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Dr. Barrionuevo is Professor in the Department of Neuroscience at the University of Pittsburgh Kenneth P. Dietrich School of Arts and Sciences. People working in this laboratory study synaptic plasticity and biophysical properties of neurons in hippocampal area CA3.
The hippocampus is a cortical structure known to play a central role in the formation and tempory storage of declarative memories. Indeed, damage to the hippocampal formation in humans and animal subjects results in deficits to form long-term episodic memories. While the mechanisms allowing the hippocampus to support the formation of such memories are still unknown, one key assumption underlying many computational models of the hippocampus is that area CA3 is capable of robust "pattern separation". Pattern separation refers to the ability of the CA3 neuronal network to represent cortical activity while minimizing overlap of cortical representations. Computer simulations indicate that pattern separation can be achieved by coordinated activation of a weak and diffuse input to convey the memory representation from the entorhinal cortex (EC), and a strong but sparse input to select the subpopulations of CA3 pyramidal cells that establish non-overlapping memory representations via their recurrent collaterals. Indeed, one unique feature of hippocampal CA3 pyramidal cells is that they receive two converging excitatory inputs from EC. One input is conveyed monosynaptically via the perforant path (PP), and is relatively weak and diffuse. The second input from EC is conveyed disynaptically via the mossy fibers (MF), the axons of dentate gyrus granule (DG) cells, and is sparse and strong. An important issue is whether the sparseness and strength of the MF synaptic input are the only features at play during pattern separation. For example, MF innervate more interneurons than pyramidal cells; thus, granule cell discharge exerts a strong inhibitory control over pyramidal cell firing, which could further "sharpen" the focus of the MF excitatory drive onto the CA3 neuronal network.
Quantitative Summary of the Excitatory Synaptic Inputs to CA3 Pyramidal Cells
The Trajectory of Biocytin Labeled Mossy Fibers in Area CA3
One long-standing hypothesis in the study of the biological mechanisms of memory storage is that the formation of new memories requires long-lasting synaptic modification. In the hippocampus, long-term potentiation (LTP) and depression (LTD) of synaptic strength has been widely studied as a possible mechanism of memory storage. LTP is a persistent increase in synaptic efficacy that can be induced by brief high frequency stimulation (HFS) of a glutamatergic input to a neuron. Generally, cortical LTP induction of AMPA receptor-mediated synaptic responses is NMDA receptor-dependent; however, at MF synapses on CA3 pyramidal cells LTP is NMDA receptor-independent and is preceded by a large posttetanic potentiation (PTP).
A substantial body of evidence indicates that MF synaptic plasticity also can be expressed at excitatory inputs to interneurons in area CA3 and dentate gyrus. Because interneurons are major regulators of principal cell output, long-term changes in the efficacy of their excitatory input will affect pattern separation, the generation of rhythmic oscillations of large populations of both principal cells, and other populations of inhibitory interneurons. The extensive heterogeneity in interneuron plasticity thus far described constitutes a major obstacle for the development of a single general principal to account for the synaptic efficacy changes in these cells.
Micrographs of CA3 Interneurons Labeled with Biocytin (left column) along with their Digital Reconstructions (right column) (for more details click here).
LTP at Mossy Fiber Synapses on Feed-forward Inhibitory Interneurons with Soma Location in the Stratum Lacunosum-Moleculare (SL-Mi) of Area CA3 is Input Specific and Expressed at Predominantly CI-AMPAR Synapses (for more details click here).
The Mechanisms of Bidirectional Plasticity at Mossy Fibers en passant Synapses on the Spineless Dendrite of L-M Interneurons (for more details click here). This form of MF LTP is dependent on postsynaptic activation of PKA and PKC.
Hippocampal Mossy Fibers Synapses on Interneurons Exhibit Multiple Forms of Long-Term Synaptic Plasticity (for more details click here).
Current Research Summary:
Current studies in the laboratory investigate: 1) the isolated AMPAR- and NMDAR-mediated excitatory unitary responses (uAMPA/uNMDA) from RC and PP inputs to CA3 pyramidal cells. The amplitude and kinetic distributions of uAMPA and uNMDA are particularly useful to constrain the corresponding local synaptic parameters in computational models of area CA3. Those local synaptic parameters on the dendrites are not directly measurable due to technical limitations; 2) the types of long term synaptic plasticity (LTP/LTD) that can be expressed at MF and RC inputs to CA3 interneurons; 3) localization of presynaptic calcium channels and metabotropic receptors in MF and RC presynaptic terminals as well as postsynaptic glutamate receptors on CA3 interneurons; and 4) to elucidate the coordination of information transfer from DG and EC to CA3 pyramidal cells. Specifically, this work seeks to understand (a) how biophysical properties of CA3 interneurons controls synaptic integration in pyramidal cells, (b) how these integrative properties are adjusted by activity and neuromodulation, (c) the oscillatory dynamics of these interneurons, and (d) performing statistical analyses to gain information regarding potential classification of interneurons based on functional characteristics.
Cosgrove, K.E., Galván, E.J., Meriney, S.D., and Barrionuevo, G. (2010). Area CA3 Interneurons Receive Two Spatially Segregated Mossy Fiber Inputs. Hippocampus 20: 1003-1004.
Anderson W., Galván E.J., Mauna J.C., Thiels E., and Barrionuevo G. (2011) Properties and Functional Implications of Ih in Hippocampal Area CA3 Interneurons. Pflügers Archiv - European Journal of Physiology 462:895-912. 10.1007/s00424-011-1025-3.
University of Pittsburgh
Department of Neuroscience
A210 Langley Hall
Pittsburgh, PA 15260
Voice: (412) 624-7330
Fax: (412) 624-9198
email: german@pitt.edu
Please visit the Department of Neuroscience home page.
These pages are maintained by German Barrionuevo.
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Last updated on
June 20, 2012