Download Stochastic Modeling the Tripartite Synapse and Applications

Stochastic Modeling the Tripartite Synapse and Applications
Mladen Veletić1,4, Fabio Mesiti1,2, Pål Anders Floor1,2,3, Ilangko Balasingham1,2,3
1
Dept of Electronics and Telecommunications, NTNU, Trondheim, Norway 2Intervention Center, Oslo University Hospital,Norway 3 Inst. of
Clinical Medicine, University of Oslo, Norway 4 University of Banja Luka, Bosnia and Herzegovina
Correspondence: [email protected], NTNU, IET, 7491 - Trondheim, Norway
Motivations: Similarly to a network of electronic communication devices, neurons are able to gather inputs
coming from other cells, process these inputs according to its own physiological characteristics and produce a
response which is forwarded to adjacent neurons in the network. In this respect, the neuronal circuits operate as a
sophisticated biological communication system, where the information is transferred bidirectionally between
nodes. Hence, the theoretical analysis of the physiological behavior of single neurons and the network topology
of intercellular connections are crucial to encompass the neuronal information processing and the neuronal
communication. From the electrical engineering perspective, the investigation of the neuronal communication
can provide novel techniques for the design of brain-machine interfaces, which could allow alternative methods
to achieve precise stimulations at micro and nanoscale of the neuronal tissue and obtain a more detailed read-out
of the neuronal activity. Several medical applications can be envisioned, from the early diagnose of neuronal
diseases to effective methods for reversing their disruptive process. Furthermore, the design of bio-mimetic
devices, mimicking the neuronal behavior, and bio-inspired autonomous machines for various applications
requires more detailed knowledge on how the neuronal information is processed and physically propagated.
Objective of our current work Recent findings shown that glia cells play an important role in actively
supporting and modulating the neuronal information. We focus on a particular element of the neuronal system,
the tripartite synapses, extending the concept of synapse to the presence of astrocytes which actively release
glutamate (Glu) and D-serine neurotransmitters in the synaptic cleft as a response to the neuronal impulses.
According to the physiological characteristics of the tripartite synapse, we propose an alternative method to
describe the peer-to-peer communication between two neurons, resorting to concepts from communication
engineering and accounting for chemical processes such as molecular diffusion of neurotransmitters and
electrical signal propagation along the axons. We divide the neuronal communication in two parts: 1) the intraneuronal communication (Fig. 1); 2) the inter-neuronal communication (Fig. 2). The intra-neuronal
communication unit identifies the signal transmission from soma up to the pre-synaptic terminal: the membrane
is described with a deterministic Integrate&Fire model using a frequency dependent definition of impedance; a
stochastic spiking model [1] accounts for the firing randomness, while a sequence of signal amplifiers model the
nodes of Ranvier found in a myelinated axon. The inter-neuronal communication unit represents the pre-synaptic
calcium gateway (CaG), the neurotransmitter diffusion in the synaptic cleft and its binding to receptors located
on the post-synaptic terminal. The role of the astrocyte is accounted for in the CaG, where the astrocytic [Ca2+]
has an indirect impact on the pre-synaptic spiking through Glu particles which bind on both neurons on
metabotropic (mGluR) and AMPA/NMDA receptors. The impact of Glu on the post-synaptic potential (EPSP) is
investigated, in particular concerning plasticity processes evoked through Glu sensitive NMDA receptors.
Fig. 1 Intra-neuronal Communication scheme
Fig. 2 Inter-neuronal Communication Scheme
Fig. 3: End-to-end attenuations
Fig. 4: Attenuation of Inter-neuronal modules
The purpose of the proposed communication model is to observe the behavior of sub- Fig. 5: Astrocytic impact on the tripartite
synapse
modules in terms of peri-stimulus time histogram (PSTH) for the stochastic scheme,
whereas gain and delay for the deterministic sub-module for a range of frequencies. In Fig. 3, the normalized gain (channel
attenuation) of the overall end-to-end channel is depicted. We notice how the attenuation depends on the pre-synaptic spiking
rate and how astrocyte (tripartite synapse scenario) impacts on the attenuation when compared with the standard synapse. In
Fig. 4, the gain (attenuation) contributions of each module of the inter-neuronal scheme are depicted as a function of the
frequency of the spike-rate function. In this way, a quick comparison among modules can be conducted.
Astrocyte to neuron communication: an example Nanotechnology is experiencing great improvements,
allowing advanced applications in medicine. We resort to the work proposed by Nakano [5], where a cellular
communication channel has been used to propagate cell-to-cell the calcium concentration level, generating the so
called calcium-wave. We use this channel to propagate calcium to astrocytes and increase the cytosolic [Ca2+].
The wave is regulated by the diffusion of a messenger, inositol-4,5-triphospate or IP3, through gap junctions
connecting the cells to each other. The increase of IP3 in the cytosol triggers the mechanism of calcium release
from intracellular calcium store (endoplasmic reticulum-CICR), then he astrocyte releases Glu in the tripartite
synaptic cleft, affecting both neurons. As an example of our scenario, in Fig. 5, the impact of the stimulated
astrocyte on the tripartite synapse (pre-synaptic and post-synaptic neuron) is depicted. We notice that an increase
of cytosolic [Ca2+] in the astrocyte triggers the spiking activity in the pre-synaptic neuron, due to the astrocyteinduced feedback on the pre-synaptic neurons through Glu release and the resulting slow inward current. On the
post-synaptic side, the ratio of open AMPA gates is increased due to the augmented pre-synaptic activity.
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