I’ve talked before about the problems series resistance [i.e. the resistance formed by the tip of your electrode and the gunk in it] poses when you’re performing whole-cell voltage clamp recordings. Simply put, it limits your ability to hold the cell at the voltages you want to, because every time you pass current, some voltage forms over the series resistance and you’re amplifier can’t tell the difference between the voltage over the membrane and the voltage over your series resistor. It also limits your temporal accuracy, as it helps to set up up a low pass filter for your command potential. Thankfully, because the problem is essentially inescapable during whole-cell voltage clamp, essentially all voltage clamp amplifiers come with series resistance compensation: an electronic procedure where the amplifier estimates how much of a problem your series resistance will be, and works to minimize it. However, in order for that circuitry to work, your amplifier needs to know the whole-cell capacitance of the cell you’re recording from (Cm) and how much series resistance (Rs) you’re up against. Typically your set these values while looking at the current response to a test pulse. However, outside of a few select examples, this process of telling the amplifier what Cm and Rs is (know as “correcting for whole-cell parameters” or “capacitance compensation”) isn’t actually trivial. Let’s have a look at why this is, and how we should be doing it in real cells