Properties and interactions of the medial and the lateral perforant pathways in rat dentate gyrus

The hippocampal formation is a crucial brain structure for spatial memory and associative learning in rats. In order to understand the neurophysiological mechanisms underlying these high cognitive functions, we have to explore the synaptic properties, connections, plasticities, and interactions in the hippocampal formation. The medial and lateral perforant pathways are the major external inputs to the hippocampal formation. Thus, knowledge of the properties and interactions of the medial and lateral perforant pathway inputs to the hippocampus is the foundation for understanding the mechanism of complex cognitive functions of hippocampal formation. The medial perforant pathway originates from medial entorhinal cortex and terminates in the middle one third of the dentate gyrus molecular layer, whereas the lateral pathway originates from lateral entorhinal cortex and terminates on the outer one third of dentate molecular layer. This anatomical organization provides an easy access to activation of the functionally different medial and lateral perforant pathways. I used extracellular field potential recordings and whole-cell patch recordings in the hippocampal slice preparation to study the two perforant pathways in vitro. In particular, I have addressed the hypothesis that by studying the synaptic properties and the LTP mechanisms in the perforant pathways, we can identify the cellular mechanism of associative learning. A number of important differences in the synaptic properties of the medial and lateral pathways were identified. The synaptic responses of medial pathway depress readily during high frequency stimulation. The medial pathway is characterised by fewer presynaptic L-AP4 sensitive receptors and weak GABA$\rm\sb{B}$ inhibition. However, it possesses high capacity for long-term potentiation (LTP) which can be further facilitated by lateral pathway during co-activation. In contrast, the synaptic responses of lateral pathway are more resistant to high frequency depression. The lateral pathway is characterised by strong GABA$\rm\sb{B}$ inhibition which can be potentiated by tetanic stimulation and thereby limit the LTP capacity of this pathway. LTP induced by medial pathway stimulation involves selective enhancement of AMPA current, but not NMDA current. This observation, with the assistance of quantal analysis, suggests recruitment of "silent" synapses as one mechanism for LTP expression. Two new roles for GABA$\rm\sb{B}$ receptors have been identified. In the lateral pathway, it was found that postsynaptic GABA$\rm\sb{B}$ inhibition plays an important role in controlling LTP capacity. The heterosynaptic depression of the medial pathway by the lateral pathway is partially mediated by presynaptic GABA$\rm\sb{B}$ receptors. Co-activation of both pathways with high frequency stimulation leads to significantly larger LTP in the medial pathway than activation of this pathway alone; whereas in the lateral pathway the co-activation has no additional effect. The synaptic properties, inhibitory inputs, and interactions of the two perforant pathways suggest that the system design favours signal transmission in the medial perforant pathway. The interactions between the two pathways are organized to maximize associative LTP in the medial pathway; this may be important for types of learning and memory attributed to the hippocampal formation.