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

Abstract

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 ϩ 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 I KA in the dendrites of CA1 neurons from fmr1-/y mice. Interestingly, the midpoint of activation for A-type K ϩ 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 ϩ 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.

Rescue of Synaptic Phenotypes and Spatial Memory in Young Fragile X Mice

“…It has been reported that the left hippocampus in young male adult fragile X permutation carriers exhibits reduced structural connectome (Leow et al, 2014), consistent with evidence of a range of cognitive impairment, including spatial processing (Hocking et al, 2012;Wong et al, 2012). The deficit may also involve a loss of some dendritic channels (Routh et al, 2013) but can be rescued with chronic bryostatin-1 treatment at a young age, as shown in our study and previously in adults (Sun et al, 2014). The treatment in our study began at least 1 month earlier than our previous study (Sun et al, 2014), in which the same dose was administered at an adult age (2 months of age) for a longer treatment period (13 weeks).…”

Bryostatin-1 Restores Hippocampal Synapses and Spatial Learning and Memory in Adult Fragile X Mice

“…For simplicity, illustration of WB is not shown. ***P , 0.001. is severely impaired in the fragile X mice (Padmashri et al, 2013), probably involving a loss of some dendritic channels (Routh et al, 2013), but can be rescued with bryostatin-1 treatment.…”

Altered Neuronal and Circuit Excitability in Fragile X Syndrome

“…2B) (Routh et al, 2013; Zhang et al, 2014). The abnormal excitability of dendrites has been linked to the altered expression of several ion channels, including reduction in Kv4.2 (Gross et al, 2011; Lee et al, 2011; Routh et al, 2013), BK channels (Zhang et al, 2014) and altered expression of HCN1 (h) channels (Brager et al, 2012; Zhang et al, 2014). Notably, the changes in dendritic properties caused by FMRP loss appear to be brain region specific.…”