RESEARCH INTERESTS
The main area of my research interests is Computational Neuroscience. I am interested in molecular, cellular and synaptic mechanisms underlying activity in neurons and neuronal networks, and how these mechanisms can affect the function of the nervous system.
Using conductance based model with Na+, K+ and Cl- dynamics the roles of we explored the roles of two CCCs (the NA-K-2Cl cotransporter, NKCC1, and the K-Cl cotransporter, KCC2) in ion concentration homeostasis and in the generation of pathological oscillatory activity in neurons. The computational studies show that reciprocal changes in the expression of NKCC1 (which elevates [Cl]i) and KCC2 (which decreases [Cl-]i) can change Cl- reversal potential (ECl) and significantly alter the effects of GABAA receptor (GABAAR) mediated inhibitory input. Under certain circumstances, this can evoke or prevent seizure-like activity, and we investigate dynamical and biophysical mechanisms of these phenomena. The model suggests that regulatory abilities of CCCs are increased with increasing GABAARs activation. Both simulated elevation of concentration of extracellular potassium ion and NA-K-2Cl cotransporter activity promote seizure-like activity. Our studies show that developmental regulation of expression of NKCC1 and KCC2, in conjunction with concentration dynamics, can alter Cl- electrochemical gradient and strength and polarity of GABAA neurotransmission. The computational studies corroborate that CCCs are potential targets for treatment of neurological diseases, which involve dysfunctions in intracellular ion concentration homeostasis.
Using model neurons with both highly simplified and real morphological structures (from a single cylindrical dendrite to a hippocampal granule cell, retinal ganglion neuron, and spinal motoneuron) the dependence of synaptic efficacy on neuronal morphology and dendritic excitability was studied. It was shown that active neuronal conductances can counterbalance the effect of decreasing synaptic efficacy with distance from the soma, especially in models with real neuronal morphology. This phenomenon is frequency dependent, with a more prominent gain in synaptic efficacy observed at lower levels of background input-output neuronal activity. The results are robust with respect to morphological variation of the model neurons.
Magnocellular neurosecretory cells (MNCs) of the hypothalamus
release the hormones oxytocin (OT) and vasopressin (VP) into the blood.
These cells demonstrate enhancement of hormone release with bursting patterns
of electrical activity. OT neurons fire synchronized bursts at long intervals
during parturition and milk ejection; VP neurons generate an asynchronous
phasic bursting in response to osmotic and cardiovascular stimuli. The
mechanisms of bursting activity in VP are not known completely and are
believed to be different in vitro and in vivo. Whereas in vitro, phasic
bursting in VP neurons appears to be governed by intrinsic deterministic
mechanisms, in vivo burst generation and termination significantly depends
on synaptic activity. Mounting evidences suggest that retrograde signaling
via endocannabinoids plays a prominent role in modulating MNC synaptic
activity.
To investigate theoretically the role of synaptic inputs
in the phasic bursting activity in VP neurons, we developed a multicompartmental
model of the MNC. The model takes into account MNC morphology
and electrotonic properties and includes a set of realistic voltage-gated
and Ca2+-activated ion currents, compartmental Ca2+
dynamics and reproduces several of the hallmark characteristics of MNC
electrophysiological properties. Phasic bursting in the model is
controlled by both intrinsic and synaptic mechanisms: bursts of action
potentials arise from the summation of slow depolarizing afterpotentials
superimposed on a tonic background activation of glutamatergic synaptic
inputs; activity-dependent release of a retrograde messenger (endocannabinoid)
from the dendrites of VP neurons attenuates tonic glutamate release and
leads to burst termination. Background synaptic activity was simulated
as independent excitatory and inhibitory inputs mediated by AMPA and GABAA
conductances.
The computational studies also suggest that GABAA receptor activation
promotes burst firing patterns, and stochastic synaptic inputs play an
important role in the modulation of phasic activity in VP neurons.
Komendantov et al. (2010), BMC Neuroscience, 11 ( Suppl 1): O1.
Using a multicompartmental model of a dopaminergic neuron, the effects of different levels of activation of NMDA and GABAA receptors as well as the modulation of the SK current on the firing activity were explored. Also, studies of a system of two model dopaminergic neurons predicted that the level of electrical coupling, within a range that is physiologically admissible for gap junctions, is likely to have a significant modulatory effect on the firing pattern in midbrain dopaminergic neurons.
The models demonstrated the major experimentally observable phenomena in bursting neurons of mollusks and allowed us to investigate roles of separate components in firing pattern regulation: neuropeptide-modulated currents, calcium dynamics and synaptic inputs. The results provided a plausible explanation for the mechanism of the irregular electrical activity in typical bursting neurons. These studies suggest an important role for nonlinear dynamics in information processing and storage at the level of a single nerve cell.