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  1. In the pilocarpine model of temporal lobe epilepsy (TLE) in rodents, systemic injections of pilocarpine induce continuous, prolonged limbic seizures, a condition termed “Status Epilepticus” (SE). With appropriate doses, many inbred strains of mice show behavioral seizures within an hour after pilocarpine is injected. With the behavioral scoring system based on a modification of the original Racine scale, one can monitor the seizures behaviorally, as they develop into more prolonged seizures and SE. SE is typically associated with damage to subsets of hippocampal neurons and other structural changes in the hippocampus and generally subsides on its own. However, more precisemore »control of the duration of SE is commonly achieved by injecting a benzodiazepine into the mouse 1 to 3 h after the onset of SE to suppress the seizures. Several days following pilocarpine-induced SE, electrographic and behavioral seizures begin to occur spontaneously. The goal of this protocol is to reliably generate mice that develop spontaneous recurrent seizures (SRS) and show the typical neuropathological changes in the brain characteristic of severe human mesial temporal lobe epilepsy (mTLE), without high mortality. To reduce mortality, multiple subthreshold injections of pilocarpine are administered, which increases the percentage of mice developing SE without concomitant mortality. Precise control of the duration of SE (1 or 3 h) is achieved by suppressing SE with the benzodiazepine Midazolam (Versed). We have found that this protocol is an efficient means for generating mice that subsequently develop characteristics of human mTLE including high-frequency interictal spike and wave activity and SRS. In addition, we and others have shown that this protocol produces mice that show excitotoxic cell death of subsets of hippocampal GABAergic interneurons, particularly in the dentate gyrus and compensatory sprouting of excitatory projections from dentate granule cells (mossy fiber sprouting). Aspects of this protocol have been described in several of our previous publications.« less
  2. The cell adhesion molecule neuroligin2 (NLGN2) regulates GABAergic synapse development, but its role inneural circuit function in the adult hippocampus is unclear. We investigated GABAergic synapses and hippo-campus-dependent behaviors following viral-vector-mediated overexpression of NLGN2. Transducing hippo-campal neurons with AAV-NLGN2 increased neuronal expression of NLGN2 and membrane localization ofGABAergic postsynaptic proteins gephyrin and GABAARγ2, and presynaptic vesicular GABA transporter protein(VGAT) suggesting trans-synaptic enhancement of GABAergic synapses. In contrast, glutamatergic postsynapticdensity protein-95 (PSD-95) and presynaptic vesicular glutamate transporter (VGLUT) protein were unaltered.Moreover, AAV-NLGN2 significantly increased parvalbumin immunoreactive (PV+) synaptic boutons co-loca-lized with postsynaptic gephyrin+puncta. Furthermore, these changes were demonstrated to lead tomore »cognitiveimpairments as shown in a battery of hippocampal-dependent mnemonic tasks and social behaviors.« less
  3. GABAergic interneuron dysfunction has been implicated in temporal lobe epilepsy (TLE), autism, and schizophrenia. Inhibitory interneuron progenitors transplanted into the hippocampus of rodents with TLE provide varying degrees of seizure suppression. We investigated whether human embryonic stem cell (hESC)-derived interneuron progenitors (hESNPs) could differentiate, correct hippocampal-dependent spatial memory deficits, and suppress seizures in a pilocarpine-induced TLE mouse model. We found that transplanted ventralized hESNPs differentiated into mature GABAergic interneurons and became electrophysiologically active with mature firing patterns. Some mice developed hESNP-derived tumor-like NSC clusters. Mice with transplants showed significant improvement in the Morris water maze test, but transplants did notmore »suppress seizures. The limited effects of the human GABAergic interneuron progenitor grafts may be due to cell type heterogeneity within the transplants.« less