Neurogenesis In The Chronic Lesions Of Multiple Sclerosis

Ansi Chang; Maria C. Smith; Xinghua Yin; Robert J. Fox; Susan M. Staugaitis; Bruce D. Trapp

Disclosures

Brain. 2008;131(9):2366-2375. 

In This Article

Summary and Introduction

Subcortical white matter in the adult human brain contains a population of interneurons that helps regulate cerebral blood flow. We investigated the fate of these neurons following subcortical white matter demyelination. Immunohistochemistry was used to examine neurons in normal-appearing subcortical white matter and seven acute and 59 chronic demyelinated lesions in brains from nine patients with multiple sclerosis and four controls. Seven acute and 44 of 59 chronic multiple sclerosis lesions had marked neuronal loss. Compared to surrounding normal-appearing white matter, the remaining 15 chronic multiple sclerosis lesions contained a 72% increase in mature interneuron density, increased synaptic densities and cells with phenotypic characteristics of immature neurons. Lesion areas with increased neuron densities contained a morphologically distinct population of activated microglia. Subventricular zones contiguous with demyelinated lesions also contained an increase in cells with phenotypes of neuronal precursors. These results support neurogenesis in a subpopulation of demyelinated subcortical white matter lesions in multiple sclerosis brains.

In the past 15 years, there has been a paradigm shift in research on multiple sclerosis. Although myelin and the oligodendrocyte are the primary targets of inflammatory demyelination, permanent disability in multiple sclerosis patients is now attributed to the impact that this process has on the viability of axons and neurons (Bjartmar et al., 2003). Numerous studies have confirmed the extent of axonal damage in white matter lesions (Ferguson et al., 1997; Trapp et al., 1998), as well as the extent of grey matter demyelination and injury to neurons (Brownell and Hughes, 1962; Kidd et al., 1999; Peterson et al., 2001). In addition, there is extensive cognitive impairment in multiple sclerosis patients (Rao et al., 1991; Beatty, 1993), which may also be attributed to the effect of demyelination on neuronal function. Therefore, the mechanisms of neuronal injury and identification of potential targets for neuroprotection have become important areas of research focus.

Study of neuronal injury in grey matter is difficult to perform because of the high neuronal density in these areas. An alternative location more conducive to analysis of neurons is the subcortical white matter. Neurons in this region are less dense than in grey matter, but display an extensive network of dendrites and receive ultrastructurally confirmed synaptic input (Kostovic and Rakic, 1980; Chun and Shatz, 1989; Okhotin and Kalinichenko, 2003). White matter neurons regulate vascular tone (Okhotin and Kalinichenko, 2003) based upon their expression of the vasoconstrictors, somatostatin (Kostovic et al., 1991) and neuropeptide Y (NPY; Kuljis and Rakic, 1989; Delalle et al., 1997), and neuronal nitric oxide synthase (nNOS), the enzyme that synthesizes the vasodilator, nitric oxide (Okhotin and Kalinichenko, 2003). Subcortical white matter neurons are readily identifiable in species with large white matter volume, such as primates and cats (Kostovic and Rakic, 1980; Chun and Shatz, 1989; Okhotin and Kalinichenko, 2003). Neurons are not a prominent feature in subcortical white matter of adult mice and rats (Robertson et al., 2000; Clancy et al., 2001).

The present report investigates the fate of subcortical white matter neurons in the lesions of multiple sclerosis. Our studies document the destruction of neurons during inflammatory demyelination of subcortical white matter. While many chronically demyelinated lesions also showed marked neuronal loss, we identified 15 lesion areas that contain a 72% increase in the density of cells that express unambiguous neuronal markers and that receive ultrastructurally confirmed synaptic input. These results support neurogenesis in a subpopulation of demyelinated subcortical white matter lesions in multiple sclerosis brains.

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