), contains two neuropeptides, feeding circuit activating peptide (FCAP) and cerebral peptide 2 (CP2). Previous studies showed that tetanic prestimulation or repeated stimulation of CBI-2, as well as perfusion of FCAP and CP2, increase the size of the cholinergic excitatory postsynaptic potentials (EPSPs) that CBI-2 evokes in the motoneurons B61/62 and shorten the latency to initiate B61/62 firing in response to CBI-2 stimulation. We used temperature-d...
In many neurons more than one peptide is colocalized with a classical neurotransmitter. The funct... more In many neurons more than one peptide is colocalized with a classical neurotransmitter. The functional consequence of such an arrangement has been rarely investigated. Here, within the feeding circuit of Aplysia, we investigate at a single synapse the actions of two modulatory neuropeptides that are present in a cholinergic interneuron. In combination with previous work, our study shows that the command-like neuron for feeding, CBI-2, contains two neuropeptides, feeding circuit activating peptide (FCAP) and cerebral peptide 2 (CP2). Previous studies showed that high-frequency prestimulation or repeated stimulation of CBI-2 increases the size of CBI-2 to B61/62 excitatory postsynaptic potentials (EPSPs) and shortens the latency of firing of neuron B61/62 in response to CBI-2 stimulation. We find that both FCAP and CP2 mimic these two effects. The variance method of quantal analysis indicates that FCAP increases the calculated quantal size ( q) and CP2 increases the calculated quantal...
Abnormal phospholipid metabolism has been implicated in the pathogenesis of schizophrenia, and it... more Abnormal phospholipid metabolism has been implicated in the pathogenesis of schizophrenia, and it was reported that phospholipase C (PLC) β1 is reduced in specific brain areas of patients with schizophrenia. However, the causal relationship of the PLCβ1 gene with behavioral symptoms of schizophrenia remains unclear. To address this issue, we have examined the mutant mice lacking PLCβ1 for schizophrenia‐related phenotypes by performing various behavioral tests, including general locomotor activity, sensorimotor gating, social behaviors, and learning and memory. Phospholipase C β1 knockout mice showed hyperactivities in an open field. They showed impaired prepulse inhibition of acoustic startle response, which was ameliorated by a systemic administration of an antipsychotic D2‐receptor antagonist, haloperidol. In addition, they showed abnormal social behaviors, such as lack of barbering behavior, socially recessive trait and lack of nesting behavior. Furthermore, they showed impaired ...
Nitric oxide (NO) acts as an orthograde neurotransmitter in the central nervous system by stimula... more Nitric oxide (NO) acts as an orthograde neurotransmitter in the central nervous system by stimulating guanylyl cyclase and increasing cGMP. We previously demonstrated this pathway for an identified synaptic follower neuron in the cerebral ganglion of the mollusc Aplysia californica. Here, we investigated the NO–cGMP pathway in other Aplysia central neurons using cGMP immunocytochemistry and intracellular recordings. NO‐induced cGMP immunoreactivity in a few neurons in the abdominal, pleural and buccal ganglia, including identified neurons L11 and R15 in the abdominal ganglion and neuron Bng in the buccal ganglion. NO depolarized all these neurons but none of the four nonimmunoreactive neurons tested. In neuron L11, NO‐induced depolarization, tonic spiking and a reduction in membrane conductance at resting potential. The NO effect was mimicked by applying the membrane permeable analogue, 8‐Br‐cGMP in L11. Neuron R15 was depolarized and its activity shifted from spike/bursts to tonic ...
Biochemical and Biophysical Research Communications, 1989
Bleomycin-induced DNA repair synthesis in the permeabilized HeLa cells was sensitive to aphidicol... more Bleomycin-induced DNA repair synthesis in the permeabilized HeLa cells was sensitive to aphidicolin, an inhibitor of DNA polymerase a and 6, and to dideoxythymidine triphosphate (ddTTP), a specific inhibitor of DNA polymerase P. Upon combined treatment with these inhibitors, the DNA repair synthesis was inhibited to an even higher degree. This indicated that the aphidicolin-and ddTTP-sensitive DNA repair syntheses may occur by independent mechanisms. The structure of incomplete repair patches being accumulated in the presence of these inhibitors was investigated by digestion of DNA with exonuclease III after incubation with Klenow fragment and T4 DNA ligase. The results have suggested that the patch accumulating in the presence of aphidicolin is a single-stranded gap made by excision enzyme(s), whereas that accumulating in the presence of ddTTP may be generated by strand displacement.
Background: Decreased expression of phospholipase C-β1 (PLC-β1) has been observed in the brains o... more Background: Decreased expression of phospholipase C-β1 (PLC-β1) has been observed in the brains of patients with schizophrenia, but, to our knowledge, no studies have shown a possible association between this altered PLC-β1 expression and the pathogenesis of schizophrenia. Although PLC-β1-null (PLC-β1 −/−) mice exhibit multiple endophenotypes of schizophrenia, it remains unclear how regional decreases in PLC-β1 expression in the brain contribute to specific behavioural defects. Methods: We selectively knocked down PLC-β1 in the medial prefrontal cortex (mPFC) using a small hairpin RNA strategy in mice. Results: Silencing PLC-β1 in the mPFC resulted in working memory deficits, as assayed using the delayed non-match-to-sample T-maze task. Notably, however, other schizophreniarelated behaviours observed in PLC-β1 −/− mice, including phenotypes related to locomotor activity, sociability and sensorimotor gating, were normal in PLC-β1 knockdown mice. Limitations: Phenotypes of PLC-β1 knockdown mice, such as locomotion, anxiety and sensorimotor gating, have already been published in our previous studies. Further, the neural mechanisms underlying the working memory deficit in mice may be different from those in human schizophrenia. Conclusion: These results indicate that PLC-β1 signalling in the mPFC is required for working memory. Importantly, these results support the notion that the decrease in PLC-β1 expression in the brains of patients with schizophrenia is a pathogenically relevant molecular marker of the disorder.
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Papers by Hae-young Koh