Regeneration of neurotransmission transcriptome in a model of epileptic encephalopathy after antiinflammatory treatment

Abstract

Inflammation is an established etiopathogenesis factor of infantile spasms (IS), a therapy-resistant epileptic syndrome of infancy. We investigated the IS-associated transcriptomic alterations of neurotransmission in rat hypothalamic arcuate nucleus, how they are corrected by antiinflamatory treatments and whether there are sex differences. IS was triggered by repeated intraperitoneal administration of N-methyl-D-aspartic acid following anti-inflammatory treatment (adreno-cortico-tropic-hormone (ACTH) or PMX53) or normal saline vehicle to prenatally exposed to betamethasone young rats. We found that treatments with both ACTH and PMX53 resulted in substantial recovery of the genomic fabrics of all types of synaptic transmission altered by IS. While ACTH represents the first line of treatment for IS, the even higher efficiency of PMX53 (an antagonist of the complement C5a receptor) in restoring the normal transcriptome was not expected. In addition to the childhood epilepsy, the recovery of the neurotransmission genomic fabrics by PMX53 also gives hope for the autism spectrum disorders that share a high comorbidity with IS. Our results revealed significant sex dichotomy in both IS-associated transcriptomic alterations (males more affected) and in the efficiency of PMX53 anti-inflammatory treatment (better for males). Our data further suggest that anti-inflammatory treatments correcting alterations in the inflammatory transcriptome may become successful therapies for refractory epilepsies.

Keywords: PMX53; adreno-cortico-tropic-hormone; autism; cholinergic transmission; hypothalamus; infantile spasms; microarrays; sex differences.

Figure 1

Experimental spasms alter the cholinergic transmission genes but both adreno-cortico-tropic-hormone (ACTH) and PMX53 treatments partially restore their normal expression. In the set of experiments with treatments, the betamethasone-primed (B) rats after the first trigger of spasms (Y) were randomized into treatment groups treated either with full molecule of rat ACTH (BYA group), PMX53 (BYP group) or Saline (BYS group). (A, B) (log₂) expression levels of cholinergic genes in BYS, BYA and BYP plotted against (log₂) expression levels in non-spasm values (BNS). In these diagrams, the representative points of the unaltered genes (same expression as in BNP) are located on the diagonal. Note that expression levels in BYA (blue dots) and BYP (green) are significantly closer to those in BNS than expression levels in BYS (red) in both males (A) and females (B). (C) Average % square deviation of the expression of cholinergic genes from the BNS in male and female rats. Note that males were more affected by the spasms (larger average square deviation) but also benefit significantly more from the treatments (larger reduction of the average % square deviation).

Figure 2

Remodelling of the cholinergic transmission gene networks. In the set of experiments with treatments, the betamethasone-primed (B) rats after the first trigger of spasms (Y) were randomized into treatment groups treated either with full molecule of rat ACTH (BYA group), PMX53 (BYP group) or Saline (BYS group). (A) Part of the pathway regulated by the activation of the cholinergic receptors of the presynaptic and postsynaptic neurons. M2/4: Muscarinic metabotropic acetylcholine receptors (Chrm2/4); Gi/o: G-proteins (Gnai1/2/3, Gnao1, Gnb1/2/3/4/5, Gng10/11/12/13/3/5/7/8); VCCC: voltage-dependent calcium channels (Cacna1a/b); AC: adenylate cyclases (Adcy2/3/4/5/7/8/9). (B–E) Gene expression correlation in the SNS (the absolute control: not betamethasone-primed no spasms pups treated with saline), BNS, BYS, BYA and BYP conditions.