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Neuroimmunol Neuroinflammation 2019;6:15 I http://dx.doi.org/10.20517/2347-8659.2019.019 Page 13 of 24

AMPA (GluA1 and GluA2) glutamate receptors was performed in the brain structures of rats at 6 or 24 h, 3,
9, and 25 days after stress for Study I, and seven days after stress for Study II.

In Study I, the most pronounced alterations of gene expression were revealed 25 days after stress: mRNA
level of GluN2a NMDA-R subunit was upregulated in the amygdala of stressed animals compared to non-
stressed control; GluN2b expression increased in the ventral hippocampus (VH) and medial prefrontal
cortex and decreased in the dorsal hippocampus (DH) of rats exposed to vital stress in comparison with
control. Expression of GluA1 and GluA2 decreased in DH and increased in VH after stress.

In Study II, mRNA expression of GluN2a, GluN2b, and GluA2 subunits was upregulated in mPFC of non-
stressed animals injected with 25 µg/kg LPS. Levels of GluA1 subunit mRNA in DH of LPS-treated (50 µg/kg)
rats increased, with no changes in VH of non-stressed LPS-treated animals. Stress-induced changes were
more prominent in animals injected with 50 µg/kg LPS. In mPFC of stressed LPS-treated rats, when
compared with vehicle-treated control groups, the levels of GluN1, GluN2a, GluN2b, GluA1, and GluA2
mRNA, as well as GluN2a/GluN2b ratio, were increased, while, in DH, GluN2a and GluA1 subunit mRNA
levels were downregulated, and GluN2a/GluN2b ratio decreased.

Thus, early-life LPS treatment aggravates stress-induced disturbances of NMDA-R and AMPA-R subunit
expression, which may contribute to severe mental illnesses.

Supported by RFBR 17-04-02116 A.

18. The pathogenic role of complement C5a receptor, C5aR1 in motor neuron disease

1
1
1,2
1,3
John D. Lee , Vinod Kumar , Jenny N. T. Fung , Peter G. Noakes , Trent M. Woodruff 1
1 School of Biomedical Sciences, the University of Queensland, QLD, Australia
2 Centre for Clinical Research, the University of Queensland, QLD, Australia
3 Queensland Brain Institute, the University of Queensland, QLD, Australia

The complement system is upregulated in MND, with recent studies indicating that the activation product
C5a may accelerate disease progression via its receptor, C5aR1. This study examined the pathological role of
C5aR1 in SOD1 G93A mice, using SOD1 G93A mice lacking C5aR1 and by means of pharmacological inhibition
of C5aR1 using PMX205. C5aR1 deficient mice were backcrossed to SOD1 G93A mice to generate SOD1 G93A
mice lacking C5aR1. The selective and orally active C5aR1 antagonist, PMX205, was also administered
to SOD1 G93A mice via their drinking water, both pre- and post-disease onset. The effect of C5aR1 genetic
ablation and/or pharmacological inhibition using PMX205 on disease progression of SOD1 G93A mice was
determined using body weight, hind limb grip strength, survival time and molecular analysis of spinal

cord, tibialis anterior and blood. SOD1 G93A mice lacking C5aR1 and SOD1 G93A mice treated with PMX205
prior to disease onset, both had significantly improved hind-limb grip strengths, slower disease progression
and extended survival, compared with control or vehicle treated SOD1 G93A mice. These improvements in
the SOD1 G93A mice lacking C5aR1 and PMX205-treated group were associated with reductions in pro-
inflammatory monocytes/macrophages/microglia in the peripheral blood, tibialis anterior and spinal cord.
There was also a reduction in pro-inflammatory cytokines in the lumbar spinal cord. Importantly, PMX205
treatment beginning several weeks following disease onset also had an attenuating effect on disease
progression, significantly extending survival. These results confirm that C5aR1 plays a pathogenic role in