Hyperexcitability precedes motoneuron loss in the Smn2B/- mouse model of spinal muscular atrophy.

Spinal motoneuron dysfunction and loss are pathological hallmarks of the neuromuscular disease spinal muscular atrophy (SMA). Changes in motoneuron physiological function precede cell death, but how these alterations vary with disease severity and motoneuron maturational state is unknown. To address this question, we assessed the electrophysiology and morphology of spinal motoneurons of presymptomatic Smn2B/- mice older than 1 wk of age and tracked the timing of motor unit loss in this model using motor unit number estimation (MUNE). In contrast to other commonly used SMA mouse models, Smn2B/- mice exhibit more typical postnatal development until postnatal day (P)11 or 12 and have longer survival (~3 wk of age). We demonstrate that Smn2B/- motoneuron hyperexcitability, marked by hyperpolarization of the threshold voltage for action potential firing, was present at P9-10 and preceded the loss of motor units. Using MUNE studies, we determined that motor unit loss in this mouse model occurred 2 wk after birth. Smn2B/- motoneurons were also larger in size, which may reflect compensatory changes taking place during postnatal development. This work suggests that motoneuron hyperexcitability, marked by a reduced threshold for action potential firing, is a pathological change preceding motoneuron loss that is common to multiple models of severe SMA with different motoneuron maturational states. Our results indicate voltage-gated sodium channel activity may be altered in the disease process.NEW & NOTEWORTHY Changes in spinal motoneuron physiologic function precede cell death in spinal muscular atrophy (SMA), but how they vary with maturational state and disease severity remains unknown. This study characterized motoneuron and neuromuscular electrophysiology from the Smn2B/- model of SMA. Motoneurons were hyperexcitable at postnatal day (P)9-10, and specific electrophysiological changes in Smn2B/- motoneurons preceded functional motor unit loss at P14, as determined by motor unit number estimation studies.

Pilocarpine-induced status epilepticus increases Homer1a and changes mGluR5 expression.

Homer1a regulates expression of group I metabotropic glutamate receptors type I (mGluR1 and mGluR5) and is involved in neuronal plasticity. It has been reported that Homer1a expression is upregulated in the kindling model and hypothesized to act as an anticonvulsant. In the present work, we investigated whether pilocarpine-induced status epilepticus (SE) would alter Homer1a and mGluR5 expression in hippocampus. Adult rats were subjected to pilocarpine-model and analyzed at 2h, 8h, 24h and 7 d following SE. mRNA analysis showed the highest expression of Homer1a at 8h after SE onset, while immunohistochemistry demonstrated that Homer1a protein expression was significantly increased in hippocampus, amygdala and piriform and entorhinal cortices at 24h after SE onset when compared to control animals. The increased Homer1a expression coincided with a significant decrease of mGluR5 protein expression in amygdala and piriform and entorhinal cortices. The data suggest that during the critical periods of epileptogenesis, overexpression of Homer1a occurs to counteract hyperexcitability and thus Homer1a may be a molecular target in the treatment of epilepsy.

Basal dendrites are present in newly born dentate granule cells of young but not aged pilocarpine-treated chronic epileptic rats.

Epilepsy is known to influence hippocampal dentate granule cell (DGC) layer neurogenesis. In young adult rats, status epilepticus (SE) increases the number DGC newly borne cells and basal dendrites (BD), which persist at long-term. In contrast, little is known on whether these phenomena occur in elderly epileptic animals. In the present study, we compare DGC proliferation and the incidence of BD in young and aged pilocarpine-treated rats. Three epileptic groups were considered: Young animals given pilocarpine at 3 months of age. Aged animals treated with pilocarpine at 3 months of age that were sacrificed at 17-20 months. Aged animals that had pilocarpine and developed SE at 20 months, being sacrificed 2 months later. Nine days prior to sacrifice, animals underwent swimming sessions in the Morris water maze as a protocol for the development of hippocampal neurogenesis. We found a higher incidence of newly born DGC cells in young as compared to aged epileptic animals (P<0.001). This later group however, was not homogeneous. While a significant increase in DGC neurogenesis was observed when aged animals with long lasting epilepsy were compared to non-epileptic controls (P<0.01), this has not been recorded in aged animals that had epilepsy for only 2 months (P>0.05). When the number of DGC containing BD was considered, a significantly higher incidence was observed in young as compared to aged epileptic rats (P=0.001). Animals in this later group virtually lacked BD in newly formed dentate gyrus (DG) cells. Based on these results we conclude that plastic changes during epileptogenesis and the development of a pathological substrate in young animals is associated with DGC proliferation and the emergence of BD. As aging occurs, DGC neurogenesis can still be induced in rats with a long-term history of epilepsy but the emergence of BD is markedly reduced.