Geeta Sharma, Ph.D. Instructor Department of Physiology & Biophysics
	UCHSC at Fitzsimons RC-1 North Tower, P18-7118 PO Box 6511, Mail Stop 8307 Tel (303) 724-4535 Fax (303) 724-4501	E-mail: geeta.sharma@UCHSC.edu Curriculum vitae

CURRENT RESEARCH

The focus of our research is to understand the mechanisms that contribute to changes in synaptic strength and neuronal plasticity.  Current projects employ rodent hippocampus as a model system to examine two aspects of synaptic physiology:
Role of miniature currents (minis) in synaptic communication:
Our knowledge of synaptic transmission stems mainly from the study of action potential-evoked release of neurotransmitter leading to fairly large post-synaptic events. At majority of synapses, however, there is considerable activity that occurs independent of incoming action potentials. This spontaneous release of neurotransmitter is believed to be calcium independent and the corresponding postsynaptic responses (miniature excitatory or inhibitory postsynaptic currents- mEPSCs or mIPSCs or “minis”) exhibit a wide variation in amplitudes. Furthermore, the low probability and random nature of these events led to the belief that they would not convey information that is critically dependent on timing.  Therefore, the potential functional relevance of this action potential – independent release is often ignored and these events are thought to be due to inherent leaks in the system.
Can spontaneous release provide an alternate, action potential-independent pathway for synaptic communication?
We work closely with the Vijayaraghavan (Link)lab on this project. Our work suggests that at the mossy fiber-CA3 synapses, calcium flux through presynaptic neuronal nicotinic receptors leads to mobilization of store calcium by calcium induced calcium release. Release of calcium from intracellular stores can induce a large increase in glutamate release even in the absence of presynaptic action potentials. The movie shows minis in response to 20 mM nicotine. TTX was used to block action potentials.
   
One way of increasing synaptic strength and the fidelity of transmission is by the release of multiple quanta closely spaced in time.
 Is there synchronized release of multiple vesicles at the mossy fiber – CA3 pyramidal neuron synapse? If so, what are the molecular mechanisms responsible for coordinating the release of multiple quanta?
We find that activation of Cam Kinase II by store calcium can lead to synchronized release of multiple vesicles across several active zones in a single mossy fiber bouton.
The coincidence of high frequency release and synchronization of multiple quanta results in postsynaptic firing, thus providing a novel action potential-independent mechanism for signal propagation across the synapse.
Action potentials elicited in CA3 pyramidal neurons upon activation of presynaptic nicotinic receptors.

We are currently examining the differences between action potential-independent and evoked release, e.g. are both kinds of release modulated by nAChRs, do they use same or different pools of vesicles?  These studies will lead to an understanding of the physiological function of this unusual form of synaptic plasticity.
Role of Adult Neurogenesis in hippocampal function:
Dentate gyrus and the Olfactory bulb are the only two regions of the CNS that show continued addition of new neurons in the adult brain. In the adult dentate gyrus, quiescent neuronal progenitors located in the subgranular zone divide to give rise to Amplifying neural progenitors (ANPs, nestin positive). ANPs receive GABAergic inputs from the surrounding dentate interneurons. This input is excitatory due to a high chloride reversal potential. After a series of cell divisions, ANPs undergo a cascade of differentiation and maturation to form neuroblasts (doublecortin positive) and finally new granule cells that are incorporated into the hippocampal circuitry. As the cells mature there is a switch in the chloride gradient that leads to hyperpolarizing GABA responses.
A number of recent studies have suggested that neurogenesis is impaired in degenerative neurological diseases and that a deficit in production of new neurons (neurogenesis) in the hippocampus may contribute to the pathophysiology of major depressive disorders. Neurogenesis itself is a tightly regulated process involving activity-dependent coupling to calcium influx.
I am using a mouse model where progenitor cells (ANPs) are labeled with the Green Fluorescence Protein (GFP) (Link to article), and therefore easy to identify, to address the following fundamental issues:
1)   Does synaptic input from the surrounding mature neurons play a role in development of progenitor cells?  If so, what are the mechanisms of communication between mature and developing neurons?
2)   ANPs have few sodium channels and cannot fire action potentials. Is there a role for action potential – independent release of neurotransmitter in this communication?

• What effect does neurogenesis have on the overall function and plasticity of the hippocampus?
• Are the newly generated granule cells incorporated into the existing network or do they form a distinct functional unit?

Reference List

   1.   Encino’s, J. M., Vaahtokari, A. & Enikolopov, G. (2006) Proc. Natl. Acad. Sci. U. S. A 103, 8233-8238.

Selected Publications

• Sharma G., and Vijayaraghavan, S. (2003). Modulation of presynaptic store calcium induces release of glutamate and postsynaptic firing. Neuron, 38, 929-39. Preview: Robert S. Zucker (2003). Can a Synaptic Signal Arise from Noise? Neuron, 38, 845-46). Prespective: Otsu Y., and Murphy T.H. (2003). Miniature Transmitter Release: Accident of Nature or Careful Design? STKE.  www.stke.org/cgi/content/full/sigtrans;2003/211/pe54. pdf
• Rizzolli, S., Sharma, G., and Vijayaraghavan, S. (2002). Calcium rise in neurons from medial septum elicits calcium waves in surrounding glial cells. Brain Res., 957, 287-97. pdf
• Sharma, G., and Vijayaraghavan, S. (2001). Nicotinic cholinergic signaling in hippocampal astrocytes involves calcium-induced calcium release from intracellular stores. Proc. Natl. Acad. Sci., 98, 4148-4153. Accompanying Comment: Temburni MK, Jacob MH. (2001). New functions for glia in the brain. Proc. Natl. Acad. Sci., 98, 3631-3632. pdf

Latest Publications in PubMed (Sharma G)