Thesis: Andrea Palomares Rodríguez

PhD supervisor: Vicente Felipo, Marta Llansola, Yaiza Mª Arenas

Title: Mechanisms by which enhanced GABAergic neurotransmission induces neuroinflammation. Sex-dependent differences in neuroinflammation, neurotransmission, and cognitive and motor function

Abstract: This doctoral thesis investigates two distinct topics.
The first of them is the modulation of neuroinflammation by GABAergic neurotransmission. While neuroinflammation is known to elevate GABAergic tone, in this work we found that overactivation of 〖»GABA» 〗_»A» receptors is sufficient to trigger pro-inflammatory activation of microglial BV2 cell cultures. We also show that blockade of 〖»GABA» 〗_»A» receptors with bicuculline in the cerebellum of hyperammonemic rats reduces neuroinflammation, reverses microglia and astrocytes activation and downregulates the inflammatory TNFα»-TNFR1-NF» κ»B-glutaminase-GAT3″ and TNFα»-TNFR1-S1PR2-CCL2-BDNF-TrkB» pathways, restoring motor coordination in hyperammonemic male rats. These findings reveal a bidirectional relationship between neuroinflammation and GABAergic neurotransmission, that modulate each other.
On the other hand, we investigate the sex-dependent differences in cognitive and motor function, neurotransmission and neuroinflammation under physiological conditions and in the effects of hyperammonemia on these parameters. This work shows that under basal conditions, female rats display reduced spatial and working memory performance compared to males, driven by lower hippocampal membrane expression of AMPA and NMDA glutamate receptor subunits, increased local neuroinflammation, and higher levels of interleukin-1 receptor antagonist (IL-1Ra). Exogenous IL-1Ra administration in males replicates this female-like receptor profile and induces cognitive impairment.
Regarding motor coordination, control females exhibit reduced motor coordination linked to higher cerebellar neuroinflammation and an altered chloride cotransporter expression ratio (reduced KCC2 and elevated NKCC1), resulting in differences in chloride gradient and GABAergic neurotransmission.
When exposed to sustained hyperammonemia, males experience marked cognitive and motor impairments due to exacerbated hippocampal and cerebellar neuroinflammation and neurotransmission disruption, whereas females require higher ammonium exposure to develop hyperammonemia and are not affected by it in their cognitive and motor performance.
Collectively, the results of this work show that 〖»GABA» 〗_»A» receptor overactivation drives neuroinflammation and that physiological sex-dependent differences in neuroinflammation and neurotransmission underly the differences observed in cognition and coordination between male and female rats and their response to hyperammonemia.