HT Automation for patch clamp based primary screen for Nav1.1 using Qube 384

The voltage-gated sodium channel, Na_V1.1, highly expressed in fast-spiking interneurons (FSIs), initiates the interneuron’s action potentials and promotes γ-oscillations. This process is critical for memory encoding and other cognitive functions. An impaired function of FSIs is associated with disorders like autism, schizophrenia, Alzheimer’s disease and others. Potentiators of Na_V1.1 can restore γ-oscillations by recovering reduced FSI function. These compounds were further shown to mitigate cognitive dysfunction in transgenic mice with decreased levels of Na_V1.1 expression in parvalbumin-positive neurons.

Na_V1.1 gating is complex, and activators of the ion channel can modulate various channel properties. Amongst many different screening techniques available, the patch clamp technique is the only one that reveals mode of action information. Recent advances of patch clamp devices have enabled the technology to be employed in large compound library screens. Qube 384 is a fully automated 384-well patch clamp device capable of testing thousands of compounds per day whilst providing true giga-ohm seal quality data. Using the Qube 384 in a drug discovery cascade enables acquisition of mode of action data simultaneous with hit detection during the primary screen, minimizing the need for many follow-up validation studies.