Loss of Functional A-Type Potassium Channels in the Dendrites of CA1 Pyramidal Neurons from a Mouse Model of Fragile X Syndrome

Despite the critical importance of voltage-gated ion channels in neurons, very little is known about their functional properties in Fragile X syndrome: the most common form of inherited cognitive impairment. Using three complementary approaches, we investigated the physiological role of A-type K+ currents (I-KA) in hippocampal CA1 pyramidal neurons from fmr1-/y mice. Direct measurement of I-KA using cell-attached patch-clamp recordings revealed that there was significantly less IKA in the dendrites of CA1 neurons from fmr1-/y mice. Interestingly, the midpoint of activation for A-type K+ channels was hyperpolarized for fmr1-/y neurons compared with wild-type, which might partially compensate for the lower current density. Because of the rapid time course for recovery from steady-state inactivation, the dendritic A-type K+ current in CA1 neurons from both wild-type and fmr1-/y mice is likely mediated by K(V)4 containing channels. The net effect of the differences in I-KA was that back-propagating action potentials had larger amplitudes producing greater calcium influx in the distal dendrites of fmr1-/y neurons. Furthermore, CA1 pyramidal neurons from fmr1-/y mice had a lower threshold for LTP induction. These data suggest that loss of I-KA in hippocampal neurons may contribute to dendritic pathophysiology in Fragile X syndrome.