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Noga Vardi, Ph.D.




Department of Neuroscience
School of Medicine
123 Anatomy/Chemistry Bldg.
Philadelphia, PA 19104-6058
(215) 898-4520
FAX (215) 898-6228

Education

1971-74 B.Sc. Hebrew University (Biology)
1975-81 Ph.D. Cornell University

Faculty Position

Research Professor, University of Pennsylvania

 

Research Interests

Perception is an incredibly abstract and complicated brain function, which enables us to see the world through the filters of the sensory systems. Sensory neurons transduce physical signals (light, sound waves, molecules in the air) into electrical signals, and these are communicated between neurons. It is the ensemble of these neurons’ activity that is interpreted as a familiar face, a pleasant music, an obnoxious smell, etc.. Neurons communicate by a variety of cellular and molecular mechanisms whose principals and details Neuroscience is seeking.

I am interested in deciphering some of these principal mechanisms, and I use the visual retina as a model system. I address questions concerning the precise connections between neurons, both at the morphological and molecular levels. By knowing which chemicals are released from a cell, and which receptors receive a particular chemical, one can figure out which information is being communicated.

The retina is used as a model system for signal processing because it has several advantages over centers in the brain. First, the input is well defined: it is the pattern of light and dark "dots" that falls on the retina. Second, the output, which is carried out of the retina by ganglion cells, has been thoroughly studied. Third, the anatomy of the retinal is well studies both on the light and electron microscopic levels. The knowledge is so detailed that the number of synapses between specific cell type is known. Finally, the questions regarding signal processing are well defined: we know that photoreceptor (through retinal circuits) transfer information to ganglion cells under a wide range of luminances, and they do it very reliably! We know that to signal reliably, the retina has to employ gain control and noise removal mechanisms. The key question is: what is the molecular basis of these principal mechanism? Figuring out the chemical architecture of the circuit will decipher this question.

The Vardi Lab

Current:

   

Anuradha Dhingra (Ph.D)
Senior Investigator

Marie Fina
Research Specialist

 

Hari S Ramakrishnan (Ph.D)
Postdoc

 

 

Sergei Nikonov (Ph.D)
Research Specialist

Shanti Tummala
Postdoc

 

Previous students and postdocs:

Tian Li Wang - Currently at John Hopkins University

Katsuko Morigiwa - Currently at Osaka Bioscience Institute

Lingli Zhang - Currently at the University of Pennsylvania

Ying Xu - Currently at Jinan University

Pyroja Sulaiman - Maternity leave

Previous staff:

Peter Auerbach (Emergency Doctor)

Yi-june Shi

Madelein Johnson

Tehila Bar-Yehuda (Entrepreneur)

 

From Left to right:

Ying Xu: Former Research Associate

Pyroja Sulaiman: Former Post doc

Marie Fina: Research Specialist

 

Schematic to illustrate information transfer in the first visual synapse. Rod photoreceptors contact a single type of second order neuron: the rod bipolar cell. Cone photoreceptors contact 10 types of second order neurons which are divided into two classes: the ON and the OFF cone bipolar cells. ON cone bipolar cells and rod bipolar cells depolarize to light, while OFF cone bipolar cells hyperpolarize to light following the same polarity of photoreceptors. This happens because glutamate has two modes of action: using the conventional AMPA/kainate receptor, it depolarizes the OFF bipolar cells; and using the metabotropic glutamate receptor mGluR6, it hyperpolarizes ON bipolar cells.

Research Techniques

Immunocytochemistry, dye injection, electron microscopy, molecular biology, physiology, recording from oocytes, and ERG.

We study:


A transgenic mouse with green flourescent ON bipolar cells

To study mGluR6 cascade in ON bipolar cells we produced a mouse that expressed EGFP under the control of mGluR6 promoter.

cone scheme

Organization of receptors in the cone synaptic complex.

 

Localization of Cl- cotransporters

Chloride cotransporters contribute greatly to maintain certain chloride concentrations in neurons. One class of these transporters (Na-K-Cl) normally accumulates chloride by using the Na+ gradient, and another class (K-Cl) extrudes chloride by using the K+ gradient. Chloride concentration is extremely important because it determines the Ecl (equilibrium potential for Chloride), and this in turn determines whether GABA (the main inhibitory transmitter in the brain) would hyperpolarize (inhibit) or depolarize (excite) the cell.

The two chloride cotranporters, NKCC and KCC2, distribute differently in the retina. Although both are present in both synaptic layers (OPL and IPL), they are generally not present in the same cell compartment. For example, in OPL, KCC is present in OFF bipolar dendrites, and NKCC is present in ON bipolar dendrites. This diferential localization enables GABA to contribute to bipolar cells' receptive field surround by hyperpolarizing the OFF cells and depolarizing the ON cells.

 

It is interesting that the two transporters can be within a single cell, in two different compartments. For example, in ON bipolar cells, the dendrites express NKCC, but the axon terminals express KCC2. In the picture on the left, we marked the rod bipolar cells (ON cells) with anti-PKC (green) and localized KCC (red). The axons of these cell is green (does not localize KCC2), but the axon terminals is orange (does localize KCC2). In the picture on the right, we marked the ON bipolar dendrites with anti-mGluR6 (green) and localize NKCC (red). All ON bipolar dendrites are yellowish, indicating that they express NKCC.


Localization and function of Go

Staining for the alpha subunit of Go - stain is localized to somas and dendrites of rod bipolar and ON cone bipolar cells.

 

 
wild type mouse stained for Go G-alpha-o knockout mouse stain for Go. Mouse that lacks the G-alpha-o subunit has no b-wave. (From Dhingra et al., 2000 J. Neuroscie, in press).  

 

 


Localization of mGluR6

Punctate staining for mGluR6 in monkey retina. Stain is localized to dendritic tips of rod and ON cone bipola cells
Electronmicrograph showing staining for mGluR6. Stain is localized to the mouth of the invaginations, in apposition to cone electron-dense membrane.

 

Monkey retina (cross section) immunostained for blue-sensitive opsin (red) and mGluR6 (green). mGluR6 is localized to dendritic tips of blue-sensitive bipolar cells..


Localization of GAD in rabbit horizontal cells

 

Rabbit retina immunoreacted for GAD65. Type A horizontal cell in the visual streak express GAD65, but those outside the visual streak do not.

 

Rabbit retina immunoreacted for GAD67. All horizontal cell terminals express this isoform.


Bibliography


Dhingra A, Fina ME, Neinstein A, Ramsey DJ, Xu y, Fishman GA,. Alexander KR, Qian H, Peachey NS,  Gregg RG, Vardi N (2011) Autoantibodies in melanoma-associated retinopathy target TRPM1 cation channels of retinal ON bipolar cells. J Neuroscie 31:3962-3967.

Borghuis BG, Tian L, Xu Y, Nikonov SS, Vardi N, Zemelman BV, Looger LL (2011) Imaging light responses of targeted neuron populations in the rodent retina. J Neurosci  31:2855-2867.

Sulaiman P, Fina M, Vardi N (2010) Ret-PCP2 localizes with PKC in a subset of primate ON bipolar cells. J Comp Neurol 518:1098-1112. PMCID 2830016

Lassová1 L, Fina M, and Vardi N. (2010) Immunocytochemical evidence that monkey rod bipolar cells use GABA. Eur. J. Neuroscience 31:685-696. NIHMSID: 183251

Xu Y, Vasuda V, Vardi N, Sterling P, Freed MA (2008) Different types of ganglion cell share a synaptic pattern. JCN 507:1871-8.

Shoshan-Barmatz V, Nahon E, Zakar M, Shmuelivich F, and Vardi N (2007) A Novel Ryanodine Receptor in Retina: Identification, Characterization and Localization. Eur J Neurosci 6:3113-25.


Zhang LL, Delpire E, and Vardi N (2007) NKCC1 does not accumulate chloride in developing retinal neurons. J. Neurophysiol. 98: 266-277.

Zhang LL, Fina ME, and Vardi N (2006) Regulation of KCC2 and NKCC during development: membrane insertion and differences between cell types. JCN 499:132-43.

Zhang LL, Pathak HR, Coulter DA, Freed MA and Vardi, N (2006). Shift of intracellular chloride concentration in ganglion and amacrine cells of developing mouse retina. J Neurophys 95:2404-16.

Gastinger M, Barber A, Vardi N and Marshak D (2006). Histamine receptors in mammalian retinas. J Comp Neurol 495:658-67.

Morgan JL, Dhingra A, Vardi N, Wong ROL (2006) Axons and dendrites originate from neuroepithelial-like processes of retinal bipolar cells. Nature Neuroscience 9:85-92.

Shoshan-Barmatz V, Orr I, Martin C and Vardi, N (2005). Novel ryanodine-binding properties in mammalian retina. Int J Biochem Cell Biol. 37:1681-95.

Norton AW, Hosier S, Terew JM, Li N, Dhingra A, Vardi N, Baehr W and Cote RH (2005). Evaluation of the 17 kDa prenyl binding protein as a regulatory protein for phototransduction in retinal photoreceptors. JBC 280:1248-56.

Kao YH, Lassová L, Bar-Yehuda T, Edwards RH, Sterling P and Vardi N (2004). Evidence that certain retinal bipolar cells use both glutamate and GABA. J Comp Neurol 478:207-218.

Shoshan-Barmatz V, Zalk R, Gincel D, Vardi N (2004) Sub-cellular localization of VDAC in cerebellum suggests function in ER-mitochondria cross-talk. BBA-bioenergetics. 1657: 105-114.

Dhingra A, Faurobert E, Sterling P, Dascal N, Vardi N (2004) Ret-RGS1 modulates the ON bipolar's mGluR6 transduction cascade. J Neurosci 24(25): 5684-93.

Singer JH, Lassová L, Vardi N, Diamond JS (2004) Coordinated multivesicular release at a ribbon synapse. Nature Neurosci 7(8): 826-833.

Venkateswar Venkataraman, Teresa Duda, Noga Vardi, Karl-Wilhelm Koch, and Rameshwar K. Sharma (2003) Calcium-modulated guanylyl cyclase (ROS-GC1) transduction machinery in the photoreceptor-bipolar synaptic region. Biochemistry. 42(19):5640-8.

Varda Shoshan-Barmatz, Dan Gincel, and Noga Vardi (2002) Retinal voltage-dependent anion channel: characterization and cellular localization. Invest Ophthalmol Vis Sci. Jul;43(7):2097-104.

Anuradha Dhingra, Meisheng Jiang, Tian-Li Wang, Arkady Lyubarsky, Tehilla Bar-Yehuda, Edward N. Pugh Jr, Peter Sterling, Lutz Birnbaumer, and Noga Vardi (2002). Light Response of Retinal ON Bipolar Cells Requires a specific splice variant of Gao. J. of Neuroscience 22: 4878-4884.

Jun Yang, Sean McBride, Don-On Daniel Mak, Noga Vardi, Krzysztof Palczewski, Françoise Haeseleer, and J. Kevin Foskett (2002) Identification of a family of calcium sensors as protein ligands of inositol trisphosphate receptor Ca2+ release channels. Proc Natl Acad Sci U S A. 2002 May 28;99(11):7711-7716.

Noga Vardi, Anuradha Dhingra, Lingli Zhang, Arkady Lyubarsky, Tian Li Wang, and Katsuko Morigiwa (2002). Neurochemical organization of the first visual synapse. Keio Journal of Medicine 51(3): 154-164.

Dhingra A., Lyubarsky A., Jiang M., Pugh, Jr., E. N., Birnbaumer L., Sterling P., and Vardi N. (2000) The Light Response of ON Bipolar Neurons Requires Gao. J. Neurosci. 20: 9053-9058.

Vardi, N., Zhang L.L., Payne J.A., and Sterling P. (2000) Evidence that different cation chloride cotransporters in retinal neurons allow opposite responses to GABA. J. of Neurosci. 20: 7657-7663.

Vardi, N., Duvoisin R., Wu, G., and Sterling P. (2000) Localization of mGluR6 to dendrites of ON bipolar cells in primate retina. J. Comp. Neurol. 423:402-412.

Wang, T.-L., Sterling, P. and Vardi, N. (1999) Localization of type I IP3 receptor in the outer segment of the mammalian cones. J. of Neurosci. 19(11): 4221-4228.

Morigiwa, K., and Vardi, N. (1999) Differential expression of inotropic glutamate receptor subunits in the outer retina. J. Comp. Neurol. 405(2): 173-184.

Vardi, N. (1998) ON bipolar dendrites in mammalian retina express Go. J. Comp. Neurol. 385:43-52.

Vardi N., Morigiwa, K., Wang, T-L., Shi, Y-J., and Sterling P. (1998) Neurochemistry of the photoreceptor synaptic complex. Vision Res. 38 (10): 1359-1369.

Johnson, M. and Vardi, N. (1998) Regional differences in GABA and GAD expression in rabbit horizontal cells. Vis. Neurosci. 15:743-753

Vardi, N. and Morigiwa K. (1997) ON cone bipolar cells in rat express the metabotropic receptor mGluR6. Visual Neuroscience, Vis. Neurosci. 14 (4): 789-794.

Jiang, H., Lyubarsky A., Vardi, N., Pugh, E.N., Chen, J., Xu, J., Simon, M.I., and Wu, D. (1996) Phospholipase §4-knockout mouse exhibits retinal phenotype. (PNAS, 93:14598-14601)

Vardi N, Smith RG (1996) The AII amacrine network: coupling can increase correlated activity. Vision Res 36:3743-3757.

Smith RG, Vardi N (1995) Simulation of the AII amacrine cell of mammalian retina: Functional consequences of electrical coupling and regenerative membrane properties. Vis Neurosci 12:851-860.

Sterling P, Smith RG, Rao R, Vardi N (1995) Functional architecture of mammalian outer retina and bipolar cells. In: Neurobiology and clinical aspects of the outer retina (Archer S, Djamgoz MBA, Vallerga S eds), pp 325-348. London UK: Chapman & Hall, Ltd.

Vardi N, Auerbach P (1995) Specific cell types in cat retina express different forms of glutamic acid decarboxylase. J Comp Neurol 351:374-384.

Vardi N, Kaufman DL, Sterling P (1994) Horizontal cells in cat and monkey retina express different isoforms of glutamic acid decarboxylase. Vis Neurosci 11:135-142.

Vardi N, Sterling P (1994) Subcellular localization of GABAA receptor on bipolar cells in macaque and human retina. Vision Res 34:1235-1246.

Vardi N, Matesic DF, Manning DR, Liebman PA, Sterling P (1993) Identification of a G-protein in depolarizing rod bipolar cells. Vis Neurosci 10:473-478.

Vardi N, Masarachia P, Sterling P (1992) Immunoreactivity to GABAA receptor in the outer plexiform layer of the cat retina. J Comp Neurol 320:394-397.

Vardi N, Masarachia P, Sterling P (1989) Structure of the starburst amacrine network and its association with alpha ganglion cells. J Comp Neurol 288:601-611.

Vardi N, Hadani I (1989) Stereopsis impairment during smooth pursuit eye tracking. Brain Behav Evol 33:99-103.

 

Daley, D.L., Vardi, N., Appingnani, B. and Camhi, J.M. (1981) Morphology of the giant interneurons and cercal nerve projection of the american cockroach. J. Comp. Neurol. 196:41-52.

Vardi, N. and Camhi, J.M. (1982) Functional recovery from lesion in the escape system of the cockroach. I. Behavioral recovery. J. Comp. Physiol. 146:291-298.

Vardi, N. and Camhi, J.M. (1982) Functional recovery from lesion in the escape system of the cockroach. II. Physiological recovery of the giant interneurons. J. Comp. Physiol. 146:299-309.

Hadani, I. and Vardi, N. (1987) Stereopsis impairment during smooth moving random dot pattern. Perception and Psychophysics: 42(2):158-165.

 

 


Family affairs:

Husband, Avi (mathematician). Three gorgeous children: Eilat Vardi-Gonen (Ph.D student; computer science), Tamar Vardi (biologist), Amir Vardi (Wharton graduate; financial analyst).

With Eilat at her wedding (1999).

 

Tamar (2004) Tamar at Cardigen Lodge, Aug. 2005  

 

At Amir's graduation (2004) Amir with my dad (2006)

 

 


The newest addition to the family:Rain Gonen (born Sept, 19, 2004)

My darling is (from left to right) 4, 6, and 10 months old

8 months old with my mom 15 months old with a random puppy 21 months old

 

 
Oct. 2007 with dady Itamar Dec. 2007 fun fun fun  

 

hordy

Rain got a brother, Jordan - born on Dec 18, 2009

 

Rain is 6 Jordy is 2 and they become good friends

 

 
  Eilat, Rain and Jordy, 2011 In LA, Apri 2011: Amir, Tamar, Eilat, Noga

 

Amir and Dorian (Engaged)

 

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