THE ROLE OF THE TRANSCRIPTION COACTIVATOR CRTC1 IN NEUROINFLAMMATION AND DEPRESSION

There is a well-established bidirectional relationship between obesity and major depressive disorder (MDD), with both conditions linked to heightened neuroinflammation. CREB-regulated transcription coactivator 1 (CRTC1) is a key transcriptional regulator in the brain, controlling genes involved in neuronal survival, synaptic plasticity, and long-term potentiation. Reduced CRTC1 expression has previously been associated with increased neuroinflammation; however, the underlying molecular mechanisms remain unclear. Our research utilizes a Crtc1 knockout (KO) mouse model, which exhibits increased aggressiveness, depressive-like behaviour, and obesity in males. We hypothesized that loss of CRTC1 in mice results in elevated neuroinflammatory responses against immune challenges, due to an overactive immune system, which contributes to their mood and metabolic phenotypes.

To test this hypothesis, we employed complementary in vitro and in vivo approaches. Primary astrocytes and microglia obtained from wild-type (WT) and Crtc1 KO mice were exposed to lipopolysaccharide (LPS) and interferon-gamma (IFNγ). KO astrocytes showed an amplified inflammatory response in monocultures, an effect that was attenuated in mixed glial cultures. In vivo, acute and subchronic LPS administrations induced prolonged and exacerbated sickness behaviour in Crtc1 KO mice alongside elevated pro-inflammatory cytokine levels in the hippocampus and blood. Moreover, KO mice displayed sustained upregulation of several inflammation-related genes in the brain following LPS exposure.

Our results suggest that the exaggerated sickness behaviour is likely driven by complex interactions among microglia, astrocytes, and neurons that exhibit prolonged pro-inflammatory activity in the absence of CRTC1. Ultimately, this research aims to clarify CRTC1’s contribution to emotional regulation, neuroinflammation, and metabolic homeostasis.