Transgenic mice with enhanced neuronal major histocompatibility complex class I expression recover locomotor function better after spinal cord injury.

Mice that are deficient in classical major histocompatibility complex class I (MHCI) have abnormalities in synaptic plasticity and neurodevelopment and have more extensive loss of synapses and reduced axon regeneration after sciatic nerve transection, suggesting that MHCI participates in maintaining synapses and axon regeneration. Little is known about the biological consequences of up-regulating MHCI's expression on neurons. To understand MHCI's neurobiological activity better, and in particular its role in neurorepair after injury, we have studied neurorepair in a transgenic mouse model in which classical MHCI expression is up-regulated only on neurons. Using a well-established spinal cord injury (SCI) model, we observed that transgenic mice with elevated neuronal MHCI expression had significantly better recovery of locomotor abilities after SCI than wild-type mice. Although previous studies have implicated inflammation as both deleterious and beneficial for recovery after SCI, our results point directly to enhanced neuronal MHCI expression as a beneficial factor for promoting recovery of locomotor function after SCI.

Changes in GABA(A) receptor subunit gamma 2 in extensor and flexor motoneurons and astrocytes after spinal cord transection and motor training.

GABA signaling plays an important role in the spinal cord response to injury and subsequent motor training. Since benzodiazepines are commonly used to treat muscle spasticity in spinal cord injured subjects and the gamma2 subunit of the GABA(A) receptor is necessary for benzodiazepine binding, this subunit may be an important factor modulating sensorimotor function after an injury. Changes in gamma2 levels in muscle-specific motoneurons and surrounding astrocytes were determined approximately 3 months after a complete mid-thoracic spinal cord transection at P5 in non-trained and in step-trained spinal rats. Soleus (ankle extensor) and tibialis anterior (TA, ankle flexor) motor pools were identified using retrograde labeling via intramuscular injections of Fast Blue or Fluoro Gold, respectively. Lumbar spinal cord sections showed gamma2 immunostaining in both soleus and TA motoneurons and astrocytes. gamma2 immunoreactivity on the soma of soleus and TA motoneurons in spinal rats was differentially modulated. Compared to intact rats, spinal rats had higher levels of gamma2 in TA, and lower levels in soleus motoneurons. Step training restored GABA(A) gamma2 levels towards control values in motoneuronal pools of both muscles. In contrast, the gamma2 levels were elevated in surrounding astrocytes of both motor pools in spinal rats, and step training had no further effect. Thus, motor training had a specific effect on those neurons that were directly involved with the motor task. Since the gamma2 subunit is involved with GABA(A) receptor trafficking and synaptic clustering, it appears that this subunit could be an important component of the activity-dependent response of the spinal cord after a spinal injury.

Changes in expression of N-methyl-D-aspartate receptor subunits occur early in the R6/2 mouse model of Huntington's disease.

A leading hypothesis of the cause of neuronal death in Huntington's disease (HD) is excitotoxicity, in which subpopulations of striatal neurons are hypersensitive to glutamate release due to changes in postsynaptic N-methyl-D-aspartate receptors (NMDARs). In the present study we used RT-PCR methods on single cells and tissue to compare the expression of NMDAR subunits, NR1, NR2A and NR2B, in the striatum of R6/2 transgenic mice with their wild-type (WT) littermates at three different age groups corresponding to different symptomatic milestones (19-25 days showing no overt evidence of abnormal behavior, 38-45 days at the onset of the overt phenotype and 78-90 days displaying the full behavioral phenotype). Single-cell RT-PCR studies also examined neurons for the expression of substance P and enkephalin to define different subpopulations of medium-sized projection neurons of the striatum. The results showed a significant decrease in the percentage of cells expressing NR2A at all ages examined. The decrease in expression was not associated with any significant change in expression of NR1 or NR2B. Cells that did not express NR2A contained both enkephalin and substance P, but proportionately more cells containing enkephalin displayed decreases in NR2A. Semi-quantitative RT-PCR studies on striatal tissue in the oldest age group confirmed the significant decrease in NR2A and also showed a decrease in NR2B. These results support the hypothesis that changes in the composition of postsynaptic NMDARs occur in the R6/2 model of HD and this effect occurs early in the expression of the phenotype.