Altered A-Type Potassium Channel Function Impairs Dendritic Spike Initiation and Temporoammonic Long-Term Potentiation in Fragile X Syndrome.

Fragile X syndrome (FXS) is the leading monogenetic cause of cognitive impairment and autism spectrum disorder. Area CA1 of the hippocampus receives current information about the external world from the entorhinal cortex via the temporoammonic (TA) pathway. Given its role in learning and memory, it is surprising that little is known about TA long-term potentiation (TA-LTP) in FXS. We found that TA-LTP was impaired in male KO mice. Although there were no significant differences in basal synaptic transmission, synaptically evoked dendritic calcium signals were smaller in KO neurons. Using dendritic recording, we found no difference in complex spikes or pharmacologically isolated Ca spikes; however, the threshold for fast, Na-dependent dendritic spikes was depolarized in KO mice. Cell-attached patch-clamp recordings found no difference in Na channels between wild-type and KO CA1 dendrites. Dendritic spike threshold and TA-LTP were restored by blocking A-type K channels with either 150 µm Ba or the more specific toxin AmmTx3. The impairment of TA-LTP shown here, coupled with previously described enhanced Schaffer collateral LTP, may contribute to spatial memory alterations in FXS. Furthermore, as both of these LTP phenotypes are attributed to changes in A-type K channels in FXS, our findings provide a potential therapeutic target to treat cognitive impairments in FXS. Alterations in synaptic function and plasticity are likely contributors to learning and memory impairments in many neurologic disorders. Fragile X syndrome is marked by dysfunctional learning and memory and changes in synaptic structure and function. This study shows a lack of LTP at temporoammonic synapses in CA1 neurons associated with biophysical differences in A-type K channels in KO CA1 neurons. Our results, along with previous findings on A-type K channel effects on Schaffer collateral LTP, reveal differential effects of a single ion channelopathy on LTP at the two major excitatory pathways of CA1 pyramidal neurons. These findings expand our understanding of memory deficits in FXS and provide a potential therapeutic target for the treatment of memory dysfunction in FXS.