Evaluation of the efficacy of a Kv3 ion channel modulator in the acute ketamine-challenge model of psychosis using pharmacological challenge functional MRI.

Poster Ref: P2-F-026 Theme: F: Nervous System Disorders Evaluation of the efficacy of a Kv3 ion channel modulator in the acute ketamine-challenge model of psychosis using pharmacological challenge functional MRI. Samaneh Maysami⁽¹⁾, Shane McKie⁽²⁾, Giuseppe Alvaro⁽³⁾, Charles Large⁽⁴⁾ and Steve Williams⁽¹⁾ ¹Centre for Imaging Science, University of Manchester, ²Neuroscience and Psychiatry Unit, University of Manchester, ³Autifony SRL, 37135, Verona Italy, ⁴Autifony Therapeutics Ltd, Imperial Incubator, Imperial College London Introduction: Schizophrenia presents with both cognitive and so cial symptoms which can progress to functional deterioration and psychosis. The pathology of schizophrenia includes dysfunction of cortical networks with contribution from parvalbumin-positive (PV+) interneurons. Recently, brain Kv3 potassium channel mRNA & protein expression was found to be significantly reduced in untreated patients (1). Kv3 channels are primarily expressed by PV+ interneurons, thus reduced expression might contribute to their dysfunction and pharmacological modulation of the channels might be a means to treat disease. Here we examine the ability of AUT9, a novel selective modulator of Kv3.1 and Kv3.2 ion channels to prevent the characteristic alterations in brain function induced by low dose ketamine in rat. Methods: We used an EPI sequence (TE/TR:15/3000ms) to acquire pharmacological-challenge fMRI (phMRI) images exploiting blood oxygenation level dependent (BOLD) contrast in a ketamine model of acute psychosis in male Sprague Dawley rats. Anaesthesia was induced with isofluorane (1.5%), maintained with α-chloralose (30-50mg/kg) and baseline scans were collected for ≥10min. Following an injection of AUT9 (60mg/kg, ip) or vehicle, animals were scanned for an additional 30min. They then received ketamine (30mg/kg, sc) and BOLD imaging was continued for 30min. All animals were monitored for vital signs (body temperature, respiratory rate, blood gasses, pH & glucose). phMRI scans were analysed using SPM8. Results: Ketamine significantly changed BOLD signal in the prefrontal and parietal cortices, striatum, hippocampus and para-hippocampal regions as described previously (2). Pre-administration of AUT9 significantly reduced the ketamine mediated BOLD changes in cortices and striatum. AUT9 did not cause changes in BOLD signal on its own when compared to vehicle. Conclusion: Using BOLD phMRI and an acute model of psychosis, we have shown that modulation of Kv3 channels might be a useful novel approach for the treatment of schizophrenia. (1)-Yanagi, M., et al. Mol Psychiatry 19, 573 (2014) (2)-Hodkinson, D.J., et al. Br J Med Med Res 2, 373 (2012).