Daniel Johnston, PhD, Principal Investigator (2010)
Darrin Brager, PhD, FRAXA Postdoctoral Fellow (2010)

FRAXA Awards:

by Darren Brager (photo) and Dan Johnston, 6/8/2011

Information processing in the brain occurs via interconnected networks of neurons that receive signals through the variety of 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.

Patients with FXS display a variety of phenotypes related to the central nervous system including impaired cognitive ability, problems with working memory, autistic behavior, and increased incidence of epilepsy. Although there has been significant investigation into the synaptic and anatomical underpinnings of FXS, the contribution of altered ion channel function to the neurological impairments associated with FXS 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 fmr1-/- mouse model of FXS. 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. It is our goal to continue to identify changes in specific voltage-gated ion channels that produce defects in dendritic integration and contribute to the cognitive impairment and/or epilepsy associated with Fragile X Syndrome.

by Darrin Brager, 4/1/2010

My main interest is in the regulation of neuronal excitability both under physiological and pathological conditions. My focus is on the cellular and molecular mechanisms of synaptic plasticity and integration in the medial temporal lobe. The structures in this area of the brain play important roles in learning and memory and in diseases of cognition.

Fragile X syndrome (FXS) is the most common form of inherited mental disability. Although the exact physiological nature of the mental impairment is unclear, many studies suggest that there are deficits at the level of individual neurons. Information processing in the brain occurs via interconnected networks of neurons that receive signals through the variety of 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.

We are especially interested in two ion channels: the A-type potassium channel and the h-channel, both of which are expressed at extremely high density in dendrites. We previously demonstrated that the function of these two channels changes in response to specific patterns of neuronal activity. Furthermore, these channels have been implicated in several neurological and psychiatric disorders. Surprisingly, little is known about the functional properties of these channels, and neuronal dendrites in general, in FXS. Our research is focused on identifying specific dendritic mechanisms that contribute to the development of the cognitive deficits associated with FXS. Deficits in metabotropic glutamate receptor (mGluR) cascades occur in FXS. Interestingly, we recently demonstrated mGluRs are also coupled to the regulation of h-channels (Ih) and that the physiological modulation and function of Ih is associated with cellular mechanisms linked to learning and memory (Brager and Johnston, 2007). This suggests that a change in mGluR function in FXS may lead to changes in both h-channels and / or Ih regulation and contribute to impaired cognitive function. In addition to impaired mental abilities, FXS patients have a higher than expected incidence of epilepsy (4% of the population worldwide vs. up to 20% for FXS). What cellular changes underlie the increase in seizure susceptibility?

We recently described a dramatic change in the dendritic expression of h-channels in a model of temporal lobe epilepsy. Taken together with our finding of mGluR control of Ih, we hypothesize that deficits in Ih expression, function or both may contribute to the cognitive impairment and/or the increased propensity for seizures in FXS patients. Changes in dendritic channels represent an interesting and potentially novel mechanism contributing to the cognitive symptoms associated with FXS. There are a large number of cellular substrates that control the expression and function of dendritic voltage-gated channels, and these represent potential new targets for therapeutic agents that could alleviate some of the debilitating effects of FXS.