Our examination of BACHD mice has revealed that there is an increase in the discharge rate of GPe neurons at 6 months of age, but not at 3 months of age. Anatomical reconstructions revealed a decrease in dendritic branching. We have verified the robustness of the physiological phenotype in Q175 mice. Q-PCR profiling suggested that the change in discharge rate could be due to a coordinated change in the expression of ion channels controlling autonomous spiking; the most important of these appear to be a down-regulation in Cav2 Ca2+ channels and SK K+ channels. We have phenocopied the adaptation using the SK antagonist apamin and shown that in GPe neurons from BACHD mice there is a down-regulation in SK current. We will verify that we can rescue the phenotype with an SK agonist. The question now is what is driving this change. There are two possibilities: that it is cell autonomous or that it is driven by altered network activity. The simplest way in which the latter might occur is by a change in synaptic strength or function. Examination of the glutamatergic input from the STN found no change in 6 month old BACHD mice; it should be noted however that the absence of a change in these properties does not preclude the possibility that there is an alteration in the activity of STN in vivo that contributes to the adaptation. The next step is to determine whether there is a change in the striatopallidal GABAergic input that might contribute to change in pacemaking.
|Effective start/end date||4/1/18 → 3/31/23|
- CHDI Foundation, Inc. (Record ID: A-5071)
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