GFAP is necessary for the integrity of CNS white matter architecture and long-term maintenance of myelination.

To investigate the structural role of glial fibrillary acidic protein (GFAP) in vivo, mice carrying a null mutation in GFAP were generated. In 7/14 mutant animals older than 18 months of age, hydrocephalus associated with white matter loss was detected. Mutant mice displayed abnormal myelination including the presence of actively myelinating oligodendrocytes in adults, nonmyelinated axons in optic nerve, and reduced myelin thickness in spinal cord. White matter was poorly vascularized and the blood-brain barrier was structurally and functionally impaired. Astrocytic structure and function were abnormal, consisting of shortened astrocytic cell processes, decreased septation of white matter, and increased CNS extracellular space. Thus, GFAP expression is essential for normal white matter architecture and blood-brain barrier integrity, and its absence leads to late-onset CNS dysmyelination.

Abnormal nerve conduction studies in mice expressing a mutant form of the POU transcription factor SCIP.

We have previously described transgenic mice that harbor a dominant-negative antagonist of the POU protein SCIP (termed deltaSCIP). Native SCIP is expressed in promyelinating Schwann cells, where it represses expression of the myelin structural genes. The deltaSCIP mice display morphologic and behavioral abnormalities, including decreased axonal diameter, increased myelin thickness, developmentally early myelination, and clinical features of neuropathy. To assess the neurophysiologic correlates of these abnormalities, a series of electrophysiologic tests was performed. Despite having smaller diameter axons, mice expressing the deltaSCIP transgene had similar maximum conduction velocities in caudal, sural, and tibial nerves compared to wild-type controls. Therefore, conduction in deltaSCIP animals was faster than predicted by axon diameter alone. Compound amplitude responses were 38% higher in the deltaSCIP caudal nerve. DeltaSCIP tibial F-wave responses showed less difference between minimum and maximum latencies than controls, suggesting less variance between fastest and slowest conducting fibers. These data further characterize the functional components of the deltaSCIP phenotype. In addition, these studies address the physiologic sequelae of altering the g-ratio in the absence of demyelination or axonal degeneration.

Peripheral neuropathy in young-old and old-old patients.

Diabetes is said to account for most cases of neuropathy in the elderly. We reviewed records of 223 young-old (65-79 years) and 77 old-old (>or=80 years) patients referred for evaluation of neuropathic symptoms over a 9-year period. We prospectively validated our findings in 102 consecutive elderly (77 young-old) patients receiving intensive evaluation for neuropathy. Diabetes was the most common cause of neuropathy (41%), but was less common in the old-old (25% versus 46%, P < 0.001). Idiopathic neuropathies were more common in the old-old (39% versus 9%, P < 0.001). Alcoholic and nutritional neuropathies were uncommon in the old-old. Electrophysiological studies showed that most patients had an axonal type of neuropathy. Sural and peroneal response amplitudes were poorly correlated with age. We obtained similar results in our prospective study. The distribution of causes of neuropathies in young-old and old-old patients, in a hospital-based sample, is age-related. Future studies need to include the old-old to better understand the nature of neuropathy in the elderly.

A transgenic mouse model for human hereditary neuropathy with liability to pressure palsies.

Mutations in the gene encoding peripheral myelin protein 22 (PMP22) account for several inherited peripheral neuropathies in humans. We now show that transgenic mice expressing antisense PMP22 RNA exhibit modestly reduced levels of PMP22 together with a phenotype that is reminiscent of hereditary neuropathy with liability to pressure palsies (HNPP), a human disease caused by a 1.5-Mb deletion of a chromosome 17 region that contains the PMP22 gene. Transgenic antisense homozygotes display a striking movement disorder and a slowing of nerve conduction that worsens with age. Morphological analysis of peripheral nerves demonstrates that a subset of axons have thickened myelin sheaths and tomacula in young adults, with significant myelin degeneration detected in older animals. Together with other recent work, these data suggest that dosage of the PMP22 gene alone underlies the pathophysiology observed in HNPP and related disorders.

CSF-1 deficiency in mice results in abnormal brain development.

Colony stimulating factor-1 (CSF-1) was initially identified as a growth factor for mononuclear phagocytes. This study examines the role of CSF-1 in the development of the central nervous system (CNS). CSF-1 treatment of neurons cultured from embryonic brain promoted survival and process outgrowth in a dose-dependent manner. By contrast, CSF-1 treatment of neurons cultured from the osteopetrotic (op/op) mouse, a null mutant for CSF-1, promoted significantly less process outgrowth, suggesting that there are neural abnormalities in op/op animals. Nuclease protection assays were used to determine whether CSF-1 and its receptor are expressed at times appropriate to regulate neural development. Both CSF-1 and its receptor are expressed in developing mouse brain, with a unique pattern of CSF-1 mRNA splice variant expression encoding secreted, and not membrane-bound, growth factor. To determine whether brain function is altered by null mutation of CSF-1, op/op mice were examined using electrophysiologic assays. Brainstem auditory and visual evoked potentials were both abnormal in op/op mice. Further, intracortical recordings revealed aberrant neuronal function within visual cortex and alterations in the cortical circuitry that balances excitation and inhibition. Daily CSF-1 injection of postnatal op/op mice largely rescued the abnormal neural phenotype, confirming that the absence of CSF-1 during development is responsible for the abnormalities. The effects of CSF-1 on cultured embryonic neural cells, the developmentally appropriate expression of CSF-1 and its receptor, and the neurological abnormalities in op/op mice suggest a role for CSF-1 in brain development.