Characterizing a novel peptide therapeutic with potential antidepressant-like effects

Major depressive disorder (MDD) affects millions of people worldwide. Most of the existing antidepressants target the same molecules in the brain. Because many individuals don’t respond fully to existing antidepressants, there is a need for new MDD treatments targeting novel mechanisms. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels mediate Ih, an important current for controlling neuronal excitability. Brain HCN channels are tightly regulated by a second protein, TRIP8b (tetratricopeptide repeat-containing Rab8b-interacting protein). Animals lacking either TRIP8b or HCN have increased antidepressant-like behavior, suggesting that inhibiting HCN channels could effectively treat depression. Unfortunately, directly targeting HCN channels throughout the body is not a viable therapeutic approach because these channels are critical in controlling heart rate. I reasoned that inhibiting brain-specific TRIP8b would be a safer way to target HCN channels and treat MDD. To validate this approach, I evaluated the effects of increasing or decreasing TRIP8b function using viral vectors. I found that restoring TRIP8b expression into the hippocampi of TRIP8b knockout mice promoted depression-like behaviors. In contrast, expressing a version of TRIP8b with impaired binding to HCN channel pore-forming subunits promoted antidepressant-like behavior. These results (enclosed as preliminary data) indicate that inhibiting the binding of TRIP8b to HCN channels will promote antidepressant-like behavior. In order to disrupt the interaction between TRIP8b and HCN, I next identified a small (11 amino acids) peptide capable of binding TRIP8b and interfering with the TRIP8b-HCN interaction. I then developed a cell permeable version of this peptide (SNL-CP) as a candidate antidepressant therapy. In my enclosed preliminary data, I show that intraperitoneal injection of SNL-CP successfully crosses the blood brain barrier and penetrates throughout the brain parenchyma. In aim 1, I will assess the ability of SNL-CP to disrupt the TRIP8b-HCN interaction after intraperitoneal injection in mice. These experiments will determine the dosing strategy necessary for therapeutic intervention. In aim 2, I will evaluate the ability of the SNL-CP to promote antidepressant-like behavior in mice. The work described in this proposal will evaluate a novel approach to producing antidepressant-like behaviors in mice and could pave the way for a new approach to treating MDD in human patients refractory to existing therapies.