Biomedical subjects

Leonid P Savtchenko

Publications and source records attributed to Leonid P Savtchenko.

6 recordsLinked to original sources

PubMed2006

Bilateral processing in chemical synapses with electrical 'ephaptic' feedback: a theoretical model.

I have developed a detailed biophysical model of the chemical synapse which hosts voltage-dependent presynaptic ion channels and takes into account the capacitance of synaptic membranes. I find that at synapses with a relatively large cleft resistance (e.g., mossy fiber or giant calyx synapse) the rising postsynaptic current could activate, within the synaptic cleft, electrochemical phenomena that induce rapid widening of the presynaptic action potential (AP). This mechanism could boost fast Ca(2+) entry into the terminal thus increasing the probability of subsequent synaptic releases. The predicted difference in the AP waveforms generated inside and outside the synapse can explain the previously unexplained fast capacitance transient recorded in the postsynaptic cell at the giant calyx synapse. I propose therefore the mechanism of positive ephaptic feedback that acts between the postsynaptic and presynaptic cell contributing to the basal synaptic transmission at large central synapses. This mechanism could also explain the supralinear voltage dependence of EPSCs recorded at hyperpolarizing membrane potentials in low extracellular calcium concentration.

Action Potentials↗

PubMed2005

Extracellular diffusivity determines contribution of high-versus low-affinity receptors to neural signaling.

Diffusion-weighted magnetic resonance imaging detects physiological changes in the human brain by highlighting alterations in local diffusivity. However, the causal link between brain tissue diffusivity and neural activity is poorly understood. Synaptic physiology studies in vitro coupled with biophysical modeling have suggested that extracellular diffusion affects the spatial profile of receptor activation during synaptic discharges. Here, we attempt to address this issue more directly, by recording synaptic currents from individual cells in acute brain slices while reducing the bath medium diffusivity by 25-30% (measured with two-photon microscopy) using inert dextran molecules. We find that retarding extracellular diffusion increases the activation of high-affinity NMDA, but not low-affinity AMPA, receptors in response to remote, spontaneous or evoked, synaptic releases of the common excitatory neurotransmitter glutamate. The results suggest that variations in extracellular diffusivity could reflect an altered contribution of higher- versus lower-affinity receptor types to the network activity of synaptic circuits.

Animals↗

PubMed2004

Electric fields of synaptic currents could influence diffusion of charged neurotransmitter molecules.

Rapid activation of synaptic receptor-channels evokes an ion current that flows through the narrow synaptic cleft; this exerts a significant voltage drop and therefore strong electric field (10(4) V/m range) directed towards the current sinks in the cleft. To what extent this field affects fast diffusion of charged neurotransmitter molecules is not known. We draw a theoretical framework for this complex electrodiffusion phenomenon and establish the basic relationships between the synaptic current and the time course of neurotransmitter in the cleft. The analyses predict that excitatory currents could significantly accelerate the dispersion of negatively charged molecules from the cleft while attracting the positively charged molecules towards the current sinks. This previously unrecognized mechanism should affect the kinetics of synaptic receptor currents, thus contributing to fast synaptic signaling in the brain.

Diffusion↗

PubMed2004

Glutamate escape from a tortuous synaptic cleft of the hippocampal mossy fibre synapse.

The time course of neurotransmitter in the synaptic cleft contributes substantially to the fast kinetics of synaptic signalling. Hippocampal mossy fibres (MFs), a well-characterised excitatory pathway from dentate granule cells to the hippocampus proper, form large glutamatergic synapses at branched spiny structures in CA3 pyramidal cell dendrites. To what extent transmission at these synapses is affected by retarded glutamate clearance from the large tortuous synaptic cleft is not known. Here, we propose a simple geometrical approximation representing the 'typical' geometry of thorny excrescences that form the tortuous cleft interface at a MF synapse. We then employ Monte Carlo simulations to monitor movements of 3000 individual glutamate molecules released within the cleft. The results predict that, in the absence of neuronal glutamate transporters, it should take approximately 10 ms for 50% and 60-70 ms for 90% of glutamate molecules to escape the MF synapse.

Algorithms↗

PubMed2002

Frequency-dependent shift from paired-pulse facilitation to paired-pulse depression at unitary CA3-CA3 synapses in the rat hippocampus.

Paired recordings between CA3 interconnected pyramidal neurons were used to study the properties of short-term depression occurring in these synapses under different frequencies of presynaptic firing (n = 22). In stationary conditions (0.05-0.067 Hz) pairs of presynaptic action potentials (50 ms apart) evoked EPSCs whose amplitude fluctuated from trial to trial with occasional response failures. In 15/20 cells, paired-pulse ratio (PPR) was characterized by facilitation (PPF) while in the remaining five by depression (PPD). Increasing stimulation frequency from 0.05-0.067 Hz to 0.1-1 Hz induced low frequency depression (LFD) of EPSC amplitude with a gradual increase in the failure rate. Overall, 9/12 cells at 1 Hz became almost "silent". In six cells in which the firing rate was sequentially shifted from 0.05 to 0.1 and 1 Hz, changes in synaptic efficacy were so strong that PPR shifted from PPF to PPD. The time course of depression of EPSC1 could be fitted with single exponentials with time constants of 98 and 36 s at 0.1 and 1 Hz, respectively. In line with the inversion of PPR at 1 Hz, the time course of depression of EPSC2 was faster than EPSC1 (7 s). Recovery from depression could be obtained by lowering the frequency of stimulation to 0.025 Hz. These results could be explained by a model that takes into account two distinct release processes, one dependent on the residual calcium and the other on the size of the readily releasable pool of vesicles.

Animals↗

PubMed2001

Theoretical estimation of the capacity of intracellular calcium stores in the Bergmann glial cell.

We propose a mathematical model for calcium dynamics ([Ca2+]i) during metabotropic activation of a specialized astrocyte, the cerebellar Bergmann glial cell. The model adequately describes the experimentally observed behaviour of the prototype in response to single and repetitive metabotropic stimuli and to the inhibition of Ca2+ uptake into the store. By means of the model, the capacity of the intracellular calcium store for two types of calcium buffer was estimated. The estimated buffer capacity of the store lies within the following intervals: (0.8-15.5).10-19 mol calmodulin, and (0.6-12.3).10-19 mol calbindin. This result reveals, that, in the store of a small Ca2+-containing compartment optically detected in the Bergmann glial cell process after electrical stimulation of parallel fibres, the amount of releasable Ca2+ does not exceed 25,000 ions. The quantitative estimates were obtained from experimentally based theoretical relationships between the capacity and volume of the store and parameters of the cytoplasmic calcium buffer. In these relationships, the estimated store capacity was proportional to the total buffer concentration, inversely proportional to the constant of buffer affinity for calcium and was smaller for a greater relative store volume.

Adenosine Triphosphate↗