The hippocampus is a major brain region responsible for learning and memory. Hippocampal learning- and memory-related functions are largely performed by principal neurons—dentate gyrus granule cells (DGGCs), and cornu ammonis (CA) 3 and CA1 pyramidal cells. These principal neurons are connected by their axons, such as the mossy fibers of DGGCs, Schaffer collaterals of CA3 cells, and their intrinsic projections. The involvement of the principal neuron connections in neuro-diseases as well as normal functioning has been a subject of extensive research.

The transverse orientation of the hippocampus has been extensively studied due to its simple cell layer structure and has long been regarded as the prime circuit board of hippocampal functions. Meanwhile, the septo-temporal (longitudinal) orientation (namely the interlamellar network) began receiving attention only recently. This study reports that each principal neuron has longitudinal projections for intrinsic connections.

Previously, the longitudinal network was considered to involve CA3 cells or CA1 pyramidal neurons, while the involvement of the DGGCs network was found in epileptic models. This thesis proposes that DGGCs project longitudinally toward neighboring granule cells. The morphology of longitudinal axons of DGGCs in the entire hippocampus and longitudinal hippocampal slices was evaluated using ex vivo two-photon microscopy. It was found that longitudinally and transversely projecting axons differed morphologically in terms of their varicosities and axonal widths. Varicosity size of longitudinal axons was associated with behavioral changes in an animal model of seizure. It is believed that a longitudinal connection exists between granule cells and is correlated with epilepsy.

Synaptic plasticity in the hippocampus has also mostly been studied in the transverse plane of the hippocampus. Long-term potentiation of the longitudinal connections of DGGCs was found in longitudinal slices. In addition, chronic stress was found to impair the long-term potentiation of the longitudinal network of granule cells. This indicates that the longitudinal network of granule cells is related to stress-induced memory deficits.

The plasticity of CA3–CA1 synapses is known to be involved in hippocampal functions related to cognition. Sensory input may also be related to cognitive functions of the hippocampus, which was demonstrated using an animal model of noise-induced hearing lesions correlated with stress, which elevates the concentrations of the neuroinflammatory mediator TNF α in hippocampus. It was determined whether hearing lesions impaired CA3–CA1 synaptic plasticity, and the inhibition of TNF α synthesis could alleviate the impairment of CA3–CA1 synaptic plasticity. Based on the findings, further studies on DGGCs are needed to ascertain the effects of hearing lesions and the related neuroinflammation.

Longitudinally projecting axons of dentate granule cells may be compared with the majority input provided through the perforant path (PP) or that propagated through mossy fibers. DGGC-related synapses—PP–granule cells, granule cells–CA3, and granule cells–granule cells synapses—are supposed to be involved in various hippocampal functions and diseases. This study will provide a foundation for future research on these hippocampal functions and diseases.