22 research outputs found
Astrocyte function from information processing to cognition and cognitive impairment.
Astrocytes serve important roles that affect recruitment and function of neurons at the local and network levels. Here we review the contributions of astrocyte signaling to synaptic plasticity, neuronal network oscillations, and memory function. The roles played by astrocytes are not fully understood, but astrocytes seem to contribute to memory consolidation and seem to mediate the effects of vigilance and arousal on memory performance. Understanding the role of astrocytes in cognitive processes may also advance our understanding of how these processes go awry in pathological conditions. Indeed, abnormal astrocytic signaling can cause or contribute to synaptic and network imbalances, leading to cognitive impairment. We discuss evidence for this from animal models of Alzheimer's disease and multiple sclerosis and from animal studies of sleep deprivation and drug abuse and addiction. Understanding the emerging roles of astrocytes in cognitive function and dysfunction will open up a large array of new therapeutic opportunities
Immunogold Detection of L-glutamate and D-serine in Small Synaptic-Like Microvesicles in Adult Hippocampal Astrocytes
Glutamate and the N-methyl-D-aspartate receptor ligand D-serine are putative gliotransmitters. Here, we show by immunogold cytochemistry of the adult hippocampus that glutamate and D-serine accumulate in synaptic-like microvesicles (SLMVs) in the perisynaptic processes of astrocytes. The estimated concentration of fixed glutamate in the astrocytic SLMVs is comparable to that in synaptic vesicles of excitatory nerve terminals (∼45 and ∼55 mM, respectively), whereas the D-serine level is about 6 mM. The vesicles are organized in small spaced clusters located near the astrocytic plasma membrane. Endoplasmic reticulum is regularly found in close vicinity to SLMVs, suggesting that astrocytes contain functional nanodomains, where a local Ca2+ increase can trigger release of glutamate and/or D-serin
Neuroinflammatory TNFα Impairs Memory via Astrocyte Signaling.
The occurrence of cognitive disturbances upon CNS inflammation or infection has been correlated with increased levels of the cytokine tumor necrosis factor-α (TNFα). To date, however, no specific mechanism via which this cytokine could alter cognitive circuits has been demonstrated. Here, we show that local increase of TNFα in the hippocampal dentate gyrus activates astrocyte TNF receptor type 1 (TNFR1), which in turn triggers an astrocyte-neuron signaling cascade that results in persistent functional modification of hippocampal excitatory synapses. Astrocytic TNFR1 signaling is necessary for the hippocampal synaptic alteration and contextual learning-memory impairment observed in experimental autoimmune encephalitis (EAE), an animal model of multiple sclerosis (MS). This process may contribute to the pathogenesis of cognitive disturbances in MS, as well as in other CNS conditions accompanied by inflammatory states or infections
Immunogold Detection of L-glutamate and D-serine in Small Synaptic-Like Microvesicles in Adult Hippocampal Astrocytes.
Glutamate and the N-methyl-D-aspartate receptor ligand D-serine are putative gliotransmitters. Here, we show by immunogold cytochemistry of the adult hippocampus that glutamate and D-serine accumulate in synaptic-like microvesicles (SLMVs) in the perisynaptic processes of astrocytes. The estimated concentration of fixed glutamate in the astrocytic SLMVs is comparable to that in synaptic vesicles of excitatory nerve terminals (∼45 and ∼55 mM, respectively), whereas the D-serine level is about 6 mM. The vesicles are organized in small spaced clusters located near the astrocytic plasma membrane. Endoplasmic reticulum is regularly found in close vicinity to SLMVs, suggesting that astrocytes contain functional nanodomains, where a local Ca(2+) increase can trigger release of glutamate and/or D-serine
A tale of two stories: astrocyte regulation of synaptic depression and facilitation
Short-term presynaptic plasticity designates variations of the amplitude of
synaptic information transfer whereby the amount of neurotransmitter released
upon presynaptic stimulation changes over seconds as a function of the neuronal
firing activity. While a consensus has emerged that changes of the synapse
strength are crucial to neuronal computations, their modes of expression in
vivo remain unclear. Recent experimental studies have reported that glial
cells, particularly astrocytes in the hippocampus, are able to modulate
short-term plasticity but the underlying mechanism is poorly understood. Here,
we investigate the characteristics of short-term plasticity modulation by
astrocytes using a biophysically realistic computational model. Mean-field
analysis of the model unravels that astrocytes may mediate counterintuitive
effects. Depending on the expressed presynaptic signaling pathways, astrocytes
may globally inhibit or potentiate the synapse: the amount of released
neurotransmitter in the presence of the astrocyte is transiently smaller or
larger than in its absence. But this global effect usually coexists with the
opposite local effect on paired pulses: with release-decreasing astrocytes most
paired pulses become facilitated, while paired-pulse depression becomes
prominent under release-increasing astrocytes. Moreover, we show that the
frequency of astrocytic intracellular Ca2+ oscillations controls the effects of
the astrocyte on short-term synaptic plasticity. Our model explains several
experimental observations yet unsolved, and uncovers astrocytic
gliotransmission as a possible transient switch between short-term paired-pulse
depression and facilitation. This possibility has deep implications on the
processing of neuronal spikes and resulting information transfer at synapses.Comment: 93 pages, manuscript+supplementary text, 10 main figures, 11
supplementary figures, 1 tabl
Astrocytes: orchestrating synaptic plasticity?
Synaptic plasticity is the capacity of a preexisting connection between two
neurons to change in strength as a function of neural activity. Because
synaptic plasticity is the major candidate mechanism for learning and memory,
the elucidation of its constituting mechanisms is of crucial importance in many
aspects of normal and pathological brain function. In particular, a prominent
aspect that remains debated is how the plasticity mechanisms, that encompass a
broad spectrum of temporal and spatial scales, come to play together in a
concerted fashion. Here we review and discuss evidence that pinpoints to a
possible non-neuronal, glial candidate for such orchestration: the regulation
of synaptic plasticity by astrocytes.Comment: 63 pages, 4 figure
Nonlinear gap junctions enable long-distance propagation of pulsating calcium waves in astrocyte networks
A new paradigm has recently emerged in brain science whereby communications
between glial cells and neuron-glia interactions should be considered together
with neurons and their networks to understand higher brain functions. In
particular, astrocytes, the main type of glial cells in the cortex, have been
shown to communicate with neurons and with each other. They are thought to form
a gap-junction-coupled syncytium supporting cell-cell communication via
propagating Ca2+ waves. An identified mode of propagation is based on
cytoplasm-to-cytoplasm transport of inositol trisphosphate (IP3) through gap
junctions that locally trigger Ca2+ pulses via IP3-dependent Ca2+-induced Ca2+
release. It is, however, currently unknown whether this intracellular route is
able to support the propagation of long-distance regenerative Ca2+ waves or is
restricted to short-distance signaling. Furthermore, the influence of the
intracellular signaling dynamics on intercellular propagation remains to be
understood. In this work, we propose a model of the gap-junctional route for
intercellular Ca2+ wave propagation in astrocytes showing that: (1)
long-distance regenerative signaling requires nonlinear coupling in the gap
junctions, and (2) even with nonlinear gap junctions, long-distance
regenerative signaling is favored when the internal Ca2+ dynamics implements
frequency modulation-encoding oscillations with pulsating dynamics, while
amplitude modulation-encoding dynamics tends to restrict the propagation range.
As a result, spatially heterogeneous molecular properties and/or weak couplings
are shown to give rise to rich spatiotemporal dynamics that support complex
propagation behaviors. These results shed new light on the mechanisms
implicated in the propagation of Ca2+ waves across astrocytes and precise the
conditions under which glial cells may participate in information processing in
the brain.Comment: Article: 30 pages, 7 figures. Supplementary Material: 11 pages, 6
figure
Neuron-glial Interactions
Although lagging behind classical computational neuroscience, theoretical and computational approaches are beginning to emerge to characterize different aspects of neuron-glial interactions. This chapter aims to provide essential knowledge on neuron-glial interactions in the mammalian brain, leveraging on computational studies that focus on structure (anatomy) and function (physiology) of such interactions in the healthy brain. Although our understanding of the need of neuron-glial interactions in the brain is still at its infancy, being mostly based on predictions that await for experimental validation, simple general modeling arguments borrowed from control theory are introduced to support the importance of including such interactions in traditional neuron-based modeling paradigms.Junior Leader Fellowship Program by “la Caixa” Banking Foundation (LCF/BQ/LI18/11630006
Neuron-Glial Interactions
Although lagging behind classical computational neuroscience, theoretical and
computational approaches are beginning to emerge to characterize different
aspects of neuron-glial interactions. This chapter aims to provide essential
knowledge on neuron-glial interactions in the mammalian brain, leveraging on
computational studies that focus on structure (anatomy) and function
(physiology) of such interactions in the healthy brain. Although our
understanding of the need of neuron-glial interactions in the brain is still at
its infancy, being mostly based on predictions that await for experimental
validation, simple general modeling arguments borrowed from control theory are
introduced to support the importance of including such interactions in
traditional neuron-based modeling paradigms.Comment: 43 pages, 2 figures, 1 table. Accepted for publication in the
"Encyclopedia of Computational Neuroscience," D. Jaeger and R. Jung eds.,
Springer-Verlag New York, 2020 (2nd edition
Synaptic modulation by astrocytes via Ca(2+)-dependent glutamate release
In the past 15 years the classical view that astrocytes play a relatively passive role in brain function has been overturned and it has become increasingly clear that signaling between neurons and astrocytes may play a crucial role in the information processing that the brain carries out. This new view stems from two seminal observations made in the early 1990s: 1. astrocytes respond to neurotransmitters released during synaptic activity with elevation of their intracellular Ca(2+) concentration ([Ca(2+)](i)); 2. astrocytes release chemical transmitters, including glutamate, in response to [Ca(2+)](i) elevations. The simultaneous recognition that astrocytes sense neuronal activity and release neuroactive agents has been instrumental for understanding previously unknown roles of these cells in the control of synapse formation, function and plasticity. These findings open a conceptual revolution, leading to rethink how brain communication works, as they imply that information travels (and is processed) not just in the neuronal circuitry but in an expanded neuron-glia network. In this review we critically discuss the available information concerning: 1. the characteristics of the astrocytic Ca(2+) responses to synaptic activity; 2. the basis of Ca(2+)-dependent glutamate exocytosis from astrocytes; 3. the modes of action of astrocytic glutamate on synaptic function