Temporal lobe epilepsy (TLE) is the most common epilepsy syndrome in adults. Current treatment options for TLE are inadequate, as too many patients suffer from uncontrolled seizures and from negative side effects of treatment. Endogenous cannabinoid signaling has been recognized as a major, potent regulator of presynaptic neurotransmitter release in the brain, and there has been a recent surge of interest in using exogenous cannabinoid compounds obtained from the marijuana plant for the control of intractable epilepsy. However, mechanisms underlying cannabinoid control of neuronal excitability are not well understood. Recently, we discovered a fundamentally new, functionally significant, postsynaptic mechanism by which cannabinoids control excitability in hippocampal pyramidal cells. This pathway involves the potent, cannabinoid type 1 receptor- (CB1) mediated modulation of the h-current (Ih), a key regulator of dendritic excitability generated by hyperpolarization-activated, cyclic nucleotide-gated channels (HCNs). Here we propose to test the hypothesis that that medically relevant cannabinoids exert their anti-convulsant actions in chronic TLE partly through the regulation of Ih in principal cells and interneurons throughout the cortical mantle. The hypothesis will be tested in experimental mouse models of TLE, and the assessment will be carried out with in vitro and in vivo electrophysiology, cell-type-specific nanoscale super-resolution molecular imaging in specific subcellular profiles of identified pyramidal cells and interneurons at a high throughput, and data-driven supercomputational network modeling. We anticipate that defining the functional consequences of a novel cannabinoid regulator of neuronal excitability in chronic epilepsy will lead to significant advances in the understanding of disease mechanisms in chronic epilepsy, and will aid the development of cannabis-based anti-epileptic treatment strategies.