Toward a Bidirectional Glutamatergic Hypothesis in BPD: Pathway Enrichment and Directional Insights from GWAS Re-Analysis

Borderline personality disorder (BPD) produces severe problems with mood regulation, relationships and impulse control, yet its molecular basis has remained unclear because early genomic screens were too small to yield stable signals. Building on the most recent meta-analysis of genome-wide association data, with a cohort with schizophrenia and bipolar cases excluded, we re-examined the data with three complementary tools: (i) MAGMA for gene-set enrichment, (ii) linkage-disequilibrium score regression for partitioned heritability and (iii) transcriptome-wide association studies for imputed brain expression. Two a priori biological themes were tested through custom gene panels: glutamatergic synaptic plasticity and complement-mediated synaptic pruning. Across all three analytic layers, glutamate-related plasticity genes showed reproducible enrichment—1.2- to 1.5-fold increases in heritability and false-discovery-rate-adjusted p values below 0.05. Directionally, risk alleles tended to raise expression of excitatory receptor subunits (for example, GRIA1, GRIN3B) while lowering expression of scaffolding or trophic genes (for example, DLG2, NGF). In contrast, pruning panels, including a refined set with glutamatergic overlap removed, displayed no comparable signal. Taken together, the findings argue against a primary role for excessive synaptic pruning in BPD and instead point to bidirectionally disrupted NMDA/AMPA-dependent plasticity within limbic–prefrontal circuits. A model centred on malleability—rather than elimination—of synapses may account for the emotional learning deficits and interpersonal hypersensitivity that typify the disorder. This framework generates testable predictions for imaging-genetics work and suggests that therapies aimed at normalizing glutamatergic plasticity could prove beneficial.