title: Metalloproteinase inhibition prevents inhibitory synapse reorganization and seizure genesis.
abstract: The integrity and stability of interneurons in a cortical network are essential for proper network function. Loss of interneuron synaptic stability and precise organization can lead to disruptions in the excitation/inhibition balance, a characteristic of epilepsy. This study aimed to identify alterations to the GABAergic interneuron network in the piriform cortex (PC: a cortical area believed to be involved in the development of seizures) after kindling-induced seizures. Immunohistochemistry was used to mark perineuronal nets (PNNs: structures in the extracellular matrix that provide synaptic stability and restrict reorganization of inhibitory interneurons) and interneuron nerve terminals in control and kindled tissues. We found that PNNs were significantly decreased around parvalbumin-positive interneurons after the induction of experimental epilepsy. Additionally, we found layer-specific increases in GABA release sites originating from calbindin, calretinin, and parvalbumin interneurons, implying that there is a re-wiring of the interneuronal network. This increase in release sites was matched by an increase in GABAergic post-synaptic densities. We hypothesized that the breakdown of the PNN could be due to the activity of matrix metalloproteinases (MMP) and that the prevention of PNN breakdown may reduce the rewiring of interneuronal circuits and suppress seizures. To test this hypothesis we employed doxycycline, a broad spectrum MMP inhibitor, to stabilize PNNs in kindled rats. We found that doxycycline prevented PNN breakdown, re-organization of the inhibitory innervation, and seizure genesis. Our observations indicate that PNN degradation may be necessary for the development of seizures by facilitating interneuron plasticity and increased GABAergic activity.
authors.affiliation: Robarts Research Institute, University of Western Ontario, London, Ontario, Canada.
authors.forename: Emily
authors.initials: E
authors.lastname: Pollock
authors.affiliation: Robarts Research Institute, University of Western Ontario, London, Ontario, Canada.
authors.forename: Michelle
authors.initials: M
authors.lastname: Everest
authors.affiliation: Robarts Research Institute, University of Western Ontario, London, Ontario, Canada.
authors.forename: Arthur
authors.initials: A
authors.lastname: Brown
authors.affiliation: Robarts Research Institute, University of Western Ontario, London, Ontario, Canada. Electronic address: mpoulter@robarts.ca.
authors.forename: Michael O
authors.initials: MO
authors.lastname: Poulter
mesh_terms: D000818:Animals; D064032:Calbindin 2 / Q000378:metabolism; D064026:Calbindins / Q000378:metabolism; D004195:Disease Models, Animal; D004318:Doxycycline / Q000494:pharmacology; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D007395:Interneurons / Q000187:drug effects / Q000502:physiology*; D007696:Kindling, Neurologic / Q000187:drug effects / Q000502:physiology*; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D010320:Parvalbumins / Q000378:metabolism; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000188:drug therapy / Q000503:physiopathology*; D013569:Synapses / Q000187:drug effects / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: C576512:Calb2 protein, rat; D064032:Calbindin 2; D064026:Calbindins; D061965:Matrix Metalloproteinase Inhibitors; D010320:Parvalbumins; D005680:gamma-Aminobutyric Acid; D020782:Matrix Metalloproteinases; D004318:Doxycycline
keywords: Doxycycline; Epilepsy; GABA; Immunohistochemistry; Interneuron; Kindling; Matrix metalloproteinase; Perineuronal net; Piriform cortex; Seizure