Astrocyte-secreted IL-33 mediates homeostatic synaptic plasticity in the adult hippocampus

Hippocampal synaptic plasticity is important for learning and memory formation. Homeostatic synaptic plasticity is a specific form of synaptic plasticity that is induced upon prolonged changes in neuronal activity to maintain network homeostasis. While astrocytes are important regulators of synaptic transmission and plasticity, it is largely unclear how they interact with neurons to regulate synaptic plasticity at the circuit level. Here, we show that neuronal activity blockade selectively increases the expression and secretion of IL-33 (interleukin-33) by astrocytes in the hippocampal cornu ammonis 1 (CA1) subregion. This IL-33 stimulates an increase in excitatory synapses and neurotransmission through the activation of neuronal IL-33 receptor complex and synaptic recruitment of the scaffold protein PSD-95. We found that acute administration of tetrodotoxin in hippocampal slices or inhibition of hippocampal CA1 excitatory neurons by optogenetic manipulation increases IL-33 expression in CA1 astrocytes. Furthermore, IL-33 administration in vivo promotes the formation of functional excitatory synapses in hippocampal CA1 neurons, whereas conditional knockout of IL-33 in CA1 astrocytes decreases the number of excitatory synapses therein. Importantly, blockade of IL-33 and its receptor signaling in vivo by intracerebroventricular administration of its decoy receptor inhibits homeostatic synaptic plasticity in CA1 pyramidal neurons and impairs spatial memory formation in mice. These results collectively reveal an important role of astrocytic IL-33 in mediating the negative-feedback signaling mechanism in homeostatic synaptic plasticity, providing insights into how astrocytes maintain hippocampal network homeostasis.

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Homeostatic Plasticity Hypothesis and Mechanisms of Neocortical Epilepsies

Epilepsy Currents ◽

10.1111/j.1535-7511.2005.00042.x ◽

2005 ◽

Vol 5 (4) ◽

pp. 133-135 ◽

Cited By ~ 1

Author(s):

Jaideep Kapur ◽

Stacey Trotter

Keyword(s):

Synaptic Plasticity ◽

Neuronal Activity ◽

Pyramidal Neurons ◽

Pyramidal Cells ◽

Homeostatic Plasticity ◽

Excitatory Synapses ◽

Excitatory Postsynaptic Currents ◽

Inhibitory Postsynaptic Currents ◽

Postsynaptic Currents ◽

Homeostatic Synaptic Plasticity

Homeostatic Synaptic Plasticity Can Explain Posttraumatic Epileptogenesis in Chronically Isolated Neocortex Houweling AR, Bazhenov M, Timofeev I, Steriade M, Sejnowski TJ Cereb Cortex 2004 [Epub ahead of print] Permanently isolated neocortex develops chronic hyperexcitability and focal epileptogenesis in a period of days to weeks. The mechanisms operating in this model of posttraumatic epileptogenesis are not well understood. We hypothesized that the spontaneous burst discharges recorded in permanently isolated neocortex result from homeostatic plasticity (a mechanism generally assumed to stabilize neuronal activity) induced by low neuronal activity after deafferentation. To test this hypothesis, we constructed computer models of neocortex incorporating a biologically based homeostatic plasticity rule that operates to maintain firing rates. After deafferentation, homeostatic upregulation of excitatory synapses on pyramidal cells, either with or without concurrent downregulation of inhibitory synapses or upregulation of intrinsic excitability, initiated slowly repeating burst discharges that closely resembled the epileptiform burst discharges recorded in permanently isolated neocortex. These burst discharges lasted a few hundred milliseconds, propagated at 1 to 3 cm/s and consisted of large (10–15 mV) intracellular depolarizations topped by a small number of action potentials. Our results support a role for homeostatic synaptic plasticity as a novel mechanism of posttraumatic epileptogenesis. Excitatory and Inhibitory Postsynaptic Currents in a Rat Model of Epileptogenic Microgyria Jacobs KM, Prince DA J Neurophysiol 2005;93:687–696 Developmental cortical malformations are common in patients with intractable epilepsy; however, mechanisms contributing to this epileptogenesis are currently poorly understood. We previously characterized hyperexcitability in a rat model that mimics the histopathology of human four-layered microgyria. Here we examined inhibitory and excitatory postsynaptic currents in this model to identify functional alterations that might contribute to epileptogenesis associated with microgyria. We recorded isolated whole-cell excitatory postsynaptic currents and GABAA receptor–mediated inhibitory currents from layer V pyramidal neurons in the region previously shown to be epileptogenic (paramicrogyral area) and in homotopic control cortex. Epileptiform-like activity could be evoked in 60% of paramicrogyral (PMG) cells by local stimulation. The peak conductance of both spontaneous and evoked inhibitory postsynaptic currents was significantly larger in all PMG cells compared with controls. This difference in amplitude was not present after blockade of ionotropic glutamatergic currents or for miniature (m) inhibitory postsynaptic currents, suggesting that it was due to the excitatory afferent activity driving inhibitory neurons. This conclusion was supported by the finding that glutamatereceptor antagonist application resulted in a significantly greater reduction in spontaneous inhibitory postsynaptic current frequency in one PMG cell group (PMGE) compared with control cells. The frequency of both spontaneous and miniature excitatory postsynaptic currents was significantly greater in all PMG cells, suggesting that pyramidal neurons adjacent to a microgyrus receive more excitatory input than do those in control cortex. These findings suggest that there is an increase in numbers of functional excitatory synapses on both interneurons and pyramidal cells in the PMG cortex, perhaps due to hyperinnervation by cortical afferents originally destined for the microgyrus proper.

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Shp2 in Forebrain Neurons Regulates Synaptic Plasticity, Locomotion, and Memory Formation in Mice

Molecular and Cellular Biology ◽

10.1128/mcb.01339-14 ◽

2015 ◽

Vol 35 (9) ◽

pp. 1557-1572 ◽

Cited By ~ 20

Author(s):

Shinya Kusakari ◽

Fumihito Saitow ◽

Yukio Ago ◽

Koji Shibasaki ◽

Miho Sato-Hashimoto ◽

...

Keyword(s):

Synaptic Plasticity ◽

Cortical Neurons ◽

Tyrosine Phosphatase ◽

Hippocampal Slices ◽

Memory Formation ◽

Conditional Knockout ◽

Abnormal Behavior ◽

Erk Activation ◽

Cultured Cortical Neurons ◽

Forebrain Neurons

Shp2 (Src homology 2 domain-containing protein tyrosine phosphatase 2) regulates neural cell differentiation. It is also expressed in postmitotic neurons, however, and mutations of Shp2 are associated with clinical syndromes characterized by mental retardation. Here we show that conditional-knockout (cKO) mice lacking Shp2 specifically in postmitotic forebrain neurons manifest abnormal behavior, including hyperactivity. Novelty-induced expression of immediate-early genes and activation of extracellular-signal-regulated kinase (Erk) were attenuated in the cerebral cortex and hippocampus of Shp2 cKO mice, suggestive of reduced neuronal activity. In contrast, ablation of Shp2 enhanced high-K+-induced Erk activation in both cultured cortical neurons and synaptosomes, whereas it inhibited that induced by brain-derived growth factor in cultured neurons. Posttetanic potentiation and paired-pulse facilitation were attenuated and enhanced, respectively, in hippocampal slices from Shp2 cKO mice. The mutant mice also manifested transient impairment of memory formation in the Morris water maze. Our data suggest that Shp2 contributes to regulation of Erk activation and synaptic plasticity in postmitotic forebrain neurons and thereby controls locomotor activity and memory formation.

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Specific depletion of the motor protein KIF5B leads to deficits in dendritic transport, synaptic plasticity and memory

eLife ◽

10.7554/elife.53456 ◽

2020 ◽

Vol 9 ◽

Cited By ~ 5

Author(s):

Junjun Zhao ◽

Albert Hiu Ka Fok ◽

Ruolin Fan ◽

Pui-Yi Kwan ◽

Hei-Lok Chan ◽

...

Keyword(s):

Synaptic Plasticity ◽

Gene Duplication ◽

Hippocampal Neurons ◽

Motor Proteins ◽

Arginine Methylation ◽

Memory Formation ◽

Conditional Knockout ◽

Excitatory Synapses ◽

Functional Specificity ◽

Spine Morphogenesis

The kinesin I family of motor proteins are crucial for axonal transport, but their roles in dendritic transport and postsynaptic function are not well-defined. Gene duplication and subsequent diversification give rise to three homologous kinesin I proteins (KIF5A, KIF5B and KIF5C) in vertebrates, but it is not clear whether and how they exhibit functional specificity. Here we show that knockdown of KIF5A or KIF5B differentially affects excitatory synapses and dendritic transport in hippocampal neurons. The functional specificities of the two kinesins are determined by their diverse carboxyl-termini, where arginine methylation occurs in KIF5B and regulates its function. KIF5B conditional knockout mice exhibit deficits in dendritic spine morphogenesis, synaptic plasticity and memory formation. Our findings provide insights into how expansion of the kinesin I family during evolution leads to diversification and specialization of motor proteins in regulating postsynaptic function.

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Protein kinase D promotes plasticity-induced F-actin stabilization in dendritic spines and regulates memory formation

The Journal of Cell Biology ◽

10.1083/jcb.201501114 ◽

2015 ◽

Vol 210 (5) ◽

pp. 771-783 ◽

Cited By ~ 8

Author(s):

Norbert Bencsik ◽

Zsófia Szíber ◽

Hanna Liliom ◽

Krisztián Tárnok ◽

Sándor Borbély ◽

...

Keyword(s):

Synaptic Plasticity ◽

Protein Kinase ◽

Dendritic Spines ◽

Morphological Changes ◽

Long Term Potentiation ◽

Memory Formation ◽

Protein Kinase D

Actin turnover in dendritic spines influences spine development, morphology, and plasticity, with functional consequences on learning and memory formation. In nonneuronal cells, protein kinase D (PKD) has an important role in stabilizing F-actin via multiple molecular pathways. Using in vitro models of neuronal plasticity, such as glycine-induced chemical long-term potentiation (LTP), known to evoke synaptic plasticity, or long-term depolarization block by KCl, leading to homeostatic morphological changes, we show that actin stabilization needed for the enlargement of dendritic spines is dependent on PKD activity. Consequently, impaired PKD functions attenuate activity-dependent changes in hippocampal dendritic spines, including LTP formation, cause morphological alterations in vivo, and have deleterious consequences on spatial memory formation. We thus provide compelling evidence that PKD controls synaptic plasticity and learning by regulating actin stability in dendritic spines.

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Noradrenergic Regulation of Synaptic Plasticity in the Hippocampal CA1 Region

Journal of Neurophysiology ◽

10.1152/jn.1997.77.6.3013 ◽

1997 ◽

Vol 77 (6) ◽

pp. 3013-3020 ◽

Cited By ~ 154

Author(s):

Hiroshi Katsuki ◽

Yukitoshi Izumi ◽

Charles F. Zorumski

Keyword(s):

Synaptic Plasticity ◽

Receptor Antagonist ◽

Hippocampal Slices ◽

Stimulus Frequency ◽

Long Term Potentiation ◽

Receptor Activation ◽

Ca1 Region ◽

Hippocampal Ca1 Region ◽

Hippocampal Ca1

Katsuki, Hiroshi, Yukitoshi Izumi, and Charles F. Zorumski. Noradrenergic regulation of synaptic plasticity in the hippocampal CA1 region. J. Neurophysiol. 77: 3013–3020, 1997. The effects of norepinephrine (NE) and related agents on long-lasting changes in synaptic efficacy induced by several patterns of afferent stimuli were investigated in the CA1 region of rat hippocampal slices. NE (10 μM) showed little effect on the induction of long-term potentiation (LTP) triggered by theta-burst-patterned stimulation, whereas it inhibited the induction of long-term depression (LTD) triggered by 900 pulses of 1-Hz stimulation. In nontreated slices, 900 pulses of stimuli induced LTD when applied at lower frequencies (1–3 Hz), and induced LTP when applied at a higher frequency (30 Hz). NE (10 μM) caused a shift of the frequency-response relationship in the direction preferring potentiation. The effect of NE was most prominent at a stimulus frequency of 10 Hz, which induced no changes in control slices but clearly induced LTP in the presence of NE. The facilitating effect of NE on the induction of LTP by 10-Hz stimulation was blocked by theβ-adrenergic receptor antagonist timolol (50 μM), but not by the α receptor antagonist phentolamine (50 μM), and was mimicked by the β-agonist isoproterenol (0.3 μM), but not by the α1 agonist phenylephrine (10 μM). The induction of LTD by 1-Hz stimulation was prevented by isoproterenol but not by phenylephrine, indicating that the activation of β-receptors is responsible for these effects of NE. NE (10 μM) also prevented the reversal of LTP (depotentiation) by 900 pulses of 1-Hz stimulation delivered 30 min after LTP induction. In contrast to effects on naive (nonpotentiated) synapses, the effect of NE on previously potentiated synapses was only partially mimicked by isoproterenol, but fully mimicked by coapplication of phenylephrine and isoproterenol. In addition, the effect of NE was attenuated either by phentolamine or by timolol, indicating that activation of both α1 and β-receptors is required. These results show that NE plays a modulatory role in the induction of hippocampal synaptic plasticity. Althoughβ-receptor activation is essential, α1 receptor activation is also necessary in determining effects on previously potentiated synapses.

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Intrinsic Theta-Frequency Membrane Potential Oscillations in Hippocampal CA1 Interneurons of Stratum Lacunosum-Moleculare

Journal of Neurophysiology ◽

10.1152/jn.1999.81.3.1296 ◽

1999 ◽

Vol 81 (3) ◽

pp. 1296-1307 ◽

Cited By ~ 98

Author(s):

C. Andrew Chapman ◽

Jean-Claude Lacaille

Keyword(s):

Membrane Potential ◽

Hippocampal Slices ◽

Stratum Radiatum ◽

Potential Oscillations ◽

Spike Threshold ◽

Hippocampal Ca1 ◽

Theta Frequency ◽

Stratum Lacunosum Moleculare ◽

Membrane Potential Oscillations

Intrinsic theta-frequency membrane potential oscillations in hippocampal CA1 interneurons of stratum lacunosum-moleculare. The ionic conductances underlying membrane potential oscillations of hippocampal CA1 interneurons located near the border between stratum lacunosum-moleculare and stratum radiatum (LM) were investigated using whole cell current-clamp recordings in rat hippocampal slices. At 22°C, when LM cells were depolarized near spike threshold by current injection, 91% of cells displayed 2–5 Hz oscillations in membrane potential, which caused rhythmic firing. At 32°C, mean oscillation frequency increased to 7.1 Hz. Oscillations were voltage dependent and were eliminated by hyperpolarizing cells 6–10 mV below spike threshold. Blockade of ionotropic glutamate and GABA synaptic transmission did not affect oscillations, indicating that they were not synaptically driven. Oscillations were eliminated by tetrodotoxin, suggesting that Na+ currents generate the depolarizing phase of oscillations. Oscillations were not affected by blocking Ca2+ currents with Cd2+ or Ca2+-free ACSF or by blocking the hyperpolarization-activated current ( I h) with Cs+. Both Ba2+ and a low concentration of 4-aminopyridine (4-AP) reduced oscillations but TEA did not. Theta-frequency oscillations were much less common in interneurons located in stratum oriens. Intrinsic membrane potential oscillations in LM cells of the CA1 region thus involve an interplay between inward Na+ currents and outward K+ currents sensitive to Ba2+ and 4-AP. These oscillations may participate in rhythmic inhibition and synchronization of pyramidal neurons during theta activity in vivo.

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Role of neuronal activity and metaplastic state in homeostatic synaptic plasticity

IBRO Reports ◽

10.1016/j.ibror.2019.07.1283 ◽

2019 ◽

Vol 6 ◽

pp. S402-S403

Author(s):

Bryce Grier ◽

Varun Chokshi ◽

Andrew Dykman ◽

Crystal Lantz ◽

Ernst Niebur ◽

...

Keyword(s):

Synaptic Plasticity ◽

Neuronal Activity ◽

Homeostatic Synaptic Plasticity

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Remodeling of astrocytes, a prerequisite for synapse turnover in the adult brain? Insights from the oxytocin system of the hypothalamus

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00755.2005 ◽

2006 ◽

Vol 290 (5) ◽

pp. R1175-R1182 ◽

Cited By ~ 52

Author(s):

Dionysia T. Theodosis ◽

Andrei Trailin ◽

Dominique A. Poulain

Keyword(s):

Synaptic Plasticity ◽

Synaptic Transmission ◽

Neuronal Activity ◽

Adult Brain ◽

Synaptic Connectivity ◽

Excitatory Synapses ◽

Neuronal Function ◽

Physiological Conditions ◽

Baseline Levels ◽

Activity Dependent

Neurons, including their synapses, are generally ensheathed by fine processes of astrocytes, but this glial coverage can be altered under different physiological conditions that modify neuronal activity. Changes in synaptic connectivity accompany astrocytic transformations so that an increased number of synapses are associated with reduced astrocytic coverage of postsynaptic elements, whereas synaptic numbers are reduced on reestablishment of glial coverage. A system that exemplifies activity-dependent structural synaptic plasticity in the adult brain is the hypothalamo-neurohypophysial system, and in particular, its oxytocin component. Under strong, prolonged activation (parturition, lactation, chronic dehydration), extensive portions of somatic and dendritic surfaces of magnocellular oxytocin neurons are freed of intervening astrocytic processes and become directly juxtaposed. Concurrently, they are contacted by an increased number of inhibitory and excitatory synapses. Once stimulation is over, astrocytic processes again cover oxytocinergic surfaces and synaptic numbers return to baseline levels. Such observations indicate that glial ensheathment of neurons is of consequence to neuronal function, not only directly, for example by modifying synaptic transmission, but indirectly as well, by preparing neuronal surfaces for synapse turnover.

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