Dispersed mossy fiber synapses as a possible cause of cognitive dysfunctions in epileptiform neuropsychiatric conditions
Temporal lobe epilepsy (TLE) is the most common form of human epilepsy which is characterized by recurrent partial seizures originating from mesial structures such as hippocampus and propagating to the other limbic constituents, finally giving rise to general convulsions. Neuropsychiatric disorders frequently co-occur with epilepsy. On the other hand patients with epilepsy are more likely than others to suffer from cognitive deficits. This suggests the common etiology of these conditions with temporal lobe as the focal point in seizure generation and in regulation of cognitive performance. Nevertheless, the neurobiological mechanisms of the relationship between TLE and psychiatric dysfunctions are poorly understood. In that respect the presented project is aimed to provide data linking epileptiform mossy fiber dispersion with cognitive disabilities.
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Hippocampus is the largest structure of the mesial temporal lobe. It plays a role in the consolidation of information from short-term to long-term memory, and in spatial memory. In hippocampus, axons (mossy fibers (MFs)) of dentate gyrus (DG) granule cells innervate CA3 pyramidal neurons via presynaptic terminal expansions known as giant mossy fiber boutons. Due to high quantal content, and quantal size, as well as multiple release sites these unique terminals are among the largest and most potent in the entire brain. Postsynaptic component of these unique synapse is founded by a complex dendritic spine with multiple post-synaptic densities known as thorny excrescence. The efficacy of DG granule cells in producing suprathreshold activation of targeted CA3 pyramids and the proper spatiotemporal integration of postsynaptic outputs in CA3 cells are both strictly controlled by the number of giant buttons, their precise positioning at the site of action, and molecular specification of pre- and post-synaptic components. This regulated physiological synaptic pattern, histologically distinguished as stratum lucidum, when impaired might lead to the destabilization of tuned glutamatergic transmission between DG-CA3 cells contributing to cognitive dysfunctions.
We hypothesize that dispersion of mossy fiber boutons comprises an important factor linking TLE with cognitive impairments. The general objective of the presented project is to investigate the physiological consequence of giant mossy fiber boutons dispersion -an underrecognized phenomenon that is associated with spectrum of epileptiform neuropsychiatric dysfunctions.
