3d-modeling-of-dendritic-spines-with-synaptic-plasticity

3D Modeling of Dendritic Spines with Synaptic Plasticity

Computational modeling of diffusion and reaction of chemical species in a three-dimensional (3D) geometry is a fundamental method to understand the ...

Federal University of ABC

Olfactory adaptation is a fundamental process for the functioning of the olfactory system, but the underlying mechanisms regulating its occurrence in intact olfactory sensory neurons (OSNs) are not fully understood. In this work, we have combined stochastic computational modeling and a systematic pharmacological study of different signaling pathways to investigate their impact during short-term adaptation (STA). We used odorant stimulation and electroolfactogram (EOG) recordings of the olfactory epithelium treated with pharmacological blockers to study the molecular mechanisms regulating the occurrence of adaptation in OSNs. EOG responses to paired-pulses of odorants showed that inhibition of phosphodiesterases (PDEs) and phosphatases enhanced the levels of STA in the olfactory epithelium, and this effect was mimicked by blocking vesicle exocytosis and reduced by blocking cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) and vesicle endocytosis. These results suggest that G-coupled receptors (GPCRs) cycling is involved with the occurrence of STA. To gain insights on the dynamical aspects of this process, we developed a stochastic computational model. The model consists of the olfactory transduction currents mediated by the cyclic nucleotide gated (CNG) channels and calcium ion (Ca(2+))-activated chloride (CAC) channels, and the dynamics of their respective ligands, cAMP and Ca(2+), and it simulates the EOG results obtained under different experimental conditions through changes in the amplitude and duration of cAMP and Ca(2+) response, two second messengers implicated with STA occurrence. The model reproduced the experimental data for each pharmacological treatment and provided a mechanistic explanation for the action of GPCR cycling in the levels of second messengers modulating the levels of STA. All together, these experimental and theoretical results indicate the existence of a mechanism of regulation of STA by signaling pathways that control GPCR cycling and tune the levels of second messengers in OSNs, and not only by CNG channel desensitization as previously thought.

Mechanisms of regulation of olfactory transduction and adaptation in the olfactory cilium.

This work consists of a computational study of the electrical responses of three classes of granule cells of the olfactory bulb to synaptic activation in different dendritic locations. The constructed models were based on morphologically detailed compartmental reconstructions of three granule cell classes of the olfactory bulb with active dendrites described by Bhalla and Bower (1993, pp. 1948-1965) and dendritic spine distributions described by Woolf et al. (1991, pp. 1837-1854). The computational studies with the model neurons showed that different quantities of spines have to be activated in each dendritic region to induce an action potential, which always was originated in the active terminal dendrites, independently of the location of the stimuli, and the morphology of the dendritic tree. These model predictions might have important computational implications in the context of olfactory bulb circuits. 

Electrical responses of three classes of granule cells of the olfactory bulb to synaptic inputs in different dendritic locations.

The guanine nucleotide protein (G protein)-coupled receptors (GPCRs) superfamily represents the largest class of membrane protein in the human genome. More than a half of all GPCRs are dedicated to interact with odorants and are termed odorant-receptors (ORs). Linda Buck and Richard Axel, the Nobel Prize laureates in physiology or medicine in 2004, first cloned and characterized the gene family that encode ORs, establishing the foundations to the understanding of the molecular basis for odor recognition. In the last decades, a lot of progress has been done to unravel the functioning of the sense of smell. This chapter gives a general overview of the topic of olfactory receptor signaling and reviews recent advances in this field. 

Olfactory receptor signaling.

Frequently, a common chemical entity triggers opposite cellular processes, which implies that the components of signalling networks must detect signals not only through their chemical natures, but also through their dynamic properties. To gain insights on the mechanisms of discrimination of the dynamic properties of cellular signals, we developed a computational stochastic model and investigated how three calcium ion (Ca(2+))-dependent enzymes (adenylyl cyclase (AC), phosphodiesterase 1 (PDE1), and calcineurin (CaN)) differentially detect Ca(2+) transients in a hippocampal dendritic spine. The balance among AC, PDE1 and CaN might determine the occurrence of opposite Ca(2+)-induced forms of synaptic plasticity, long-term potentiation (LTP) and long-term depression (LTD). CaN is essential for LTD. AC and PDE1 regulate, indirectly, protein kinase A, which counteracts CaN during LTP. Stimulations of AC, PDE1 and CaN with artificial and physiological Ca(2+) signals demonstrated that AC and CaN have Ca(2+) requirements modulated dynamically by different properties of the signals used to stimulate them, because their interactions with Ca(2+) often occur under kinetic control. Contrarily, PDE1 responds to the immediate amplitude of different Ca(2+) transients and usually with the same Ca(2+) requirements observed under steady state. Therefore, AC, PDE1 and CaN decode different dynamic properties of Ca(2+) signals.

Modelling intracellular competition for calcium: kinetic and thermodynamic control of different molecular modes of signal decoding.

Mirror neurons fire action potentials both when the agent performs a certain behavior and watches someone performing a similar action. Here, we present an original mirror neuron model based on the spike-timing-dependent plasticity (STDP) between two morpho-electrical models of neocortical pyramidal neurons. Both neurons fired spontaneously with basal firing rate that follows a Poisson distribution, and the STDP between them was modeled by the triplet algorithm. Our simulation results demonstrated that STDP is sufficient for the rise of mirror neuron function between the pairs of neocortical neurons. This is a proof of concept that pairs of neocortical neurons associating sensory inputs to motor outputs could operate like mirror neurons. In addition, we used the mirror neuron model to investigate whether channelopathies associated with autism spectrum disorder could impair the modeled mirror function. Our simulation results showed that impaired hyperpolarization-activated cationic currents (Ih) affected the mirror function between the pairs of neocortical neurons coupled by STDP.

Article	Year
Mechanisms of regulation of olfactory transduction and adaptation in the olfactory cilium. PloS one\| PubMed ID: 25144232	2014
Electrical responses of three classes of granule cells of the olfactory bulb to synaptic inputs in different dendritic locations. Frontiers in computational neuroscience\| PubMed ID: 25360108	2014
Olfactory receptor signaling. Methods in cell biology\| PubMed ID: 26928542	2016
Modelling intracellular competition for calcium: kinetic and thermodynamic control of different molecular modes of signal decoding. Scientific reports\| PubMed ID: 27033299	2016
Mirror Neurons Modeled Through Spike-Timing-Dependent Plasticity are Affected by Channelopathies Associated with Autism Spectrum Disorder. International journal of neural systems\| PubMed ID: 29297264	2018

Gabriela Antunes

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