Epilepsy is a common comorbidity of mTORopathies such a Tuberous Sclerosis Complex (TSC) and mTOR hyperactivity-associated Fragile X Syndrome (FXS), both characterized by severe cognitive dysfunctions. On the other hand, medial Temporal Lobe Epilepsy (mTLE) is associated with mTOR hyperactivity within the hippocampal formation and cognitive deficits, particularly pertaining to pattern separation and episodic memory. The hippocampal dentate gyrus (DG) subregion is crucial for gating the flow and separating the patterns of cortical information inputs, transmitting them via DG granule cell mossy fiber axons (mossy fiber path) and their synaptic connections (giant boutons) to the CA3 subregion. Input randomization and plasticity of giant boutons onto the apical dendrites of CA3 pyramidal neurons are critical for episodic memory formation and consolidation. The disturbance of this physiological synaptic pattern may underly certain aspects of cognitive deficits such as pattern separation dysfunction. Dispersion of mossy fiber boutons in CA3 is an underrecognized phenomenon that seems to be associated with DG mTOR hyperactivity and a spectrum of mTLE's cognitive comorbidities, warranting further exploration in animal model studies. Using structural and functional imaging in conjunction with behavioral and electrophysiological studies, we demonstrate that mTOR hyperactivation in DG granule cells may lead to dispersion of mossy fiber boutons with severe implications for pattern separation and episodic memory formation. We hypothesize that the dispersion of mossy fiber boutons is a connectopathy associated with mTOR hyperactivity, playing a role in the development of temporal lobe seizures and deficits in DG/CA3 circuit-dependent cognitive functions.