With a $95,000 grant from FRAXA Research Foundation from 2010-2011, Dr. Daniel Johnston and Dr. Darrin Brager at the University of Texas at Austin investigated alterations in ion channels in Fragile X syndrome. They explored potential therapeutic effects of drugs which open and close these channels. Results published.
Many proteins are misregulated as a result of the absence of FMRP. It is known that many ion channels, the pores in the cell membrane which allow neurons to conduct electrical impulses, have altered levels in Fragile X. This state is sometimes called a channelopathy.
Information processing in the brain occurs via interconnected networks of neurons that receive signals through synaptic contacts onto neuronal dendrites. These synaptic signals are shaped and combined in part by the numerous voltage-gated ion channels expressed in the dendrites of individual neurons.
My main interest is in the regulation of neuronal excitability, by modulation of dendritic ion channels, both under physiological and pathological conditions in the medial temporal lobe; a region of the brain that plays important roles in learning and memory and in diseases of cognition.
The contribution of altered ion channel function to the neurological impairments associated with Fragile X syndrome remains largely unexplored. One ion channel in particular, the h-channel (which mediates Ih), is expressed at high density in dendrites and has been implicated in several neurological and psychiatric disorders. We previously demonstrated that h-channels undergo bidirectional modulation in response to patterns of neuronal activity associated with cellular models of learning and memory.
During our first year of FRAXA support, we found that dendritic but not somatic Ih is elevated in hippocampal neurons from the mouse model of Fragile X syndrome. These results represent the first description of a channelopathy involving dendritic h channels associated with FXS.
Channelopathies have increasingly become the focus of numerous neurological disorders, and therapeutic agents that act on voltage-gated ion channels are an active area of drug development and discovery.
Results Published (1/1/2012)
Our results support the conclusion that dendritic h-channel dysregulation occurs in the fmr1-/- mouse model of Fragile X syndrome (FXS). We demonstrated that dendritic Ih, the current carried by h-channels, is elevated in the distal dendrites of hippocampal pyramidal neurons of the fmr1-/- mouse. These results were published in Cell Reports (Brager et al., 2012).
We are excited to continue our investigation of changes in voltage-gated ion channels in FXS. Recent evidence suggests that as many as twenty different proteins associated with voltage-gated ion channels may be affected in FXS. Furthermore, there are conflicting reports as to the nature of the change in KV4.2, the putative subunit of A-type K+ channels in hippocampus, in FXS. Electrophysiological experiments carried out during the second year of funding from FRAXA produced intriguing preliminary data to suggest that A-type potassium channels are also altered in FXS. The currents carried by these channels, IKA, as well as Ih, exert powerful control over neuronal excitability, integration, and plasticity.
Darrin Brager, PhD