Peripheral lipid metabolism influences synaptic signalling to regulate cortical excitability and network plasticity associated with mental disorder phenotypes

Background

Mental disorders represent a leading cause of disability, yet advances in pharmacological treatment have been limited in recent decades. A central pathophysiological mechanism implicated across multiple psychiatric conditions is the imbalance between neuronal excitation and inhibition (E/I) [1]. However, direct pharmacological modulation of this balance often results in substantial adverse effects, limiting clinical applicability. An alternative approach involves lipid-mediated synaptic signalling. In particular, the astrocyte-dependent enzyme autotaxin (ATX) regulates the conversion of lysophosphatidylcholine (LPC) into lysophosphatidic acid (LPA) at glutamatergic synapses [2]. Elevated LPA levels, as observed in carriers of the human SNP PRG1-R345T, have been associated with intermediate phenotypes of mental disorders, including altered E/I balance [3]. Preclinical studies further suggest that these processes can be altered by peripheral metabolic alterations as well as pharmacological inhibition of ATX [4]. Thus, targeting LPC–ATX–LPA signalling may provide a novel and potentially safer strategy for restoring cortical function and alleviating psychiatric symptoms.

Methods

We conducted a randomized, counterbalanced within-subject study including 60 healthy male participants of European descent (aged 18–49 years; BMI 20–30 kg/m²). Each participant underwent either a 48-hour and 72-hour water-only fasting intervention. Fasting was employed as a physiological manipulation to induce systemic metabolic changes, particularly affecting lipid pathways. We hypothesized that fasting would (1) increase circulating LPA levels and induce behavioural phenotypes associated with mental disorders, (2) enhance cortical excitability as reflected by a reduction in the electrophysiological 1/f exponent, (3) engage astrocytic processes (elevated levels of glial fibrillary acidic protein (GFAP) and associations with diffusion-based measures of white matter integrity), and (4) demonstrate specificity for glutamatergic systems through structural changes in grey matter and their relationship to receptor density profiles.

Results

Fasting led to an increase in depressive symptomatology after 72-hours and 48-hours of fasting (both p<.0001), accompanied by elevated concentrations of LPA18:1 (48h: p=.046; 72h: p<.0001). Electrophysiological analyses revealed a significant reduction in the 1/f exponent (both p<.05), consistent with increased cortical excitability; notably, this effect correlated with LPA18:1 levels after 72 hours of fasting (p<.05). In parallel, GFAP concentrations were significantly increased (48h: p=.0012; 72h: p=.0042), indicating astrocytic activation, and were associated with reduced integrity of white matter tracts (both p<.0001). Structural neuroimaging further demonstrated widespread reductions in grey matter volume across frontal, sensorimotor, temporal, insular, and subcortical regions (both p<.0001). These volumetric changes showed a positive association with glutamatergic receptor density and a negative association with GABAA receptor density, suggesting involvement of glutamatergic neurotransmission systems.

Interpretation. This study provides the first evidence in humans that peripheral metabolic modulation via fasting influences central nervous system function through LPC–ATX–LPA signalling. The observed increase in cortical excitability, engagement of astrocytic mechanisms, and structural alterations in glutamatergic brain regions collectively result in phenotypes relevant to mental disorders. These findings bridge peripheral metabolic processes with synaptic and network-level brain function, highlighting lipid signalling as a critical mediator of brain plasticity. Importantly, the LPC–ATX–LPA axis emerges as a promising therapeutic target, offering a novel avenue for the development of ATX-directed interventions aimed at restoring E/I balance and improving clinical outcomes in mental disorders.

References

1. Harrison PJ, Weinberger DR. Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry. 2005;10(1):40-68. doi:10.1038/sj.mp.4001558
2. Tüscher O, Muthuraman M, Horstmann JP, et al. Altered cortical synaptic lipid signaling leads to intermediate phenotypes of mental disorders. Mol Psychiatry. Published online May 28, 2024. doi:10.1038/s41380-024-02598-2
3. Knierim E, Vogt J, Kintscher M, et al. Mutations in plasticity-related-gene-1 (PRG-1) protein contribute to hippocampal seizure susceptibility and modify epileptic phenotype. Cerebral Cortex. 2023;33(12):7454-7467. doi:10.1093/cercor/bhad051
4. Endle H, Horta G, Stutz B, et al. AgRP neurons control feeding behaviour at cortical synapses via peripherally derived lysophospholipids. Nat Metab. 2022;4(6):683-692. doi:10.1038/s42255-022-00589-7