Modification of microglia function protects from lesion‐induced neuronal alterations and promotes sprouting in the hippocampus

230

202

Microglia are the resident macrophage population of the CNS and are considered its major immunocompetent elements. They are activated by any type of brain pathology and can migrate to the lesion site. The chemokine CXCL10 is expressed in neurons in response to brain injury and is a signaling candidate for activating microglia and directing them to the lesion site. We recently identified CXCR3, the corresponding receptor for CXCL10, in microglia and demonstrated that this receptor system controls microglial migration. We have now tested the impact of CXCR3 signaling on cellular responses after entorhinal cortex lesion. In wild-type mice, microglia migrate within the first 3 d after lesion into the zone of axonal degeneration, where 8 d after lesion denervated dendrites of interneurons are subsequently lost. In contrast, the recruitment of microglia was impaired in CXCR3 knock-out mice, and, strikingly, denervated distal dendrites were maintained in zones of axonal degeneration. No differences between wild-type and knock-out mice were observed after facial nerve axotomy, as a lesion model for assessing microglial proliferation. This shows that CXCR3 signaling is crucial in microglia recruitment but not proliferation, and this recruitment is an essential element for neuronal reorganization.

Section: Discussionmentioning

confidence: 92%

CXCR3-Dependent Microglial Recruitment Is Essential for Dendrite Loss after Brain Lesion

Rappert¹,

Bechmann²,

Pivneva³

et al. 2004

230

202

“…Intracellular recordings often showed a depolarizing inhibitory postsynaptic potential (with a reversal potential of ϳ60 mV) that was synchronized with the extracellular paroxysmal event. Extracellular recordings further suggest that inhibitory transmission participates in the paroxysmal events, because these were reduced in amplitude and duration and, when spontaneous, the frequency of appearance was reduced at low concen- Eyupoglu et al, 2003). g, h, A prominent increase in the number of GFAP-stained astrocytes is seen in an albumin-treated cortex compared with the nontreated contralateral cortex.…”

Section: Discussionmentioning

confidence: 99%

Lasting Blood-Brain Barrier Disruption Induces Epileptic Focus in the Rat Somatosensory Cortex

Seiffert¹,

Dreier²,

Ivens³

et al. 2004

458

395

Perturbations in the integrity of the blood-brain barrier have been reported in both humans and animals under numerous pathological conditions. Although the blood-brain barrier prevents the penetration of many blood constituents into the brain extracellular space, the effect of such perturbations on the brain function and their roles in the pathogenesis of cortical diseases are unknown.In this study we established a model for focal disruption of the blood-brain barrier in the rat cortex by direct application of bile salts. Exposure of the cerebral cortex in vivo to bile salts resulted in long-lasting extravasation of serum albumin to the brain extracellular space and was associated with a prominent activation of astrocytes with no inflammatory response or marked cell loss. Using electrophysiological recordings in brain slices we found that a focus of epileptiform discharges developed within 4 -7 d after treatment and could be recorded up to 49 d postoperatively in Ͼ60% of slices from treated animals but only rarely (10%) in sham-operated controls. Epileptiform activity involved both glutamatergic and GABAergic neurotransmission. Epileptiform activity was also induced by direct cortical application of native serum, denatured serum, or albumin-containing solution. In contrast, perfusion with serum-adapted electrolyte solution did not induce abnormal activity, thereby suggesting that the exposure of the serum-devoid brain environment to serum proteins underlies epileptogenesis in the blood-brain barrier-disrupted cortex. Although many neuropathologies entail a compromised bloodbrain barrier, this is the first direct evidence that it may have a role in the pathogenesis of focal cortical epilepsy, a common neurological disease.

“…Lesion-induced dendrite retraction can result from activated microglia (Eyupoglu et al, 2003;Rappert et al, 2004) or excitotoxic "injury potentials." However, previous electron micrographic studies of NL neurons deafferented in vivo do not support such a role for glia (Deitch and Rubel, 1989), and time-lapse imaging of deafferented NL neurons did not reveal the dendritic "blebbing" that often occurs in response to an excitotoxic insult (Bindokas and Miller, 1995).…”

Section: Is Afferent Input Necessary For Maintaining Nl Dendrites In mentioning

confidence: 99%

The Level and Integrity of Synaptic Input Regulates Dendrite Structure

Sorensen

Rubel

2006

How localized synaptic input regulates dendritic branch structure is not well understood. For these experiments, we used single-cell electroporation, live cell imaging, in vitro deafferentation, pharmacology, and electrophysiological stimulation to study how local alterations in synaptic input affect dendritic branch structure in nucleus laminaris (NL). We found that interrupting or modulating synaptic input to distinct sets of NL dendrites can regulate their structure on a very short timescale. Specifically, eliminating synaptic input by deafferenting only one set of the bitufted NL dendrites caused a selective reduction in the total dendritic branch length of the deafferented dendrites but relatively few changes in the normally innervated dendrites on the same cell. An analysis of individual dendritic branch changes demonstrated that both control and deafferented NL dendrites exhibit branch extension and retraction. However, the presence of intact synaptic inputs balanced these changes, maintaining the total dendritic branch length of control dendrites. When glutamate receptor signaling was blocked (DNQX and AP-5), NL neurons exhibited significant dendrite retraction, demonstrating that NL dendrite maintenance depends in part on presynaptic glutamatergic input. Electrophysiological experiments further confirmed that modulating the level of synaptic input regulates NL dendrite structure. Differential stimulation of the two sets of dendrites resulted in a selective reduction in the total dendritic branch length of the unstimulated dendrites and a selective increase in the total dendritic branch length of the stimulated dorsal dendrites. These results suggest that balanced activation of the two sets of NL dendrites is required to maintain the relative amount of dendritic surface area allotted to each input.