Unmasking recurrent excitation generated by mossy fiber sprouting in the epileptic dentate gyrus: an emergent property of a complex system

Abstract

Seizure-induced sprouting of the mossy fiber pathway in the dentate gyrus has been observed nearly universally in experimental models of limbic epilepsy and in the epileptic human hippocampus. The observation of progressive mossy fiber sprouting induced by kindling demonstrated that even a few repeated seizures are sufficient to alter synaptic connectivity and circuit organization. As it is now recognized that seizures induce synaptic reorganization in hippocampal and cortical pathways, the implications of seizure-induced synaptic reorganization for circuit properties and function have been subjects of intense interest. Detailed anatomical characterization of the sprouted mossy fiber pathway has revealed that the overwhelming majority of sprouted synapses in the inner molecular layer of the dentate gyrus form recurrent excitatory connections, and are thus likely to contribute to recurrent excitation and potentially to enhanced susceptibility to seizures. Nevertheless, difficulties in detecting functional abnormalities in circuits reorganized by mossy fiber sprouting and the fact that some sprouted axons appear to form synapses with inhibitory interneurons have been cited as evidence that sprouting may not contribute to seizure susceptibility, but could form recurrent inhibitory circuits and be a compensatory response to prevent seizures. Quantitative analysis of the synaptic connections of the sprouted mossy fiber pathway, assessment of the functional features of sprouted circuitry using reliable physiological measures, and the perspective of complex systems analysis of neural circuits strongly support the view that the functional effects of the recurrent excitatory circuits formed by mossy fiber sprouting after seizures or injury emerge only conditionally and intermittently, as observed with spontaneous seizures in human epilepsy. The recognition that mossy fiber sprouting is induced after hippocampal injury and seizures and contributes conditionally to emergence of recurrent excitation has provided a conceptual framework for understanding how injury and seizure-induced circuit reorganization may contribute to paroxysmal network synchronization, epileptogenesis, and the consequences of repeated seizures, and thus has had a major influence on understanding of fundamental aspects of the epilepsies.