Circuit integration of afferent inputs in the hippocampus and its dysfunction in temporal lobe epilepsy
Abstract
The hippocampus is necessary for learning and memory. The best-characterized sensory input to the hippocampus is the perforant path projection from entorhinal cortex to the dentate gyrus. Signals are then processed sequentially through the hippocampal CA fields before returning to the cortex. However, there is another pathway that sends information directly to the hippocampus - the temporoammonic pathway. The temporoammonic pathway impinging onto the distal dendrites of CA1 pyramidal cells is the most electrotonically distant from the soma, yet is critical in regulating CA1 place cell firing. How does local hippocampal circuitry integrate this essential, but electrotonically distant, input? In this dissertation, I have addressed this fundamental question using voltage sensitive dye imaging and whole cell dendritic recordings, demonstrating that under control conditions, feedforward inhibition maintains temporoammonic pathway segregation. Through a joint, co-dependent mechanism involving activation of NMDA receptors and presynaptic inhibition of GABAergic terminals, an expansion of temporoammonic activity to the soma was generated when Schaffer collateral activity precedes temporoammonic inputs. These afferent interactions are in turn modulated by feedback inhibition. Therefore, CA1 circuit integration of excitatory inputs endows the CA1 principal cell with the ability to function as a temporally specific "AND" gate, providing for sequence-dependent readout of distal inputs. ^ The hippocampus is extremely susceptible to seizures. In temporal lobe epilepsy (TLE), impairments of hippocampal-specific memory are especially common among patients. In animal models of epilepsy, rodents with TLE exhibit deteriorated performance in hippocampal-dependent spatial memory, suggesting impairments in hippocampal circuitry. How do seizure-induced changes in circuitry affect processing of afferent inputs? In the second portion of the dissertation, I have addressed this fundamental question in an animal model of TLE. I have demonstrated that in pilocarpine-treated rats, the disruption of feedforward inhibitory control of temporoammonic pathway results in a loss of spatial segregation and specificity of temporoammonic EPSPs to CA1 distal dendrites, with propagation of temporoammonic EPSPs to the soma. The loss of oriens/alveus interneurons leads to the inability of the CA1 circuitry to gate temporoammonic inputs. With enhanced excitability, the temporoammonic pathway is positioned to participate in the generation of seizure activity in the hippocampus. ^
Subject Area
Biology, Neuroscience|Health Sciences, Pathology
Recommended Citation
Chyze-Whee Ang,
"Circuit integration of afferent inputs in the hippocampus and its dysfunction in temporal lobe epilepsy"
(January 1, 2006).
Dissertations available from ProQuest.
Paper AAI3211030.
http://repository.upenn.edu/dissertations/AAI3211030