CA3 pyramidal cells (CA3pcs) constitute a central crossroad of synaptic integration in the hippocampus, and play a key role in spatial mapping and memory storage. CA3pcs are monosynaptically excited by the entorhinal cortex, dentate granule cells, and other CA3pcs. The electrophysiological repertoire of CA3pcs includes single spiking and bursting, spanning a broad range of frequencies. Despite a general understanding of the anatomy and physiology of CA3pcs, little is known about the correspondence between a given pattern of synaptic inputs and the resulting firing output. This information, which is essential to relate hippocampal activity and function, constitutes the main goal of this project. First, we will investigate CA3pc dendrite biophysics (passive properties, channel distributions and kinetics), and the unitary synaptic inputs from each pathway. This will be achieved with voltage- and current-clamp recordings, calcium imaging, and the creation of a detailed, data-driven computational model. Next, the firing patterns of CA3pcs will be examined in response to systematic combinations of excitatory inputs. Surgically and pharmacologically isolated pathways will be stimulated extracellularly at various intensities and frequencies, while recording from individual CA3pcs. Corresponding compartmental simulations, implemented and validated against the experiments, will extensively characterize the computational properties of CA3pcs with respect to non-linear summation, pathway specificity, and coincidence detection of synaptic input. The public health relevance of this project directly relates to the mission of the NIA. Malfunction of the hippocampus is linked to devastating age-related conditions such as Alzheimer's disease. The combination of state-of-the-art experimental techniques with the ever-increasing computational power of biophysical modeling will accelerate research progress and help develop highly trained neuroscientists. In addition to the dissemination of results in conferences and peer-reviewed publications, all models will be publicly distributed through internet archives.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG025633-03
Application #
7102590
Study Section
Special Emphasis Panel (ZRG1-MDCN-C (50))
Program Officer
Wise, Bradley C
Project Start
2004-09-30
Project End
2009-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
3
Fiscal Year
2006
Total Cost
$304,316
Indirect Cost
Name
George Mason University
Department
Type
Organized Research Units
DUNS #
077817450
City
Fairfax
State
VA
Country
United States
Zip Code
22030
Berzhanskaya, Julia; Chernyy, Nick; Gluckman, Bruce J et al. (2013) Modulation of hippocampal rhythms by subthreshold electric fields and network topology. J Comput Neurosci 34:369-89
Migliore, Michele; Migliore, Rosanna (2012) Know your current I(h): interaction with a shunting current explains the puzzling effects of its pharmacological or pathological modulations. PLoS One 7:e36867
Baker, John L; Perez-Rosello, Tamara; Migliore, Michele et al. (2011) A computer model of unitary responses from associational/commissural and perforant path synapses in hippocampal CA3 pyramidal cells. J Comput Neurosci 31:137-58
Perez-Rosello, Tamara; Baker, John L; Ferrante, Michele et al. (2011) Passive and active shaping of unitary responses from associational/commissural and perforant path synapses in hippocampal CA3 pyramidal cells. J Comput Neurosci 31:159-82
Ascoli, Giorgio A; Gasparini, Sonia; Medinilla, Virginia et al. (2010) Local control of postinhibitory rebound spiking in CA1 pyramidal neuron dendrites. J Neurosci 30:6434-42
Hemond, P; Migliore, M; Ascoli, G A et al. (2009) The membrane response of hippocampal CA3b pyramidal neurons near rest: Heterogeneity of passive properties and the contribution of hyperpolarization-activated currents. Neuroscience 160:359-70
Ascoli, Giorgio A; Brown, Kerry M; Calixto, Eduardo et al. (2009) Quantitative morphometry of electrophysiologically identified CA3b interneurons reveals robust local geometry and distinct cell classes. J Comp Neurol 515:677-95
Komendantov, Alexander O; Ascoli, Giorgio A (2009) Dendritic excitability and neuronal morphology as determinants of synaptic efficacy. J Neurophysiol 101:1847-66
Ferrante, Michele; Migliore, Michele; Ascoli, Giorgio A (2009) Feed-forward inhibition as a buffer of the neuronal input-output relation. Proc Natl Acad Sci U S A 106:18004-9
Li, Xiaoshen; Ascoli, Giorgio A (2008) Effects of synaptic synchrony on the neuronal input-output relationship. Neural Comput 20:1717-31

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