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:
- Are Kir4.1 channels crucial for extracellular potassium buffering in the central and peripheral nervous system?
- Why mutations in Kir4.1 channel lead to neurological symptoms such as epilepsy, hearing loss and ataxia?
- 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 mice:
- single cell electrophysiological recordings of EGFP-positive neurons in whole mount retinas to characterize their functional properties during development
- 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.)
- Lines J, Martin ED, Kofuji P, Aguilar J, Araque A. Astrocytes modulate sensory-evoked neuronal network activity. Nat Commun. 2020;11(1):3689.
- Cavaccini A, Durkee C, Kofuji P, Tonini R, Araque A. Astrocyte signaling gates long-term depression at corticostriatal synapses of the direct pathway. J Neurosci. 2020 Jun 15. pii: JN-RM-2369-19.
- Kofuji P, Araque A. G-protein-coupled receptors in astrocyte-neuron communication. Neuroscience. 2020 Mar 26. pii: S0306-4522(20)30177-9.
- Torres Jimenez N, Lines JW, Kueppers RB, Kofuji P, Wei H, Rankila A, Coyle JT, Miller RF, McLoon LK. Electroretinographic abnormalities and sex differences detected with mesopic adaptation in a mouse model of schizophrenia: a and b wave analysis. nvest Ophthalmol Vis Sci. 2020 Feb 7;61(2):16.
- Corkrum M, Covelo A, Lines J, Bellocchio L, Pisansky M, Loke K, Quintana R, Rothwell PE, Lujan R, Marsicano G, Martin ED. Thomas MJ, Kofuji P, Araque A. Dopamine-evoked synaptic regulation in the nucleus accumbens requires astrocyte activity. Neuron. 2020 Mar 18;105(6):1036-1047.
- Engeland WC, Massman L, Miller L, Leng S, Pignatti E, Pantano L, Carlone DL, Kofuji P, Breault DT. Sex differences in adrenal Bmal1 deletion-induced augmentation of glucocorticoid responses to stress and ACTH in mice. Endocrinology. 2019;160(10):2215-2229.
- Corkrum M, Rothwell PE, Thomas MJ, Kofuji P, Araque A. Opioid-mediated astrocyte-neuron signaling in the nucleus accumbens. Cells. 2019 Jun 14;8(6). pii: E586.
- Kofuji P, Araque A. Swelling gliotransmission by SWELL1 channels. Neuron. 2019;102(4):711-713.
- Durkee CA, Covelo A, Lines J, Kofuji P, Aguilar J, Araque A. Gi/o protein-coupled receptors inhibit neurons but activate astrocytes and stimulate gliotransmission. Glia. 2019;67(6):1076-1093.
- Engeland WC, Massman L, Mishra S, Yoder JM, Leng S, Pignatti E, Piper ME, Carlone DL, Breault DT, Kofuji P. The adrenal clock prevents aberrant light-induced alterations in circadian glucocorticoid rhythms. Endocrinology. 2018;159(12):3950-3964.
- Kofuji P, Mure LS, Massman LJ, Purrier N, Panda S, Engeland WC. Intrinsically photosensitive retinal ganglion cells (ipRGCs) are necessary for light entrainment of peripheral clocks. PLoS One. 2016 Dec 16;11(12):e0168651.
- Biesecker KR, Srienc AI, Shimoda AM, Agarwal A, Bergles DE, Kofuji P, Newman EA. Glial cell calcium signaling mediates capillary regulation of blood flow in the retina. J Neurosci. 2016;36(36):9435-9445.
- Engeland WC, Yoder JM, Karsten CA, Kofuji P. Phase-dependent shifting of the adrenal clock by acute stress-induced ACTH. Front Endocrinol (Lausanne). 2016 Jun 29;7:81.
- 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.
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).