Channelopathies and dendritic dysfunction in fragile X syndrome.
Dendritic spine abnormalities and the metabotropic glutamate receptor theory put the focus squarely on synapses and protein synthesis as the cellular locus of fragile X syndrome. Synapses however, are only partly responsible for information processing in neuronal networks. Neurotransmitter triggered excitatory postsynaptic potentials (EPSPs) are shaped and integrated by dendritic voltage-gated ion channels. These EPSPs, and in some cases the resultant dendritic spikes, are further modified by dendritic voltage-gated ion channels as they propagate to the soma. If the resultant somatic depolarization is large enough, action potential(s) will be triggered and propagate both orthodromically down the axon, where it may trigger neurotransmitter release, and antidromically back into the dendritic tree, where it can activate and modify dendritic voltage-gated and receptor activated ion channels. Several channelopathies, both soma-dendritic (L-type calcium channels, Slack potassium channels, h-channels, A-type potassium channels) and axo-somatic (BK channels and delayed rectifier potassium channels) were identified in the fmr1-/y mouse model of fragile X syndrome. Pathological function of these channels will strongly influence the excitability of individual neurons as well as overall network function. In this chapter we discuss the role of voltage-gated ion channels in neuronal processing and describe how identified channelopathies in models of fragile X syndrome may play a role in dendritic pathophysiology.
Center for Learning and Memory, University of Texas at Austin, Austin, TX 78712, United States. Electronic address: dbrager@mail.clm.utexas.edu.
Darrin H
DH
Brager
Center for Learning and Memory, University of Texas at Austin, Austin, TX 78712, United States.
Daniel
D
Johnston
D000818:Animals; D053447:Channelopathies / Q000503:physiopathology*; D003712:Dendrites / Q000502:physiology*; D005260:Female; D005600:Fragile X Syndrome / Q000503:physiopathology*; D006801:Humans; D008297:Male; D009473:Neuronal Plasticity
Dendrites; FMRP; Fmr1; Integration; Voltage-gated ion channels