A major effort in our laboratory aims to elucidate the role of inwardly rectifying potassium channels for glial cell function. Glial buffering of the extracellular potassium concentration in retina has been elegantly demonstrated using electrophysiological methods. Inwardly rectifying potassium channels in these glial cells are spatially localized to optimally perform this function. Research in our laboratory has established the essential role of Kir4.1 channel in mouse retina for the buffering of extracellular potassium concentration. More recently we have been investigating the role of accessory proteins for the modulation and subcellular localization of Kir4.1 channels in Müller cells. We have identified a potential macromolecular complex (Aquaporin-4, Kir4.1 and alpha syntrophin) that hold this cluster together. We are now expanding our research to glial cells in the brain and peripheral nervous system. Standing questions are:
1) Are Kir4.1 channels crucial for extracell!
ular potassium buffering in the central and peripheral nervous system?,
2) Why mutations in Kir4.1 channel lead to neurological symptoms such as epilepsy, hearing loss and ataxia?;
3) What are the cellular mechanisms that control Kir4.1 channel density and expression in glial cells?
Another research program in our lab is to elucidate the structure and function of intrinsically photosensitive ganglion cells in the mammalian retina. In mammals, photic information is exclusively processed by the retina and reaches the brain through the optic nerve. The eyes are equipped with at least two functionally and anatomically distinct light-detecting streams, the classic image-forming stream involving rods and cones and the non-image forming stream. The non–image-forming photoreceptive stream entrains the circadian timing system and regulates pineal melatonin secretion and pupillary constriction. A small subpopulation of ganglion cells in the mammalian retina expresses the opsin-family photopigment melanopsin (Opn4). These ganglion cells are intrinsically photosensitive (ipRGC) and play a crucial role in “non-image forming” visual responses.
Because melanopsin-containing ganglion cells are few in number and scattered throughout the retina, they are difficult to study. To address these limitations, we engineered a mouse line in which the Enhanced Green Fluorescent Protein (EGFP) is expressed under the control of the mouse melanopsin promoter employing BAC (bacterial artificial
chromosome) transgenesis. We are performing two types of studies in these
(1) single cell electrophysiological recordings of EGFP-positive neurons in whole mount retinas to characterize their functional properties during development,
(2) electrophysiological recordings of acutely isolated EGFP-positive neurons to characterize their intrinsic properties.
(For a comprehensive list of recent publications, refer to PubMed, a service provided by the National Library of Medicine.)
Purrier N, Engeland WC, Kofuji P. Mice deficient of glutamatergic signaling from intrinsically photosensitive retinal ganglion cells exhibit abnormal circadian photoentrainment. PLoS One. 2014 Oct 30;9(10):e111449.
Chew KS, Schmidt TM, Rupp AC, Kofuji P, Trimarchi JM. Loss of gq/11 genes does not abolish melanopsin phototransduction. PLoS One. 2014 May 28;9(5):e98356.
Schmidt TM, Alam NM, Chen S, Kofuji P, Li W, Prusky GT, Hattar S. A role for melanopsin in alpha retinal ganglion cells and contrast detection. Neuron. 2014 May 21;82(4):781-8.
Sand A, Schmidt TM, Kofuji P. Diverse types of ganglion cell photoreceptors in the mammalian retina. Prog Retin Eye Res. 2012 Jul;31(4):287-302.
Schmidt TM, Kofuji P. Structure and function of bistratified intrinsically photosensitive retinal ganglion cells in the mouse. J Comp Neurol. 2011 Jun 1;519(8):1492-504. doi: 10.1002/cne.22579.
Schmidt TM, Kofuji P. An isolated retinal preparation to record light response from genetically labeled retinal ganglion cells. J Vis Exp. 2011 Jan 26;(47). pii: 2367. doi: 10.3791/2367.
Perez-Leighton CE, Schmidt TM, Abramowitz J, Birnbaumer L, Kofuji P. Intrinsic phototransduction persists in melanopsin-expressing ganglion cells lacking diacylglycerol-sensitive TRPC subunits. Eur J Neurosci. 2011 Mar;33(5):856-67. doi: 10.1111/j.1460-9568.2010.07583.x. Epub 2011 Jan 24.
Schmidt TM, Kofuji P. Differential cone pathway influence on intrinsically photosensitive retinal ganglion cell subtypes. J Neurosci. 2010 Dec 1;30(48):16262-71.
Tang X, Hang D, Sand A, Kofuji P. Variable loss of Kir4.1 channel function in SeSAME syndrome mutations. Biochem Biophys Res Commun. 2010 Sep 3;399(4):537-41. Epub 2010 Aug 3.
Clark, JP, and Kofuji P. The Stoichiometry of N-Methyl-D-Aspartate within the suprachiasmatic nucleus. J Neurophysiol. 103: 3448-3468, 2010.
Tang X, Schmidt TM, Perez-Leighton CE, Kofuji P. Inwardly rectifying potassium channel Kir4.1 is responsible for the native inward potassium conductance of satellite glial cells in sensory ganglia. Neuroscience 166: 397-407, 2010.
Tang X, Taniguchi K, and Kofuji, P. Heterogeneity of Kir4.1 channel expression in glia revealed by mouse transgenesis. Glia 57: 1706-1715, 2009.
Schmidt TM, and Kofuji, P. Functional and morphological differences among intrinsically photosensitive retinal ganglion cells. J Neuroscience. 29: 476-482, 2009
Schmidt TM, Taniguchi K and Kofuji, P. Intrinsic and extrinsic light responses in melanopsin-expressing ganglion cells during mouse development. J Neurophysiol. 100: 371-384, 2008.
Schmidt TM and Kofuji, P. Novel insights into non-image forming visual processing in the retina. Cell Science Reviews 5:77-83, 2008.
Metea,M., Kofuji, P., and Newman,E.A. Neurovascular coupling is not mediated by potassium siphoning from glial Cells. J Neurosc.: 2468-2471, 2007.
Ma,H., Lesne,S., Kotilinek,L., Steidl-Nichols,J.V., Sherman,M., Younkin,L., Younkin,S., Forster,C., Sergeant,N., Delacourte,A., Vassar,R., Citron,M., Kofuji, P., Boland,L.M., Ashe,K.H. Involvement of beta-site APP cleaving enzyme 1 (BACE1) in amyloid precursor protein-mediated enhancement of memory and activity-dependent synaptic plasticity. Proc Natl Acad Sci USA. 104:8167-872, 2007.
Former Graduate Students:
John Patrick (JP) Clark (Ph.D. 2004, Neuroscience, University of Minnesota).
Nathan Connors (Ph.D. 2004, Neuroscience, University of Minnesota).
Carol Ma (Ph.D. 2006, Neuroscience, University of Minnesota).
Tiffany Schmidt (Ph.D. 2010, Neuroscience, University of Minnesota).