Reciprocal changes of CD44 and GAP-43 expression in the dentate gyrus inner molecular layer after status epilepticus in mice

Borges, Karin; McDermott, Dayna L.; Dingledine, Raymond

doi:10.1016/j.expneurol.2004.03.019

Cited by 42 publications

(49 citation statements)

References 60 publications

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“…Previous studies have also reported elevated numbers of peripheral immune leukocytes after epileptiform activity (46,47). The current data confirm and extend these earlier findings in numerous notable ways.…”

Section: Discussionsupporting

confidence: 82%

Infiltrating monocytes promote brain inflammation and exacerbate neuronal damage after status epilepticus

Varvel

Neher

Bosch

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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288

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The generalized seizures of status epilepticus (SE) trigger a series of molecular and cellular events that produce cognitive deficits and can culminate in the development of epilepsy. Known early events include opening of the blood-brain barrier (BBB) and astrocytosis accompanied by activation of brain microglia. Whereas circulating monocytes do not infiltrate the healthy CNS, monocytes can enter the brain in response to injury and contribute to the immune response. We examined the cellular components of innate immune inflammation in the days following SE by discriminating microglia vs. brain-infiltrating monocytes. Chemokine receptor 2 (CCR2 + ) monocytes invade the hippocampus between 1 and 3 d after SE. In contrast, only an occasional CD3 + T lymphocyte was encountered 3 d after SE. The initial cellular sources of the chemokine CCL2, a ligand for CCR2, included perivascular macrophages and microglia. The induction of the proinflammatory cytokine IL-1β was greater in FACS-isolated microglia than in brain-invading monocytes. However, Ccr2 knockout mice displayed greatly reduced monocyte recruitment into brain and reduced levels of the proinflammatory cytokine IL-1β in hippocampus after SE, which was explained by higher expression of the cytokine in circulating and brain monocytes in wild-type mice. Importantly, preventing monocyte recruitment accelerated weight regain, reduced BBB degradation, and attenuated neuronal damage. Our findings identify brain-infiltrating monocytes as a myeloid-cell subclass that contributes to neuroinflammation and morbidity after SE. Inhibiting brain invasion of CCR2 + monocytes could represent a viable method for alleviating the deleterious consequences of SE. myeloid cell heterogeneity | epileptogenesis | neuroprotection | seizure | microgliosis S tatus epilepticus (SE) is a serious medical emergency that triggers a series of cellular and molecular events that can result in the development of epilepsy, a chronic neurological disorder characterized by a persistently lowered seizure threshold (1). The early consequences of SE in rodents include a robust neuroinflammatory response, selective neuronal degeneration, and transient opening of the blood-brain barrier (BBB), leading to later cognitive decline. Although the neuroinflammatory features of SE in man are less well known, extravasation of albumin into the brain was observed for patients who died in SE (2), elevated cerebrospinal fluid levels of the cytokines IL-6, IL-8, and CXCL10 are typically found in patients with refractory SE compared with patients with other inflammatory neurologic disorders (3), and intense gliosis (both astrocytes and microglia) was observed in the temporal cortex of a patient with new-onset focal seizures that progressed to refractory SE (4). These admittedly sparse clinical findings are consistent with the much more extensive animal literature in demonstrating a florid inflammatory response of the brain to SE (5). We and others have provided evidence in animal models of epilepsy that quenching inflamma...

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Section: Discussionsupporting

confidence: 82%

Infiltrating monocytes promote brain inflammation and exacerbate neuronal damage after status epilepticus

Varvel

Neher

Bosch

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

288

291

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“…This occurs when COS-7 cells, which do not express GAP-43, are transfected with a constitutively active form of cdc42 [34]. Consistent with this idea, the effects of GAP-43 (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14) and constitutively active cdc42 together are additive [34]. Since the first 14 residues of GAP-43 do not contain the protein kinase C phosphorylation site, it was suggested that interaction of only the first 14 residues with membranes is sufficient to Fig.…”

Section: Gap-43 G Proteins Small Gtpases and Filopodiasupporting

confidence: 57%

“…The hippocampus receives noradrenergic innervation soley from the locus coeruleus, which contains GAP-43 mRNA in the adult [48]. When status epilepticus was induced in mice following treatment with pilocarpine, the level of GAP-43 was shown to decrease in the inner molecular layer of the dentate gyrus [12]. GAP-43 immunoreactivity was decreased in the inner molecular layer at 3-10 days following the induction of status epilepticus [12].…”

Section: Gap-43 Neurotransmitters and Pharma-cological Agentsmentioning

confidence: 99%

“…When status epilepticus was induced in mice following treatment with pilocarpine, the level of GAP-43 was shown to decrease in the inner molecular layer of the dentate gyrus [12]. GAP-43 immunoreactivity was decreased in the inner molecular layer at 3-10 days following the induction of status epilepticus [12]. In rats, GAP-43 has been implicated in mossy fiber sprouting, which contributes to hippocampal hyperexcitability [12].…”

Section: Gap-43 Neurotransmitters and Pharma-cological Agentsmentioning

confidence: 99%

“…GAP-43 immunoreactivity was decreased in the inner molecular layer at 3-10 days following the induction of status epilepticus [12]. In rats, GAP-43 has been implicated in mossy fiber sprouting, which contributes to hippocampal hyperexcitability [12]. Treatment of rats with amphetamine followed by a withdrawal period caused an enhancement of amphetamine-induced dopamine release [43].…”

Section: Gap-43 Neurotransmitters and Pharma-cological Agentsmentioning

confidence: 99%

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Molecular Mechanisms, Biological Actions, and Neuropharmacology of the Growth-Associated Protein GAP-43

Denny

2006

203

166

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GAP-43 is an intracellular growth-associated protein that appears to assist neuronal pathfinding and branching during development and regeneration, and may contribute to presynaptic membrane changes in the adult, leading to the phenomena of neurotransmitter release, endocytosis and synaptic vesicle recycling, long-term potentiation, spatial memory formation, and learning. GAP-43 becomes bound via palmitoylation and the presence of three basic residues to membranes of the early secretory pathway. It is then sorted onto vesicles at the late secretory pathway for fast axonal transport to the growth cone or presynaptic plasma membrane. The palmitate chains do not serve as permanent membrane anchors for GAP-43, because at steady-state most of the GAP-43 in a cell is membrane-bound but is not palmitoylated. Filopodial extension and branching take place when GAP-43 is phosphorylated at Ser-41 by protein kinase C, and this occurs following neurotrophin binding and the activation of numerous small GTPases. GAP-43 has been proposed to cluster the acidic phospholipid phosphatidylinositol 4,5-bisphosphate in plasma membrane rafts. Following GAP-43 phosphorylation, this phospholipid is released to promote local actin filament-membrane attachment. The phosphorylation also releases GAP-43 from calmodulin. The released GAP-43 may then act as a lateral stabilizer of actin filaments. N-terminal fragments of GAP-43, containing 10-20 amino acids, will activate heterotrimeric G proteins, direct GAP-43 to the membrane and lipid rafts, and cause the formation of filopodia, possibly by causing a change in membrane tension. This review will focus on new information regarding GAP-43, including its binding to membranes and its incorporation into lipid rafts, its mechanism of action, and how it affects and is affected by extracellular agents.

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Organotypic Hippocampal Slice Cultures as a Model of Limbic Epileptogenesis

Bausch

2009

Neuromethods

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Reciprocal changes of CD44 and GAP-43 expression in the dentate gyrus inner molecular layer after status epilepticus in mice

Cited by 42 publications

References 60 publications

Infiltrating monocytes promote brain inflammation and exacerbate neuronal damage after status epilepticus

Infiltrating monocytes promote brain inflammation and exacerbate neuronal damage after status epilepticus

Molecular Mechanisms, Biological Actions, and Neuropharmacology of the Growth-Associated Protein GAP-43

Organotypic Hippocampal Slice Cultures as a Model of Limbic Epileptogenesis

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