Loss of lysophosphatidic acid receptor LPA1 alters oligodendrocyte differentiation and myelination in the mouse cerebral cortex.

Lysophosphatidic acid (LPA) is an intercellular signaling lipid that regulates multiple cellular functions, acting through specific G-protein coupled receptors (LPA(1-6)). Our previous studies using viable Malaga variant maLPA1-null mice demonstrated the requirement of the LPA1 receptor for normal proliferation, differentiation, and survival of the neuronal precursors. In the cerebral cortex LPA1 is expressed extensively in differentiating oligodendrocytes, in parallel with myelination. Although exogenous LPA-induced effects have been investigated in myelinating cells, the in vivo contribution of LPA1 to normal myelination remains to be demonstrated. This study identified a relevant in vivo role for LPA1 as a regulator of cortical myelination. Immunochemical analysis in adult maLPA1-null mice demonstrated a reduction in the steady-state levels of the myelin proteins MBP, PLP/DM20, and CNPase in the cerebral cortex. The myelin defects were confirmed using magnetic resonance spectroscopy and electron microscopy. Stereological analysis limited the defects to adult differentiating oligodendrocytes, without variation in the NG2+ precursor cells. Finally, a possible mechanism involving oligodendrocyte survival was demonstrated by the impaired intracellular transport of the PLP/DM20 myelin protein which was accompanied by cellular loss, suggesting stress-induced apoptosis. These findings describe a previously uncharacterized in vivo functional role for LPA1 in the regulation of oligodendrocyte differentiation and myelination in the CNS, underlining the importance of the maLPA1-null mouse as a model for the study of demyelinating diseases.

An immunocytochemical mapping of methionine-enkephalin-Arg6-Gly7-Leu8 in the cat brainstem.

The distribution of methionine-enkephalin-Arg6-Gly7-Leu8-immunoreactive cell bodies and fibres was studied in the brainstem of the cat using an indirect immunoperoxidase technique. In the mesencephalon, immunoreactive cell bodies were observed in the periaqueductal grey, the dorsal raphe nucleus, the central and pericentral nuclei of the inferior colliculus and the pericentral division of the dorsal tegmental nucleus. In the pons, immunoreactive cell bodies were observed in the dorsolateral division of the pontine nucleus; below the central division of the dorsal tegmental nucleus; above the dorsolateral division of the pontine nucleus, and close to the superior cerebellar peduncle. In the medulla oblongata, immunoreactive cell bodies were observed in the laminar spinal trigeminal nucleus and in the lateral tegmental field; the dorsal motor nucleus of the vagus; the prepositus hypoglossal nucleus; the medial nucleus of the solitary tract; the rostral division of the cuneate nucleus, and close to the parvocellular division of the alaminar spinal trigeminal nucleus. The highest (moderate) density of immunoreactive fibres was observed in the periaqueductal grey; the parvocellular and magnocellular divisions of the alaminar spinal trigeminal nucleus; the laminar spinal trigeminal nucleus; the rostral division of the cuneate nucleus; the dorsal motor nucleus of the vagus; the lateral nucleus of the solitary tract, and in the midline between the central divisions of the reticulotegmental pontine nucleus. The widespread distribution of methionine-enkephalin-Arg6-Gly7-Leu8 in the cat brainstem indicates that the peptide might be involved in several physiological functions.