Mouse mutants for the nicotinic acetylcholine receptor ß2 subunit display changes in cell adhesion and neurodegeneration response genes.

Mice lacking expression of the ß2 subunit of the neuronal nicotinic acetylcholine receptor (CHRNB2) display abnormal retinal waves and a dispersed projection of retinal ganglion cell (RGC) axons to their dorsal lateral geniculate nuclei (dLGNs). Transcriptomes of LGN tissue from two independently generated Chrnb2-/- mutants and from wildtype mice were obtained at postnatal day 4 (P4), during the normal period of segregation of eye-specific afferents to the LGN. Microarray analysis reveals reduced expression of genes located on the cell membrane or in extracellular space, and of genes active in cell adhesion and calcium signaling. In particular, mRNA for cadherin 1 (Cdh1), a known axon growth regulator, is reduced to nearly undetectable levels in the LGN of P4 mutant mice and Lypd2 mRNA is similarly suppressed. Similar analysis of retinal tissue shows increased expression of crumbs 1 (Crb1) and chemokine (C-C motif) ligand 21 (Ccl21) mRNAs in Chrnb2-/- mutant animals. Mutations in these genes are associated with retinal neuronal degeneration. The retinas of Chrnb2-/- mutants are normal in appearance, but the increased expression of these genes may also be involved in the abnormal projection patterns of RGC to the LGN. These data may provide the tools to distinguish the interplay between neural activity and molecular expression. Finally, comparison of the transcriptomes of the two different Chrnb2-/- mutant strains reveals the effects of genetic background upon gene expression.

[Surgical options for hearing loss in patients with osteogenesis imperfecta]. / Posibilidades de tratamiento quirúrgico de la hipoacusia en pacientes afectados de osteogénesis imperfecta.

The aim of the study is to present the severe, extensive lesions in the temporal bone appearing in the mildest forms of osteogenesis imperfecta, correlate these with audiometric results and discuss the possible surgical treatments available. We present three patients suffering hearing loss due to osteogenesis imperfecta type 1 to various functional degrees. All patients underwent an audiological, medical and radiological evaluation and were then treated with different surgical procedures. The patients presented mild, severe and profound mixed hearing losses and the radiological images showed extensive areas of demineralization affecting the ossicular chain and removal of protection for the vital structures inside the temporal bone. Also, the cochlea showed otic capsule demineralization, dehiscence, distortions and even destructions. The various surgical treatments, indicated under current international criteria, obtained limited functional results. This study reviews the need to evaluate the current surgical criteria for this specific condition.

Posibilidades de tratamiento quirúrgico de la hipoacusia en pacientes afectados de osteogénesis imperfecta / Surgical options for hearing loss in patients with osteogenesis imperfecta

El objetivo del estudio es presentar las extensas y severas lesiones óticas que acontecen en la forma más leve de osteogénesis imperfecta, correlacionarlas con las alteraciones audiométricas y discutir las posibilidades quirúrgicas disponibles. Se presenta a 3 pacientes afectados de osteogénesis imperfecta tipo 1 con hipoacusia en distintos estadios funcionales. Se realizó a cada paciente estudio audiológico, médico y radiológico, y se sometieron a distintos tratamientos quirúrgicos. Los pacientes presentaron hipoacusias mixtas de carácter moderado, severo y profundo, imágenes radiológicas con extensas áreas de desmineralización que afectaban la cadena osicular y con desprotección de las estructuras vitales alojadas en el peñasco temporal, desmineralización de la cápsula ótica, dehiscencias, distorsiones y destrucciones cocleares. Los tratamientos quirúrgicos realizados, e indicados según los criterios actualmente aceptados, obtuvieron escasos resultados funcionales. El presente estudio plantea la necesidad de evaluar los criterios quirúrgicos específicos para esta enfermedad(AU)

The aim of the study is to present the severe, extensive lesions in the temporal bone appearing in the mildest forms of osteogenesis imperfecta, correlate these with audiometric results and discuss the possible surgical treatments available. We present three patients suffering hearing loss due to osteogenesis imperfecta type 1 to various functional degrees. All patients underwent an audiological, medical and radiological evaluation and were then treated with different surgical procedures. The patients presented mild, severe and profound mixed hearing losses and the radiological images showed extensive areas of demineralization affecting the ossicular chain and removal of protection for the vital structures inside the temporal bone. Also, the cochlea showed otic capsule demineralization, dehiscence, distortions and even destructions. The various surgical treatments, indicated under current international criteria, obtained limited functional results. This study reviews the need to evaluate the current surgical criteria for this specific condition(AU)

Retinal waves in mice lacking the beta2 subunit of the nicotinic acetylcholine receptor.

The structural and functional properties of the visual system are disrupted in mutant animals lacking the beta2 subunit of the nicotinic acetylcholine receptor. In particular, eye-specific retinogeniculate projections do not develop normally in these mutants. It is widely thought that the developing retinas of beta2(-/-) mutants do not manifest correlated activity, leading to the notion that retinal waves play an instructional role in the formation of eye-specific retinogeniculate projections. By multielectrode array recordings, we show here that the beta2(-/-) mutants have robust retinal waves during the formation of eye-specific projections. Unlike in WT animals, however, the mutant retinal waves are propagated by gap junctions rather than cholinergic circuitry. These results indicate that lack of retinal waves cannot account for the abnormalities that have been documented in the retinogeniculate pathway of the beta2(-/-) mutants and suggest that other factors must contribute to the deficits in the visual system that have been noted in these animals.

Formation of eye-specific retinogeniculate projections occurs prior to the innervation of the dorsal lateral geniculate nucleus by cholinergic fibers.

We compared the developmental periods in the mouse when projections from the two eyes become segregated in the dorsal lateral geniculate nucleus with the time when this nucleus becomes innervated by cholinergic fibers from the brainstem. Changes in labeling patterns of different tracers injected into each eye revealed that segregation of retinogeniculate inputs commences at postnatal day five (P5) and is largely complete by P8. Immunocytochemical staining showed that cholinergic neurons are present in the parabrachial region of the brain stem on the day of birth. However, cholinergic fibers are not evident in the geniculate until P5, and these are sparse at this age, increasing in density to form well-defined clusters by P12. These results indicate that segregation of eye-specific projections during normal development is unlikely to be regulated by cholinergic inputs from the brainstem.