2026 ECNP Congress

PS03-3100

Investigating the role of diacylglycerol kinase eta in bipolar disorder and lithium response

Deniz Güçsavaş — Z. Schickardt, S. Kittel-Schneider, R. McNeill · Universitätsklinikum Würzburg, Klinik und Poliklinik für Psychiatrie- Psychosomatik und Psychotherapie, Würzburg, Germany

2026 ECNP Congress

Introduction

Bipolar disorder (BD) is a highly heritable neuropsychiatric condition marked by episodes of mania and depression. Although lithium remains the frontline treatment, its response rate is limited. DGKH, a well-replicated BD risk gene encoding diacylglycerol kinase eta (DGKη), is highly expressed in the brain, particularly in mood-regulating regions such as the prefrontal cortex and hippocampus, and has been associated with lithium responsiveness, yet its molecular role remains poorly understood [1, 2]. DGKη modulates signalling pathways involved in mood regulation and circadian rhythms, which are systems disrupted in BD and overlap with lithium’s targets; lithium has been shown to rescue phenotypes in DGKη-deficient models, but the precise molecular relationship remains unclear [3, 4]. A risk haplotype of three SNPs (rs994856/rs9525580/rs9525584, GAT) has been identified and linked to BD [5].

Methods

To investigate DGKη-associated cellular mechanisms, we are generating human induced pluripotent stem cell (hiPSC)-derived cortical neurons from healthy controls and BD patients differing in their DGKHGAT risk haplotype and lithium response. The generated hiPSC lines are quality controlled to confirm pluripotency factor expression and differentiation capacity, and the derived NPC and cortical neuron models are characterised using RT-PCR and immunofluorescence to verify stage-specific marker expression and successful differentiation. Using this hiPSC-derived model, we aim to evaluate the cellular phenotypes associated with the DGKHrisk haplotype by quantifying DGKη protein expression and diacylglycerol kinase activity using functional biochemical assays. The downstream consequences of altered DGKη signalling are examined by assessing neuronal excitability and calcium signalling via calcium imaging and whole-cell patch-clamp recordings. We further assess whether the lithium treatment rescues or differentially modulates these phenotypes in line with the clinical response profiles of the patients. Single-cell RNA sequencing is planned to characterise genotype and treatment-associated transcriptional changes, on a subset of cell lines.

Results

Preliminary findings showed increased DGKη protein expression in hiPSCs derived from GAT haplotype carriers compared to wildtype controls. Upon treatment with lithium chloride, the expression was decreased compared to untreated controls. Diacylglycerol kinase activity was decreased in hiPSCs derived from GAT haplotype carrier BD patients relative to both healthy controls and BD non-carriers. Subsequent lithium treatment was shown to increase kinase activity in a time-dependent manner. Additional experiments confirmed successful reprogramming of new hiPSC lines, including validated pluripotency and trilineage differentiation capacity; generation of functional cortical neurons was also achieved, with detectable DGKHexpression. Ongoing work focuses on expanding these cell models, and identifying DGKHhaplotype-dependent alterations in signalling pathways and neuronal excitability, as well as their modulation by lithium treatment.

Conclusions

Preliminary results support a role for DGKη in BD aetiology and lithium response and ongoing experiments aim to identify DGKH-dependent alterations in signalling pathways and neuronal excitability, as well as their modulation by lithium treatment. This hiPSC-based approach enables mechanistic investigation of DGKHfunction in human cortical neurons and may provide insights into the molecular basis of variable lithium response in BD, supporting the development of more targeted therapeutic strategies.

References

  1. H. Weber, S. Kittel-Schneider, A. Gessner, K. Domschke, M. Neuner, C.P. Jacob, et al., Cross-disorder analysis of bipolar risk genes: Further evidence of DGKH as a risk gene for bipolar disorder, but also unipolar depression and adult ADHD, Neuropsychopharmacol. 36 (2011) 2076–2085. doi:10.1038/npp.2011.98.
  2. L. Weißflog, N. Becker, N. Bossert, F. Freudenberg, S. Kittel-Schneider, A. Reif, Expressional profile of the diacylglycerol kinase ETA gene DGKH, Eur Arch Psychiatry Clin Neurosci. 267 (2016) 445–454. doi:10.1007/s00406-016-0695-4.
  3. H.C. Whalley, M. Papmeyer, L. Romaniuk, E.C. Johnstone, J. Hall, S.M. Lawrie, et al., Effect of variation in diacylglycerol kinase ETA (DGKH) gene on brain function in a cohort at familial risk of bipolar disorder, Neuropsychopharmacol. 37 (2011) 919–928. doi:10.1038/npp.2011.272.
  4. T. Isozaki, S. Komenoi, Q. Lu, T. Usuki, S. Tomokata, D. Matsutomo, et al., Deficiency of diacylglycerol kinase η induces lithium‐sensitive mania‐like behavior, J Neurochem. 138 (2016) 448–456. doi:10.1111/jnc.13661.
  5. S. Kittel-Schneider, C. Lorenz, J. Auer, L. Weißflog, A. Reif, DGKH genetic risk variant influences gene expression in bipolar affective disorder, J Affect Disord. 198 (2016) 148–157. doi:10.1016/j.jad.2016.03.041.