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

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Somatostatin (SST) is a neuropeptide regulating neuronal activity via somatostatin receptors (SSTRs).
• SST signaling dysregulation is linked to neurodevelopmental disorders like tuberous sclerosis complex (TSC).
• The exact role of SST in TSC pathogenesis is not fully understood.

Purpose of the Study:

• To investigate SST and SSTR expression and function in control and TSC cortical samples.
• To elucidate the specific roles of SSTR subtypes in GABAergic transmission.
• To explore therapeutic potential of targeting SST signaling in TSC.

Main Methods:

• Single-cell RNA sequencing (scRNA-seq) to analyze gene expression in distinct cell types.
• Electrophysiological recordings in Xenopus laevis oocytes to assess functional SST signaling.
• Pharmacological modulation of SSTR activity.

Main Results:

• SST is mainly expressed in GABAergic interneurons; SSTR1 and SSTR2 are in both GABAergic and glutamatergic neurons.
• TSC samples showed altered SSTR expression: SSTR5 upregulated in GABAergic neurons, SSTR2 in glutamatergic neurons, and SSTR3 downregulated in neurons and microglia.
• SST enhanced GABAergic currents in controls but suppressed them in TSC samples, with SSTR3 inhibition exacerbating the effect.

Conclusions:

• SST signaling is disrupted in TSC, leading to imbalanced excitatory-inhibitory activity and epileptogenesis.
• Altered SSTR expression contributes to the observed functional deficits.
• Modulating SST signaling offers a potential therapeutic strategy for TSC and related disorders.