Research Project
9907138
Project Summary Tinnitus or ?ringing in the ears? is a hearing disorder that disproportionately impacts those who are or have served in the military. There is currently no effective cure for tinnitus. Patients with tinnitus exhibit broad changes in brain activity in the auditory system and elsewhere. One of the fundamental characteristics of tinnitus is a dysregulation in the excitatory/inhibitory balance in the central auditory system (CAS) leading to neuronal hyperexcitability and synchrony. The large conductance calcium-activated potassium (BK) channel is implicated in other neuronal excitability disorders like temporal lobe epilepsy, tonic-clonic seizures and alcohol withdrawal seizures. Gated by both voltage and intracellular calcium, and expressed throughout the peripheral and central auditory system, the BK channel is able to modulate auditory neuronal signaling across a wide variety of conditions. Recently, Lobarinas et al. found that two BK channel openers, Maxipost and its enantiomer, reduced behavioral evidence of salicylate-induced tinnitus in rats. Though Maxipost was originally developed as a BK channel opener, in fact it is a more potent KCNQ channel opener. Nonetheless, these findings provided the impetus for our preliminary studies showing that BMS-191011, a more specific BK channel opener, reduces behavioral manifestations of tinnitus in two mouse models. Consistent with a mechanistic aim of counteracting hyperactivity in the CAS, our preliminary data and other?s shows that BK channel openers reduce neuronal activity in the auditory midbrain. The overall aim of the proposed studies is to test whether treatment with a class of BK channel openers, exemplified by BMS-191011, can reduce behavioral and neurophysiological manifestations of chronic tinnitus. Behavioral assays will probe whether treatment with the BK channel opener modifies responses that can be linked to CAS function. Both invasive and non-invasive neurophysiological recordings in vivo will characterize treatment effects on neural correlates of tinnitus in the CAS to 1) provide cross-methodological confirmation for the behavioral effects, 2) facilitate preclinical target validation and engagement studies, and 3) allow translation to clinically-measurable markers of tinnitus. The studies will employ a mouse model of acoustic trauma-induced tinnitus that matches the etiology of a substantial portion of the patient population. The use of mice will enable a longitudinal study design in which treatment begins ~2-3 months after acoustic trauma. Many mammals preclude long duration studies or higher usage rates, but the CBA/CaJ mouse is both affordable and now considered a reliable model of tinnitus following noise trauma. Together, the proposed preclinical studies will explore whether administration of a class of BK channel openers exemplified by BMS-191011 is a valid strategy to counteract maladaptive CAS function underlying stable tinnitus. This therapeutic approach clinically would allow a lapse in time following noise trauma before treatment onset, in line with the practical needs of at-risk members of the Armed Forces who may develop tinnitus while deployed, and the many patients who already have acoustic trauma-related tinnitus.
