Astrocyte-mediated spike-timing-dependent long-term depression modulates synaptic properties in the developing cortex

Abstract

Astrocytes have been shown to modulate synaptic transmission and plasticity in specific cortical synapses, but our understanding of the underlying molecular and cellular mechanisms remains limited. Here we present a new biophysicochemical model of a somatosensory cortical layer 4 to layer 2/3 synapse to study the role of astrocytes in spike-timing-dependent long-term depression (t-LTD) in vivo. By applying the synapse model and electrophysiological data recorded from rodent somatosensory cortex, we show that a signal from a postsynaptic neuron, orchestrated by endocannabinoids, astrocytic calcium signaling, and presynaptic N-methyl-D-aspartate receptors coupled with calcineurin signaling, induces t-LTD which is sensitive to the temporal difference between post- and presynaptic firing. We predict for the first time the dynamics of astrocyte-mediated molecular mechanisms underlying t-LTD and link complex biochemical networks at presynaptic, postsynaptic, and astrocytic sites to the time window of t-LTD induction. During t-LTD a single astrocyte acts as a delay factor for fast neuronal activity and integrates fast neuronal sensory processing with slow non-neuronal processing to modulate synaptic properties in the brain. Our results suggest that astrocytes play a critical role in synaptic computation during postnatal development and are of paramount importance in guiding the development of brain circuit functions, learning and memory.

The role of astrocyte‐mediated plasticity in neural circuit development and function

“…Interestingly, the authors also found that while direct neuronal activation impaired memory formation, delayed activation through astrocytes strongly enhanced memory allocation [ 190 ], suggesting that indirect signaling through astrocytes may be necessary to gate LTP. Indeed, a recent report suggests that gliotransmission by astrocytes recruits metabotropic glutamate receptors to the presynaptic terminal during spike timing-dependent plasticity, a process that shifts developing hippocampal synapses from long term depression (LTD) to LTP [ 191 , 192 ] (Fig. 3 ).…”

“…Similarly, astrocytic activation in the limbic system can drive depression of excitatory synapses and enhancement of inhibitory synapses in the central amygdala [ 179 ]. In the developing somatosensory cortex, astrocytic signaling mediates spike-timing-dependent LTD [ 192 , 193 ]; and in the developing prefrontal cortex, astrocytic GABA B receptors monitor local concentrations of GABA and in turn, regulate low gamma oscillations (see more below) and goal-directed behaviors [ 194 ]. Thus, bidirectional signaling between neurons and astrocytes ensures proper E/I balance in multiple brain regions to shapes the flow of information through neural circuits and facilitate neuronal plasticity that is essential for learning, memory, and goal-directed behaviors.…”

Astrocytes as Key Regulators of Brain Energy Metabolism: New Therapeutic Perspectives

“…Decreased energy availability for neurons results in neurodegeneration, cognitive impairment, as well as abnormalities in neuronal function and excitability ( Muddapu et al, 2020 ). Astrocytes, a type of glial cells in the brain, support essential functions such as maintenance of neurotransmitter pools, trophic support, metabolism, synaptic formation and plasticity, myelin sheath formation, injury healing, and immune surveillance ( Burda et al, 2016 ; Manninen et al, 2020 ). They are key in regulating neurometabolic and neurovascular couplings, thereby linking neuronal activity to brain energy consumption.…”

Increasing Liquid State Machine Performance with Edge-of-Chaos Dynamics Organized by Astrocyte-modulated Plasticity

“…A long-neglected non-neuronal cell in the brain, astrocytes, is now known to play key roles in modulating brain networks [34][35][36][37][38][39], from modifying synaptic plasticity [40][41][42] to facilitating switching between cognitive states [43][44][45][46] that have been linked to a narrow spectrum of dynamics around the critical phase transition [47][48][49][50][51]. The mechanisms that astrocytes use to modulate neurons include the integration of the activity of thousands of synapses into a slow intracellular continuous signal that feeds back to neurons by affecting their synaptic plasticity [52][53][54][55]42].…”