Long-term changes of spine dynamics and microglia after transient peripheral immune response triggered by LPS in vivo

Satoru Kondo,Shigeo Okabe,Shinichi Kohsaka

doi:10.1186/1756-6606-4-27

Abstract

BackgroundAn episode of peripheral immune response may create long-lasting alterations in the neural network. Recent studies indicate a glial involvement in synaptic remodeling. Therefore it is postulated that both synaptic and glial changes could occur under the peripheral inflammation.ResultsWe tested this possibility by in vivo two-photon microscopy of dendritic spines after induction of a peripheral immune response by lipopolysaccharide (LPS) treatment of mice.We observed that the spines were less stable in LPS-treated mice. The accumulation of spine changes gradually progressed and remained low over a week after LPS treatment but became significantly larger at four weeks. Over eight weeks after LPS treatment, the fraction of eliminated spines amounted to 20% of the initial population and this persistent destabilization resulted in a reduction of the total spine density.We next evaluated glial activation by LPS administration. Activation of microglia was confirmed by a persistent increase of Iba1 immunoreactivity. Morphological changes in microglia were observed two days after LPS administration and were partially recovered within one week but sustained over a long time period.ConclusionsThese results indicate long-lasting aggravating effects of a single transient peripheral immune response on both spines and microglia. The parallel persistent alterations of both spine turnover and the state of microglia in vivo suggest the presence of a pathological mechanism that sustains the enhanced remodeling of neural networks weeks after peripheral immune responses. This pathological mechanism may also underlie long-lasting cognitive dysfunctions after septic encephalopathy in human patients.

Highlights

An episode of peripheral immune response may create long-lasting alterations in the neural network
To detect spines generated and eliminated, we obtained image stacks of green fluorescence protein (GFP)-filled dendrites by two-photon microscopy at two time points separated by two days, seven days, four weeks or eight weeks (Figure 1A)
The fraction of dynamic spines was less than 5% over a period of seven days, 5% over four weeks, and still less than 10% over a period of eight weeks

Summary

Introduction

An episode of peripheral immune response may create long-lasting alterations in the neural network. Recent studies have demonstrated that patients recovered from septic conditions can have long-term cognitive impairment, including memory deficits and attention disorders [1]. Consistent with cognitive impairment in human subjects who recovered from sepsis, peripheral administration of LPS in rodents has been shown to affect cognitive functions [8]. In line with these findings, LPS has been demonstrated to impair long-term potentiation (LTP), a key cellular process in learning and memory [9,10]. How does LPS-evoked peripheral inflammation affect functions of the neural network? Direct contact of microglia with synapses may be involved in synapse stripping in pathological conditions [19]

Methods

Results

Discussion

Conclusion