Ildiko Aradi - Academia.edu (original) (raw)
Papers by Ildiko Aradi
Computers & mathematics with applications, Dec 1, 1996
The generation and propagation of action potentials in the two major cell types of the olfactory ... more The generation and propagation of action potentials in the two major cell types of the olfactory bulb, i.e., in the mitral and granule cells, are simulated by applying the multicompartmental modeling technique. The specific effects of the individual ionic currents, the propagation of the signals through the compartments, and several dynamic phenomena occurring in small networks (such as synchronized oscillation due to excitatory and inhibitory coupling) have been demonstrated. Ueywords-Single neuron dynamics, Neural simulation, Rhythmogenesis.
International Journal of Intelligent Systems, 1995
A mathematical model is given for describing activity dynamics, learning, and associative memory ... more A mathematical model is given for describing activity dynamics, learning, and associative memory in the olfactory bulb. Numerical bifurcation analysis and the calculation of Lyapunov-exponents suggest that chaotic behavior only occurs in the case of strong excitatory coupling in the mitral layer. A Hebbian-type learning rule, supplemented with a nonlinear decay term and a selective decreasing term, is defined and analyzed. Slow learning modifies the bulbar activity dynamics hence it plays a crucial role in odor information processing. 0 1995 John Wiley & Sons, Inc. ' Supported by the Japan Society for the Promotion of Science. 2Supported by the Hungarian Scientific Research Fund under Grant No. OTKA 3Supported by the Academy of Finland.
Multicompartmental Modeling of the Olfactory Bulb
Cybernetics and Systems, Dec 1, 1996
The generation and propagation of action potentials in the two major cell types of the olfactory ... more The generation and propagation of action potentials in the two major cell types of the olfactory bulb the mitral and granule cells are simulated by applying the multicompartmental modeling technique The specific effects of the individual ionic currents the propagation of the signals through the compartments and several dynamic phenomena occurring in small networks such as synchronized oscillation due to excitatory and inhibitory coupling have been demonstrated
Osteoporosis International, 2018
To demonstrate the clinical comparability between RGB-10 (a biosimilar teriparatide) and the orig... more To demonstrate the clinical comparability between RGB-10 (a biosimilar teriparatide) and the originator, a comparative pharmacokinetic trial was conducted. The study was successful in establishing bioequivalence. Marketing authorisation for RGB-10 (Terrosa®) was granted by the European Medicines Agency in 2017. Introduction Teriparatide, the first bone anabolic agent, is the biologically active fragment of human parathyroid hormone. The imminent patent expiry of the originator will open the door for biosimilars to enter the osteology market, thereby improving access to a highly effective, yet prohibitively expensive therapy. Methods Subsequent to establishing comparability on the quality and non-clinical levels between RGB-10, a biosimilar teriparatide, and its reference product (Forsteo®), a randomised, double-blind, 2-way cross-over comparative study (duration: four days) was conducted in 54 healthy women (ages: 18 to 55 years) to demonstrate the pharmacokinetic/pharmacodynamic (PK/PD) equivalence and comparable safety of these products. Extents of exposure (AUC 0-tlast) and peak exposure (C max), as measured by means of ELISA, were evaluated as co-primary PK endpoints, and serum calcium levels, as measured using standard automated techniques, were assessed for PD effects. Safety was monitored throughout the study. Results The 94.12% CIs for the ratio of the test to the reference treatments, used due to the two-stage design (85.20-98.60% and 85.51-99.52% for AUC 0-tlast and C max , respectively), fell within the 80.00-125.00% acceptance range. The calcium PD parameters were essentially identical with geometric mean ratios (GMRs) of 99.93% and 99.87% for AUC and C max , respectively. Analysis of the safety data did not reveal any differences between RGB-10 and its reference. Conclusion Based on the high level of similarity in the preclinical data and the results of this clinical study, marketing authorisation for RGB-10 (Terrosa®) was granted by the European Medicines Agency (EMA) in 2017.
Hippocampal Pyramidal Cells -Mediated IPSPs in B Reversal Potential of GABA -Dependent Chloride Influx Modulates
Diversity of interneurons as a major determinant of network excitability and stability
Epilepsia 41(Suppl, Mar 13, 2000
Additional file 1: of Efficacy and safety of RGB-02, a pegfilgrastim biosimilar to prevent chemotherapy-induced neutropenia: results of a randomized, double-blind phase III clinical study vs. reference pegfilgrastim in patients with breast cancer receiving chemotherapy
List of Ethical Committees who approved the study RGB-02-101.(DOCX 12 kb)
BMC Cancer, 2019
Background: Treatment with recombinant human granulocyte-colony stimulating factor (G-CSF) is acc... more Background: Treatment with recombinant human granulocyte-colony stimulating factor (G-CSF) is accepted standard for prevention of chemotherapy-induced neutropenia. RGB-02 (Gedeon Richter) is a proposed biosimilar to pegylated G-CSF (Neulasta®, Amgen) with sustained release properties. This is a randomized, comparative, doubleblind, multicenter study to evaluate efficacy and safety of RGB-02 in breast cancer patients receiving cytotoxic regimen. Methods: Two hundred thirty-nine women presenting with breast cancer were randomized to RGB-02 (n = 121) and the reference product (n = 118). All patients received up to 6 cycles of docetaxel/doxorubicin chemotherapy combination and a once-per-cycle injection of a fixed 6 mg dose of pegfilgrastim. Primary endpoint was the duration of severe neutropenia (ANC < 0.5 × 10 9 /L) in Cycle 1 (2-sided CI 95%). Secondary endpoints included incidence and duration of severe neutropenia (in cycles 2-4), incidence of febrile neutropenia, time to ANC recovery, depth of ANC nadir, and safety outcomes. Results: The mean duration of severe neutropenia in Cycle 1 was 1.7 (RGB-02) and 1.6 days (reference), with a difference (LS Mean) of 0.1 days (95% CI-0.2, 0.4). Equivalence could be established as the CI for the difference in LS Mean lay entirely within the pre-defined range of ±1 day. This positive result was supported by the analysis of secondary endpoints, which also revealed no clinical meaningful differences. Safety profiles were comparable between groups. No neutralizing antibodies against pegfilgrastim were identified. Conclusions: Treatment equivalence in reducing the duration of chemotherapy induced neutropenia between RGB-02 and Neulasta® could be demonstrated. Similar efficacy and safety profiles of the once-per-cycle administration of RGB-02 and the pegfilgrastim reference were demonstrated.
Future Oncology, 2019
Pegfilgrastim is widely used for the prevention of chemotherapy-induced neutropenia. The developm... more Pegfilgrastim is widely used for the prevention of chemotherapy-induced neutropenia. The development and use of biosimilar agents help to rationalize healthcare expenditure and improve access to modern therapies to all who need them. This review focuses on pegfilgrastims with important role in oncology supportive care. RGB-02 (Gedeon Richter) is a proposed biosimilar to pegylated granulocyte-colony stimulating factor (Neulasta R , Amgen) with sustained release properties. The clinical analyses in three randomized clinical studies provided comparative data between RGB-02 and Neulasta, in a Phase III study patients receiving docetaxel-doxorubicin chemotherapy treatment equivalence was found. No difference was detected in any safety measure including immunogenicity; treatment switch, from the reference product to RGB-02 proved safe. Long-acting pegylated filgrastim RGB-02 has successfully accomplished various steps of biosimilar development.
1700PSafe switch of treatment from the reference product to RGB-02, a proposed biosimilar pegfilgrastim: Analysis of the results of three clinical trials
Annals of Oncology, 2018
Multicompartmental Modeling of Neural Circuits in the Olfactory Bulb
International Journal of Neural Systems, 1996
The generation and propagation of action potentials in the excitatory and inhibitory cell types o... more The generation and propagation of action potentials in the excitatory and inhibitory cell types of the olfactory bulb are simulated by applying multi-compartmental modeling technique. Detailed models of the main cell types of the olfactory bulb have been presented previously.1 Further simulations on granule and periglomerular cells have been done to find proper parameters matching to the physiological recordings.22 Elementary synaptic interactions and dynamic behaviour of small networks of excitatory and inhibitory neurons have been studied. To investigate the relationship between the anatomical structure of the neural circuits of whole olfactory bulb and the generated firing patterns, further series of simulations have been done.
We have constructed a detailed model of a hippocampal dentate granule (DG) cell that includes nin... more We have constructed a detailed model of a hippocampal dentate granule (DG) cell that includes nine different channel types. Channel densities and distributions were chosen to reproduce reported physiological responses observed in normal solution and when blockers were applied. The model was used to explore the contribution of each channel type to spiking behavior with particular emphasis on the mechanisms underlying postspike events. T-type calcium current in more distal dendrites contributed prominently to the appearance of the depolarizing after-potential, and its effect was controlled by activation of BK-type calcium-dependent potassium channels. Coactivation and interaction of N-, and/or L-type calcium and AHP currents present in somatic and proximal dendritic regions contributed to the adaptive properties of the model DG cell in response to long-lasting current injection. The model was used to predict changes in channel densities that could lead to epileptogenic burst discharges and to predict the effect of altered buffering capacity on firing behavior. We conclude that the clustered spatial distributions of calcium related channels, the presence of slow delayed rectifier potassium currents in dendrites, and calcium buffering properties, together, might explain the resistance of DG cells to the development of epileptogenic burst discharges.
Modeling the Contributions of Calcium Channels and NMDA Receptor Channels to Calcium Current in Dendritic Spines
Computational Neuroscience, 1998
A model of a dentate granule cell that explicitly included all dendritic spines was used to explo... more A model of a dentate granule cell that explicitly included all dendritic spines was used to explore the relative contributions of voltage-gated calcium channels and NMDA receptor channels to calcium influx in dendritic spines following tetanic stimulation. Up to 10 T, N, or L calcium channels were placed in each dendritic spine. It was found that calcium currents through calcium channels in spines had a much shorter duration than the NMDA calcium current, except for T channels, and had an amplitude that was in many cases comparable in magnitude to the NMDA calcium current.
The Journal of Physiology, 2007
The integration of synaptic signalling in the mammalian hippocampus underlies higher cognitive fu... more The integration of synaptic signalling in the mammalian hippocampus underlies higher cognitive functions such as learning and memory. We have studied the gap junction-mediated cell-to-cell and network propagation of GABA A receptor-mediated events in stratum lacunosum moleculare interneurons of the rat hippocampus. Propagated events were identified both in voltage-and current-clamp configurations. After blockade of ionotropic excitatory synaptic transmission, voltage-clamp recordings with chloride-loaded electrodes (predicted GABA A receptor reversal potential: 0 mV) at −15 mV revealed the unexpected presence of spontaneous events of opposite polarities. Inward events were larger and kinetically faster when compared to outward currents. Both types of events were blocked by gabazine, but only outward currents were significantly affected by the gap junction blocker carbenoxolone, indicating that outward events originated in electrically coupled neurons. These results were in agreement with computational modelling showing that propagated events were modulated in size and shape by their relative distance to the gap junction site. Paired recordings from electrically coupled interneurons performed with highand low-chloride pipettes (predicted GABA A receptor reversal potentials: 0 mV and −80 mV, respectively) directly demonstrated that depolarizing postsynaptic events could propagate to the cell recorded with the low-chloride solution. Cell-to-cell propagation was abolished by carbenoxolone, and was not observed in uncoupled pairs. Application of 4-aminopyridine on slices resulted in spontaneous network activation of interneurons, which was driven by excitatory GABA A receptor-mediated input. Population activity was greatly depressed by carbenoxolone, suggesting that propagation of depolarizing synaptic GABAergic potentials may be a critical determinant of interneuronal synchronous bursting in the hippocampus.
Journal of Neuroscience, 2004
A mutation in the sodium channel SCN1A was identified in a small Italian family with dominantly i... more A mutation in the sodium channel SCN1A was identified in a small Italian family with dominantly inherited generalized epilepsy with febrile seizures plus (GEFSϩ). The mutation, D1866Y, alters an evolutionarily conserved aspartate residue in the C-terminal cytoplasmic domain of the sodium channel ␣ subunit. The mutation decreased modulation of the ␣ subunit by 1, which normally causes a negative shift in the voltage dependence of inactivation in oocytes. There was less of a shift with the mutant channel, resulting in a 10 mV difference between the wild-type and mutant channels in the presence of 1. This shift increased the magnitude of the window current, which resulted in more persistent current during a voltage ramp. Computational analysis suggests that neurons expressing the mutant channels will fire an action potential with a shorter onset delay in response to a threshold current injection, and that they will fire multiple action potentials with a shorter interspike interval at a higher input stimulus. These results suggest a causal relationship between a positive shift in the voltage dependence of sodium channel inactivation and spontaneous seizure activity. Direct interaction between the cytoplasmic C-terminal domain of the wild-type ␣ subunit with the 1 or 3 subunit was first demonstrated by yeast two-hybrid analysis. The SCN1A peptide K1846-R1886 is sufficient for  subunit interaction. Coimmunoprecipitation from transfected mammalian cells confirmed the interaction between the C-terminal domains of the ␣ and 1 subunits. The D1866Y mutation weakens this interaction, demonstrating a novel molecular mechanism leading to seizure susceptibility.
Active dendrites regulate spatio-temporal synaptic integration in hippocampal dentate granule cells
Neurocomputing, 1999
Compartmental modeling experiments were carried out to compare spatio-temporal synaptic integrati... more Compartmental modeling experiments were carried out to compare spatio-temporal synaptic integration in a model of a fully reconstructed hippocampal dentate granule (DG) cell containing either passive dendrites or dendrites with voltage-dependent conductances. The presence of active channels in dendrites increased the elastic properties of dendritic membrane, increased the sensitivity of the response to synapse clustering (up to an optimal degree
Biosystems, 1998
A new strategy for building artificial gas sensing systems is suggested based on knowledge of the... more A new strategy for building artificial gas sensing systems is suggested based on knowledge of the dynamic response mechanism of the olfactory system. Difficulties with the processing of time-dependent inputs by neural networks are discussed.
Biosystems, 1997
Dynamics of single cells, small networks and large cell populations are the subject of investigat... more Dynamics of single cells, small networks and large cell populations are the subject of investigation. The generation and propagation of action potentials in the two major cell types of the olfactory bulb, i.e. in the mitral and granule cells, are simulated by multi-compartmental modeling techniques. The specific effects of the individual ionic currents, the propagation of the signals through the compartments, and dynamic phenomena occurring in small networks (such as synchronized oscillation due to excitatory and inhibitory coupling) have been demonstrated. A statistical model is given to describe the electrical activity patterns of large neural populations. The model is applied for describing the CA3 region of the hippocampus by incorporating some basic electrophysiological properties of hippocampal pyramidal and inhibitory neurons. Population activities as well as underlying single cell voltages are simulated during population bursts in the model of disinhibited hippocampal CA3 slice.
Simulation of the whole olfactory bulb based on detailed single cell models
Neuropharmacology, 2002
GABAergic synaptic inputs to principal cells are heterogeneous in terms of their anatomical, mole... more GABAergic synaptic inputs to principal cells are heterogeneous in terms of their anatomical, molecular and physiological properties. Whether diversity in GABAergic synaptic inputs affects the efficacy of GABAergic inhibition is not understood. Here we show that alterations in the heterogeneity of IPSC populations arriving at single cells can significantly modify the effects of GABAergic inputs on neuronal excitability. The effects of IPSC diversity were examined in a computational model that incorporated experimentally measured values for spontaneous IPSCs and CA1 pyramidal cell electrophysiological properties. The simulations showed that increased variance in the conductance or decay of IPSCs could potently modulate the firing rate of the postsynaptic cells. The actual direction of the IPSC variance-induced modulation in postsynaptic cell discharges depended on the mean IPSC conductance and mean decay time constant around which the variance was introduced, as well as on the degree of depolarization and firing of the postsynaptic cell. Further analysis of the underlying mechanisms determined that these effects of IPSC variance on neuronal excitability were entirely predicted from the non-linear actions of IPSCs on action potential generation. The variance effects on neuronal excitability could be strong enough to overcome even large changes in mean IPSC conductance, demonstrating that increased mean synaptic conductance (or increased mean IPSC or IPSP) alone does not necessarily imply a more effective inhibition, a finding which has important implications for epilepsy research. These data show that the degree of heterogeneity of the GABAergic synaptic inputs to principal cells can powerfully modulate the efficacy of GABAergic inhibition. The results indicate the functional importance of the diversity of interneurons in cortical and hippocampal circuits, and suggest that plastic changes in GABAergic synaptic diversity may modulate neuronal excitability under both normal and pathological conditions.
Computers & mathematics with applications, Dec 1, 1996
The generation and propagation of action potentials in the two major cell types of the olfactory ... more The generation and propagation of action potentials in the two major cell types of the olfactory bulb, i.e., in the mitral and granule cells, are simulated by applying the multicompartmental modeling technique. The specific effects of the individual ionic currents, the propagation of the signals through the compartments, and several dynamic phenomena occurring in small networks (such as synchronized oscillation due to excitatory and inhibitory coupling) have been demonstrated. Ueywords-Single neuron dynamics, Neural simulation, Rhythmogenesis.
International Journal of Intelligent Systems, 1995
A mathematical model is given for describing activity dynamics, learning, and associative memory ... more A mathematical model is given for describing activity dynamics, learning, and associative memory in the olfactory bulb. Numerical bifurcation analysis and the calculation of Lyapunov-exponents suggest that chaotic behavior only occurs in the case of strong excitatory coupling in the mitral layer. A Hebbian-type learning rule, supplemented with a nonlinear decay term and a selective decreasing term, is defined and analyzed. Slow learning modifies the bulbar activity dynamics hence it plays a crucial role in odor information processing. 0 1995 John Wiley & Sons, Inc. ' Supported by the Japan Society for the Promotion of Science. 2Supported by the Hungarian Scientific Research Fund under Grant No. OTKA 3Supported by the Academy of Finland.
Multicompartmental Modeling of the Olfactory Bulb
Cybernetics and Systems, Dec 1, 1996
The generation and propagation of action potentials in the two major cell types of the olfactory ... more The generation and propagation of action potentials in the two major cell types of the olfactory bulb the mitral and granule cells are simulated by applying the multicompartmental modeling technique The specific effects of the individual ionic currents the propagation of the signals through the compartments and several dynamic phenomena occurring in small networks such as synchronized oscillation due to excitatory and inhibitory coupling have been demonstrated
Osteoporosis International, 2018
To demonstrate the clinical comparability between RGB-10 (a biosimilar teriparatide) and the orig... more To demonstrate the clinical comparability between RGB-10 (a biosimilar teriparatide) and the originator, a comparative pharmacokinetic trial was conducted. The study was successful in establishing bioequivalence. Marketing authorisation for RGB-10 (Terrosa®) was granted by the European Medicines Agency in 2017. Introduction Teriparatide, the first bone anabolic agent, is the biologically active fragment of human parathyroid hormone. The imminent patent expiry of the originator will open the door for biosimilars to enter the osteology market, thereby improving access to a highly effective, yet prohibitively expensive therapy. Methods Subsequent to establishing comparability on the quality and non-clinical levels between RGB-10, a biosimilar teriparatide, and its reference product (Forsteo®), a randomised, double-blind, 2-way cross-over comparative study (duration: four days) was conducted in 54 healthy women (ages: 18 to 55 years) to demonstrate the pharmacokinetic/pharmacodynamic (PK/PD) equivalence and comparable safety of these products. Extents of exposure (AUC 0-tlast) and peak exposure (C max), as measured by means of ELISA, were evaluated as co-primary PK endpoints, and serum calcium levels, as measured using standard automated techniques, were assessed for PD effects. Safety was monitored throughout the study. Results The 94.12% CIs for the ratio of the test to the reference treatments, used due to the two-stage design (85.20-98.60% and 85.51-99.52% for AUC 0-tlast and C max , respectively), fell within the 80.00-125.00% acceptance range. The calcium PD parameters were essentially identical with geometric mean ratios (GMRs) of 99.93% and 99.87% for AUC and C max , respectively. Analysis of the safety data did not reveal any differences between RGB-10 and its reference. Conclusion Based on the high level of similarity in the preclinical data and the results of this clinical study, marketing authorisation for RGB-10 (Terrosa®) was granted by the European Medicines Agency (EMA) in 2017.
Hippocampal Pyramidal Cells -Mediated IPSPs in B Reversal Potential of GABA -Dependent Chloride Influx Modulates
Diversity of interneurons as a major determinant of network excitability and stability
Epilepsia 41(Suppl, Mar 13, 2000
Additional file 1: of Efficacy and safety of RGB-02, a pegfilgrastim biosimilar to prevent chemotherapy-induced neutropenia: results of a randomized, double-blind phase III clinical study vs. reference pegfilgrastim in patients with breast cancer receiving chemotherapy
List of Ethical Committees who approved the study RGB-02-101.(DOCX 12 kb)
BMC Cancer, 2019
Background: Treatment with recombinant human granulocyte-colony stimulating factor (G-CSF) is acc... more Background: Treatment with recombinant human granulocyte-colony stimulating factor (G-CSF) is accepted standard for prevention of chemotherapy-induced neutropenia. RGB-02 (Gedeon Richter) is a proposed biosimilar to pegylated G-CSF (Neulasta®, Amgen) with sustained release properties. This is a randomized, comparative, doubleblind, multicenter study to evaluate efficacy and safety of RGB-02 in breast cancer patients receiving cytotoxic regimen. Methods: Two hundred thirty-nine women presenting with breast cancer were randomized to RGB-02 (n = 121) and the reference product (n = 118). All patients received up to 6 cycles of docetaxel/doxorubicin chemotherapy combination and a once-per-cycle injection of a fixed 6 mg dose of pegfilgrastim. Primary endpoint was the duration of severe neutropenia (ANC < 0.5 × 10 9 /L) in Cycle 1 (2-sided CI 95%). Secondary endpoints included incidence and duration of severe neutropenia (in cycles 2-4), incidence of febrile neutropenia, time to ANC recovery, depth of ANC nadir, and safety outcomes. Results: The mean duration of severe neutropenia in Cycle 1 was 1.7 (RGB-02) and 1.6 days (reference), with a difference (LS Mean) of 0.1 days (95% CI-0.2, 0.4). Equivalence could be established as the CI for the difference in LS Mean lay entirely within the pre-defined range of ±1 day. This positive result was supported by the analysis of secondary endpoints, which also revealed no clinical meaningful differences. Safety profiles were comparable between groups. No neutralizing antibodies against pegfilgrastim were identified. Conclusions: Treatment equivalence in reducing the duration of chemotherapy induced neutropenia between RGB-02 and Neulasta® could be demonstrated. Similar efficacy and safety profiles of the once-per-cycle administration of RGB-02 and the pegfilgrastim reference were demonstrated.
Future Oncology, 2019
Pegfilgrastim is widely used for the prevention of chemotherapy-induced neutropenia. The developm... more Pegfilgrastim is widely used for the prevention of chemotherapy-induced neutropenia. The development and use of biosimilar agents help to rationalize healthcare expenditure and improve access to modern therapies to all who need them. This review focuses on pegfilgrastims with important role in oncology supportive care. RGB-02 (Gedeon Richter) is a proposed biosimilar to pegylated granulocyte-colony stimulating factor (Neulasta R , Amgen) with sustained release properties. The clinical analyses in three randomized clinical studies provided comparative data between RGB-02 and Neulasta, in a Phase III study patients receiving docetaxel-doxorubicin chemotherapy treatment equivalence was found. No difference was detected in any safety measure including immunogenicity; treatment switch, from the reference product to RGB-02 proved safe. Long-acting pegylated filgrastim RGB-02 has successfully accomplished various steps of biosimilar development.
1700PSafe switch of treatment from the reference product to RGB-02, a proposed biosimilar pegfilgrastim: Analysis of the results of three clinical trials
Annals of Oncology, 2018
Multicompartmental Modeling of Neural Circuits in the Olfactory Bulb
International Journal of Neural Systems, 1996
The generation and propagation of action potentials in the excitatory and inhibitory cell types o... more The generation and propagation of action potentials in the excitatory and inhibitory cell types of the olfactory bulb are simulated by applying multi-compartmental modeling technique. Detailed models of the main cell types of the olfactory bulb have been presented previously.1 Further simulations on granule and periglomerular cells have been done to find proper parameters matching to the physiological recordings.22 Elementary synaptic interactions and dynamic behaviour of small networks of excitatory and inhibitory neurons have been studied. To investigate the relationship between the anatomical structure of the neural circuits of whole olfactory bulb and the generated firing patterns, further series of simulations have been done.
We have constructed a detailed model of a hippocampal dentate granule (DG) cell that includes nin... more We have constructed a detailed model of a hippocampal dentate granule (DG) cell that includes nine different channel types. Channel densities and distributions were chosen to reproduce reported physiological responses observed in normal solution and when blockers were applied. The model was used to explore the contribution of each channel type to spiking behavior with particular emphasis on the mechanisms underlying postspike events. T-type calcium current in more distal dendrites contributed prominently to the appearance of the depolarizing after-potential, and its effect was controlled by activation of BK-type calcium-dependent potassium channels. Coactivation and interaction of N-, and/or L-type calcium and AHP currents present in somatic and proximal dendritic regions contributed to the adaptive properties of the model DG cell in response to long-lasting current injection. The model was used to predict changes in channel densities that could lead to epileptogenic burst discharges and to predict the effect of altered buffering capacity on firing behavior. We conclude that the clustered spatial distributions of calcium related channels, the presence of slow delayed rectifier potassium currents in dendrites, and calcium buffering properties, together, might explain the resistance of DG cells to the development of epileptogenic burst discharges.
Modeling the Contributions of Calcium Channels and NMDA Receptor Channels to Calcium Current in Dendritic Spines
Computational Neuroscience, 1998
A model of a dentate granule cell that explicitly included all dendritic spines was used to explo... more A model of a dentate granule cell that explicitly included all dendritic spines was used to explore the relative contributions of voltage-gated calcium channels and NMDA receptor channels to calcium influx in dendritic spines following tetanic stimulation. Up to 10 T, N, or L calcium channels were placed in each dendritic spine. It was found that calcium currents through calcium channels in spines had a much shorter duration than the NMDA calcium current, except for T channels, and had an amplitude that was in many cases comparable in magnitude to the NMDA calcium current.
The Journal of Physiology, 2007
The integration of synaptic signalling in the mammalian hippocampus underlies higher cognitive fu... more The integration of synaptic signalling in the mammalian hippocampus underlies higher cognitive functions such as learning and memory. We have studied the gap junction-mediated cell-to-cell and network propagation of GABA A receptor-mediated events in stratum lacunosum moleculare interneurons of the rat hippocampus. Propagated events were identified both in voltage-and current-clamp configurations. After blockade of ionotropic excitatory synaptic transmission, voltage-clamp recordings with chloride-loaded electrodes (predicted GABA A receptor reversal potential: 0 mV) at −15 mV revealed the unexpected presence of spontaneous events of opposite polarities. Inward events were larger and kinetically faster when compared to outward currents. Both types of events were blocked by gabazine, but only outward currents were significantly affected by the gap junction blocker carbenoxolone, indicating that outward events originated in electrically coupled neurons. These results were in agreement with computational modelling showing that propagated events were modulated in size and shape by their relative distance to the gap junction site. Paired recordings from electrically coupled interneurons performed with highand low-chloride pipettes (predicted GABA A receptor reversal potentials: 0 mV and −80 mV, respectively) directly demonstrated that depolarizing postsynaptic events could propagate to the cell recorded with the low-chloride solution. Cell-to-cell propagation was abolished by carbenoxolone, and was not observed in uncoupled pairs. Application of 4-aminopyridine on slices resulted in spontaneous network activation of interneurons, which was driven by excitatory GABA A receptor-mediated input. Population activity was greatly depressed by carbenoxolone, suggesting that propagation of depolarizing synaptic GABAergic potentials may be a critical determinant of interneuronal synchronous bursting in the hippocampus.
Journal of Neuroscience, 2004
A mutation in the sodium channel SCN1A was identified in a small Italian family with dominantly i... more A mutation in the sodium channel SCN1A was identified in a small Italian family with dominantly inherited generalized epilepsy with febrile seizures plus (GEFSϩ). The mutation, D1866Y, alters an evolutionarily conserved aspartate residue in the C-terminal cytoplasmic domain of the sodium channel ␣ subunit. The mutation decreased modulation of the ␣ subunit by 1, which normally causes a negative shift in the voltage dependence of inactivation in oocytes. There was less of a shift with the mutant channel, resulting in a 10 mV difference between the wild-type and mutant channels in the presence of 1. This shift increased the magnitude of the window current, which resulted in more persistent current during a voltage ramp. Computational analysis suggests that neurons expressing the mutant channels will fire an action potential with a shorter onset delay in response to a threshold current injection, and that they will fire multiple action potentials with a shorter interspike interval at a higher input stimulus. These results suggest a causal relationship between a positive shift in the voltage dependence of sodium channel inactivation and spontaneous seizure activity. Direct interaction between the cytoplasmic C-terminal domain of the wild-type ␣ subunit with the 1 or 3 subunit was first demonstrated by yeast two-hybrid analysis. The SCN1A peptide K1846-R1886 is sufficient for  subunit interaction. Coimmunoprecipitation from transfected mammalian cells confirmed the interaction between the C-terminal domains of the ␣ and 1 subunits. The D1866Y mutation weakens this interaction, demonstrating a novel molecular mechanism leading to seizure susceptibility.
Active dendrites regulate spatio-temporal synaptic integration in hippocampal dentate granule cells
Neurocomputing, 1999
Compartmental modeling experiments were carried out to compare spatio-temporal synaptic integrati... more Compartmental modeling experiments were carried out to compare spatio-temporal synaptic integration in a model of a fully reconstructed hippocampal dentate granule (DG) cell containing either passive dendrites or dendrites with voltage-dependent conductances. The presence of active channels in dendrites increased the elastic properties of dendritic membrane, increased the sensitivity of the response to synapse clustering (up to an optimal degree
Biosystems, 1998
A new strategy for building artificial gas sensing systems is suggested based on knowledge of the... more A new strategy for building artificial gas sensing systems is suggested based on knowledge of the dynamic response mechanism of the olfactory system. Difficulties with the processing of time-dependent inputs by neural networks are discussed.
Biosystems, 1997
Dynamics of single cells, small networks and large cell populations are the subject of investigat... more Dynamics of single cells, small networks and large cell populations are the subject of investigation. The generation and propagation of action potentials in the two major cell types of the olfactory bulb, i.e. in the mitral and granule cells, are simulated by multi-compartmental modeling techniques. The specific effects of the individual ionic currents, the propagation of the signals through the compartments, and dynamic phenomena occurring in small networks (such as synchronized oscillation due to excitatory and inhibitory coupling) have been demonstrated. A statistical model is given to describe the electrical activity patterns of large neural populations. The model is applied for describing the CA3 region of the hippocampus by incorporating some basic electrophysiological properties of hippocampal pyramidal and inhibitory neurons. Population activities as well as underlying single cell voltages are simulated during population bursts in the model of disinhibited hippocampal CA3 slice.
Simulation of the whole olfactory bulb based on detailed single cell models
Neuropharmacology, 2002
GABAergic synaptic inputs to principal cells are heterogeneous in terms of their anatomical, mole... more GABAergic synaptic inputs to principal cells are heterogeneous in terms of their anatomical, molecular and physiological properties. Whether diversity in GABAergic synaptic inputs affects the efficacy of GABAergic inhibition is not understood. Here we show that alterations in the heterogeneity of IPSC populations arriving at single cells can significantly modify the effects of GABAergic inputs on neuronal excitability. The effects of IPSC diversity were examined in a computational model that incorporated experimentally measured values for spontaneous IPSCs and CA1 pyramidal cell electrophysiological properties. The simulations showed that increased variance in the conductance or decay of IPSCs could potently modulate the firing rate of the postsynaptic cells. The actual direction of the IPSC variance-induced modulation in postsynaptic cell discharges depended on the mean IPSC conductance and mean decay time constant around which the variance was introduced, as well as on the degree of depolarization and firing of the postsynaptic cell. Further analysis of the underlying mechanisms determined that these effects of IPSC variance on neuronal excitability were entirely predicted from the non-linear actions of IPSCs on action potential generation. The variance effects on neuronal excitability could be strong enough to overcome even large changes in mean IPSC conductance, demonstrating that increased mean synaptic conductance (or increased mean IPSC or IPSP) alone does not necessarily imply a more effective inhibition, a finding which has important implications for epilepsy research. These data show that the degree of heterogeneity of the GABAergic synaptic inputs to principal cells can powerfully modulate the efficacy of GABAergic inhibition. The results indicate the functional importance of the diversity of interneurons in cortical and hippocampal circuits, and suggest that plastic changes in GABAergic synaptic diversity may modulate neuronal excitability under both normal and pathological conditions.