Altered somatostatin receptor 3 expression and functional dysregulation in tuberous sclerosis complex

Somatostatin (SST), a neuropeptide primarily synthesized by GABAergic interneurons, modulates neuronal excitability and synaptic transmission through its interaction with somatostatin receptors (SSTRs). Dysregulation of SST signaling has been implicated in neurodevelopmental disorders, including tuberous sclerosis complex (TSC). However, its precise role in these pathologies remains incompletely understood. We investigated SST and SSTR expression across diverse brain cell types in control and TSC cortical samples using single-cell RNA sequencing (scRNA-seq). We conducted functional assessments of SST signaling using electrophysiological recordings in Xenopus laevis oocytes microtransplanted with human brain membranes. We pharmacologically modulated SST receptor activity to elucidate receptor-specific effects on GABAergic transmission. scRNA-seq analysis revealed that SST expression is predominantly confined to GABAergic interneurons, while SSTR1 and SSTR2 exhibit strong expression in both glutamatergic and GABAergic neuronal populations. In TSC samples, SSTR5 was upregulated in GABAergic neurons, SSTR2 in glutamatergic neurons, while SSTR3 was downregulated in both glutamatergic neurons and microglia. Functional experiments demonstrated that SST enhances GABAergic currents in control tissues through a receptor-mediated mechanism involving protein kinase C activation. In contrast, SST application in TSC samples resulted in a significant suppression of GABAergic currents. Pharmacological inhibition of SSTR3 further exacerbated this effect, suggesting a compensatory role for this receptor subtype. Our findings reveal a disruption of SST signaling in TSC, contributing to altered coordination of excitatory-inhibitory activity and epileptogenesis. Targeting SST signaling may represent a therapeutic strategy for restoring inhibitory network function in TSC and related disorders.