Abstract
Over the past decades, our view of astrocytes has switched from passive support cells to active processing elements in the brain. The current view is that astrocytes shape neuronal communication and also play an important role in many neurodegenerative diseases. Despite the growing awareness of the importance of astrocytes, the exact mechanisms underlying neuron-astrocyte communication and the physiological consequences of astrocytic-neuronal interactions remain largely unclear. In this work, we define a modeling framework that will permit to address unanswered questions regarding the role of astrocytes. Our computational model of a detailed glutamatergic synapse facilitates the analysis of neural system responses to various stimuli and conditions that are otherwise difficult to obtain experimentally, in particular the readouts at the sub-cellular level. In this paper, we extend a detailed glutamatergic synaptic model, to include astrocytic glutamate transporters. We demonstrate how these glial transporters, responsible for the majority of glutamate uptake, modulate synaptic transmission mediated by ionotropic AMPA and NMDA receptors at glutamatergic synapses. Furthermore, we investigate how these local signaling effects at the synaptic level are translated into varying spatio-temporal patterns of neuron firing. Paired pulse stimulation results reveal that the effect of astrocytic glutamate uptake is more apparent when the input inter-spike interval is sufficiently long to allow the receptors to recover from desensitization. These results suggest an important functional role of astrocytes in spike timing dependent processes and demand further investigation of the molecular basis of certain neurological diseases specifically related to alterations in astrocytic glutamate uptake, such as epilepsy.
Highlights
Until a few decades ago the quest to better understand high level brain functions, such as learning, memory, and cognition, mainly focused on investigating the rapid, spike-based information processing performed by neurons
We demonstrate how these glial transporters, responsible for the majority of glutamate uptake, modulate synaptic transmission mediated by ionotropic AMPA and NMDA receptors at glutamatergic synapses
These results suggest an important functional role of astrocytes in spike timing dependent processes and demand further investigation of the molecular basis of certain neurological diseases related to alterations in astrocytic glutamate uptake, such as epilepsy
Summary
Until a few decades ago the quest to better understand high level brain functions, such as learning, memory, and cognition, mainly focused on investigating the rapid, spike-based information processing performed by neurons. The activation of receptors at single synapses, which are distributed along the dendritic tree of pyramidal neurons, sum in a non-linear fashion, which changes the membrane potential (Poirazi et al, 2003) These responses influence the network level, along with additional modulatory inputs from other pathways and inhibitory connections. We focus on the role of astrocytic glutamate uptake on synaptic responses and how it can modify neuronal spiking within the context of this modeling framework (Figures 1A,B). The diffusion model used here has been adapted from Savtchenko and Rusakov (2007) to calculate glutamate concentration inside the cleft as a function of the distance of the receptor from the release site using Eq 1. The synaptic strength was tuned by a factor of 6 to reach threshold levels for neuronal spiking such that spiking probability was 1
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
