BACKGROUND

The field of the invention relates to methods and compositions for treating neurological disorders. In particular, the field of the invention relates to gene therapy and small molecules for treating major depressive disorder by inhibiting trafficking of hyperpolarization-activated cyclic nucleotide gated (HCN) channels or subunits thereof.

Major depressive disorder (MDD) is a highly prevalent public health problem. Although there are many drugs available to treat patients with MDD, nearly all of the drugs target the same chemicals in the brain and have limited therapeutic efficacy. In order to better treat patients with MDD, we have developed a gene therapy based treatment that targets a distinct therapeutic mechanism. Our therapy could be used to treat patients who are refractory to existing antidepressants or could be used in combination with pharmaceutical therapies. In addition, the therapeutic mechanism that we have targeted with gene therapy also may be targeted with small molecule inhibitors.

SUMMARY

Disclosed are methods and compositions for treating a subject having a neurological disorder such as major depressive disorder (MDD). The methods and compositions disclosed herein may be utilized in order to inhibit trafficking of hyperpolarization-activated cyclic nucleotide gated (HCN) channels or subunits thereof. The HCN channels of the disclosed methods may comprise, for example, HCN1 subunits, HCN2 subunits, HCN3 subunits, HCN4 subunits, or a combination thereof. In the disclosed methods, trafficking of the HCN channels or subunits may result in inhibiting distal dendritic enrichment of HCN1 and HCN2 in pyramidal neurons of hippocampal area CAL

