| 1. |
- Wallén-Mackenzie, Åsa, et al.
(författare)
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Restricted cortical and amygdaloid removal of vesicular glutamate transporter 2 in preadolescent mice impacts dopaminergic activity and neuronal circuitry of higher brain function.
- 2009
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Ingår i: The Journal of neuroscience : the official journal of the Society for Neuroscience. - 1529-2401 .- 0270-6474. ; 29:7, s. 2238-51
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Tidskriftsartikel (refereegranskat)abstract
- A major challenge in neuroscience is to resolve the connection between gene functionality, neuronal circuits, and behavior. Most, if not all, neuronal circuits of the adult brain contain a glutamatergic component, the nature of which has been difficult to assess because of the vast cellular abundance of glutamate. In this study, we wanted to determine the role of a restricted subpopulation of glutamatergic neurons within the forebrain, the Vglut2-expressing neurons, in neuronal circuitry of higher brain function. Vglut2 expression was selectively deleted in the cortex, hippocampus, and amygdala of preadolescent mice, which resulted in increased locomotor activity, altered social dominance and risk assessment, decreased sensorimotor gating, and impaired long-term spatial memory. Presynaptic VGLUT2-positive terminals were lost in the cortex, striatum, nucleus accumbens, and hippocampus, and a downstream effect on dopamine binding site availability in the striatum was evident. A connection between the induced late-onset, chronic reduction of glutamatergic neurotransmission and dopamine signaling within the circuitry was further substantiated by a partial attenuation of the deficits in sensorimotor gating by the dopamine-stabilizing antipsychotic drug aripiprazole and an increased sensitivity to amphetamine. Somewhat surprisingly, given the restricted expression of Vglut2 in regions responsible for higher brain function, our analyses show that VGLUT2-mediated neurotransmission is required for certain aspects of cognitive, emotional, and social behavior. The present study provides support for the existence of a neurocircuitry that connects changes in VGLUT2-mediated neurotransmission to alterations in the dopaminergic system with schizophrenia-like behavioral deficits as a major outcome.
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| 2. |
- Andersson, My, 1980
(författare)
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Astrocyte-mediated short-term synaptic depression
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Short-term synaptic plasticity, the activity-dependent regulation of synaptic efficacy that occurs in the timeframe of milliseconds to seconds, is a fundamental property of the synapse, mostly attributed to changes in release probability. These changes are commonly ascribed to intrinsic mechanisms in the presynaptic terminal and to different transmitters acting on the presynaptic terminal. Astrocytes are the most abundant cell type in the brain. It has become increasingly clear that they can have a more active role in regulating neuronal signalling than their first established role of providing neuronal support. Astrocytes send out processes, which enwrap the synapses, in an ideal position to respond to synaptic transmission and in turn modulate synaptic function, such as short-term plasticity. However, not much is known about how astrocytes affect short-term synaptic plasticity. The overall objective of this thesis was to examine the possible involvement of astrocyte-synapse signalling in short-term synaptic plasticity in the hippocampus. We used the acute rat hippocampal slice preparation and recorded the transmission at the glutamatergic CA3-CA1 synapses using extracellular and whole-cell patch-clamp recordings. Hippocampal CA3-CA1 synapses as a population exhibit facilitation or augmentation milliseconds and seconds after a brief synaptic burst. However, we found that in the intermediate timeframe, between a couple of hundred milliseconds to seconds, these synapses exhibit a postburst depression (PBD). This PBD was found to be expressed as a reduction of release probability. The PBD displayed a cooperativity threshold as it was necessary to activate a critical number of synapses in order to elicit the depression. We found that the PBD develops over the first three postnatal weeks and that it is blocked when astrocyte metabolism is compromised. The PBD was blocked when a calcium chelator was delivered into the astrocytic network through a patch pipette, showing a requirement for astrocytic signalling. Activation leading to PBD homosynaptically, also gave rise to a decrease in release probability in neighbouring inactive synapses, a transient heterosynaptic depression (tHeSD). The tHeSD developed over the same period as the PBD and was blocked by a blocker of astrocyte metabolism. In addition, the tHeSD was blocked by application of gap junction blockers. The tHeSD relied on GABAB and mGlu II/III receptors, but not on NMDA, adenosine A1 or mGlu I receptors. Analysis of paired-pulse plasticity and relative vesicle pool size suggest that the tHeSD is expressed as a depression of resting vesicular release probability, causing a large increase of the paired-pulse ratio. In addition, the PBD was suggested to be a combination of vesicle depletion and augmentation, causing no change and a large decrease in paired-pulse ratio, respectively. Hippocampal pyramidal neurons typically fire action potentials in short bursts in the behaving animal, at frequencies suitable for eliciting the PBD and the tHeSD. This suggests that astrocytes are critically involved in mediating a negative feedback synaptic transmission after a burst of synaptic activity.
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| 3. |
- Andersson, My, 1980, et al.
(författare)
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Astrocyte-mediated short-term synaptic depression in the rat hippocampal CA1 area: two modes of decreasing release probability.
- 2011
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Ingår i: BMC neuroscience. - : Springer Science and Business Media LLC. - 1471-2202. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- ABSTRACT: BACKGROUND: Synaptic burst activation feeds back as a short-term depression of release probability at hippocampal CA3-CA1 synapses. This short-term synaptic plasticity requires functional astrocytes and it affects both the recently active (< 1 s) synapses (post-burst depression) as well as inactive neighboring synapses (transient heterosynaptic depression). The aim of this study was to investigate and compare the components contributing to the depression of release probability in these two different scenarios. RESULTS: When tested using paired-pulses, following a period of inactivity, the transient heterosynaptic depression was expressed as a reduction in the response to only the first pulse, whereas the response to the second pulse was unaffected. This selective depression of only the first response in a high-frequency burst was shared by the homosynaptic post-burst depression, but it was partially counteracted by augmentation at these recently active synapses. In addition, the expression of the homosynaptic post-burst depression included an astrocyte-mediated reduction of the pool of release-ready primed vesicles. CONCLUSIONS: Our results suggest that activated astrocytes depress the release probability via two different mechanisms; by depression of vesicular release probability only at inactive synapses and by imposing a delay in the recovery of the primed pool of vesicles following depletion. These mechanisms restrict the expression of the astrocyte-mediated depression to temporal windows that are typical for synaptic burst activity.
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| 4. |
- Andersson, My, 1980, et al.
(författare)
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Astrocytes impose postburst depression of release probability at hippocampal glutamate synapses.
- 2010
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Ingår i: The Journal of neuroscience : the official journal of the Society for Neuroscience. - 1529-2401. ; 30:16, s. 5776-80
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Tidskriftsartikel (refereegranskat)abstract
- Many neurons typically fire action potentials in brief, high-frequency bursts with specific consequences for their synaptic output. Here we have examined short-term plasticity engaged during burst activation using electrophysiological recordings in acute rat hippocampal slices. We show that CA3-CA1 glutamate synapses exhibit a prominent depression of presynaptic release probability for approximately 1 s after such a burst. This postburst depression exhibits a distinct cooperativity threshold, is abolished by inhibiting astrocyte metabolism and astrocyte calcium signaling, and is not operational in the developing hippocampus. Our results suggest that astrocytes are actively involved in short-term synaptic depression, shaping synaptic activity during behaviorally relevant neural activity.
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| 5. |
- Andersson, My, 1980, et al.
(författare)
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Astrocytes play a critical role in transient heterosynaptic depression in the rat hippocampal CA1 region.
- 2007
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Ingår i: The Journal of physiology. - : Wiley. - 0022-3751. ; 585:Pt 3, s. 843-52
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Tidskriftsartikel (refereegranskat)abstract
- Active synapses can reduce the probability of transmitter release at neighbouring synapses. Depending on whether such heterosynaptic depression is mediated by intersynaptic diffusion of transmitter or by release of gliotransmitters, astrocytes should either hinder or promote the heterosynaptic depression. In the present study we have examined the developmental profile and astrocytic involvement in a transient heterosynaptic depression (tHeSD) in the CA1 region of the rat hippocampal slice preparation. A short stimulus burst (3 impulses at 50 Hz) to one group of synapses elicited a depression of the field EPSP evoked in another group of synapses that amounted to about 25% 0.5 s after the conditioning burst. This tHeSD was associated with an increase in the paired-pulse ratio of about 30%. The tHeSD was not present in slices from rats younger than 10 postnatal days and developed towards the adult magnitude between postnatal days 10 and 20. The tHeSD was totally prevented by the glia-specific toxin fluoroacetate (FAC), by carbenoxolone, a general blocker of connexin-based channels, and by endothelin, an endogenous peptide that has been shown to block astrocytic connexin-based channels. Antagonists to GABA(B) receptors and group II/III metabotropic glutamate receptors (mGluRs) abolished the tHeSD whereas antagonists to NMDA- and adenosine A1 receptors, and to group I mGluRs, did not affect the tHeSD. These results suggest that the tHeSD relies on GABA(B) receptors, group II/III mGluRs and on gliotransmitter release from functionally mature astrocytes.
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| 6. |
- Wasling, Pontus, et al.
(författare)
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Synaptic retrogenesis and amyloid-beta in Alzheimer's disease.
- 2009
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Ingår i: Journal of Alzheimer's disease : JAD. - 1387-2877. ; 16:1, s. 1-14
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Forskningsöversikt (refereegranskat)abstract
- Pathological hallmarks of Alzheimer's disease (AD) include synaptic and neuronal degeneration and the presence of extracellular deposits of amyloid-beta (Abeta) in senile plaques in the cerebral cortex. Although these brain lesions may be seen also in aged non-demented individuals, the increase in brain Abeta is believed by many to represent the earliest event in the disease process. Accumulating evidence suggests that Abeta, which is highly conserved by evolution, may have an important physiological role in synapse elimination during brain development. An intriguing idea is that this putative function can become pathogenic if activated in the aging brain. Here, we review the literature on the possible physiological roles of Abeta and its precursor protein AbetaPP during development with special focus on electrophysiological findings.
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