Temporal lobe epilepsy (TLE) is a devastating disease in which aberrant synaptic plasticity plays a major role. We identify matrix metalloproteinase (MMP) 9 as a novel synaptic enzyme and a key pathogenic factor in two animal models of TLE: kainate-evoked epilepsy and pentylenetetrazole (PTZ) kindling–induced epilepsy. Notably, we show that the sensitivity to PTZ epileptogenesis is decreased in MMP-9 knockout mice but is increased in a novel line of transgenic rats overexpressing MMP-9. Immunoelectron microscopy reveals that MMP-9 associates with hippocampal dendritic spines bearing asymmetrical (excitatory) synapses, where both the MMP-9 protein levels and enzymatic activity become strongly increased upon seizures. Further, we find that MMP-9 deficiency diminishes seizure-evoked pruning of dendritic spines and decreases aberrant synaptogenesis after mossy fiber sprouting. The latter observation provides a possible mechanistic basis for the effect of MMP-9 on epileptogenesis. Our work suggests that a synaptic pool of MMP-9 is critical for the sequence of events that underlie the development of seizures in animal models of TLE.

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The umbilical cord blood-derived neural stem/progenitor cells (HUCB-NSCs) potentially represent a rich source of transplantable material for treatment of a wide range of neurological diseases. Although, recently reported effects of their implementation in animal models of brain pathology are still controversial. As a simplified alternative to in vivo transplantation in this work we have applied a long-term organotypic rat hippocampal slice culture (OHC) as a recipient tissue to study bilateral graft/host cells interactions ex vivo. This type of culture can be considered as a kind of reductionistic model of brain transplantation where direct influence of systemic immunological responses to transplanted human cells would be excluded. The transplantation material derived from a HUCB-NSC line developed and characterized in our laboratory and delivered to the slices either as a single-cell suspension or after formation of typical neurospheres in serum-free medium in vitro (N-HUCBs). Experiments were focused on space-temporal context of cell transplantation in relation to their ability to ingrown, migrate, and differentiate within the slice cytoarchitecture. We gain evidences that these responses are strictly dependent on the engraftment site and that cell movement reflects typical routes used for migratory neuroblasts in vivo. The cells implanted at the second week of slice cultivation ingrown readily and deeply into host cytoarchitecture then matured to the level never observed in our transplantation animal models in vivo. Importantly, transplanted neurospheres, in addition to yield exogenous migratory cells to the host tissue can locally inhibit astrocytosis and promote outgrow of DCX-reactive neuroblasts in the surrounding OHC tissue.

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