The γ-Protocadherins Regulate the Survival of GABAergic Interneurons during Developmental Cell Death.

Inhibitory interneurons integrate into developing circuits in specific ratios and distributions. In the neocortex, inhibitory network formation occurs concurrently with the apoptotic elimination of a third of GABAergic interneurons. The cell surface molecules that select interneurons to survive or die are unknown. Here, we report that members of the clustered Protocadherins (cPCDHs) control GABAergic interneuron survival during developmentally-regulated cell death. Conditional deletion of the gene cluster encoding the γ-Protocadherins (Pcdhgs) from developing GABAergic neurons in mice of either sex causes a severe loss of inhibitory populations in multiple brain regions and results in neurologic deficits such as seizures. By focusing on the neocortex and the cerebellar cortex, we demonstrate that reductions of inhibitory interneurons result from elevated apoptosis during the critical postnatal period of programmed cell death (PCD). By contrast, cortical interneuron (cIN) populations are not affected by removal of Pcdhgs from pyramidal neurons or glial cells. Interneuron loss correlates with reduced AKT signaling in Pcdhg mutant interneurons, and is rescued by genetic blockade of the pro-apoptotic factor BAX. Together, these findings identify the PCDHGs as pro-survival transmembrane proteins that select inhibitory interneurons for survival and modulate the extent of PCD. We propose that the PCDHGs contribute to the formation of balanced inhibitory networks by controlling the size of GABAergic interneuron populations in the developing brain.SIGNIFICANCE STATEMENT A pivotal step for establishing appropriate excitatory-inhibitory ratios is adjustment of neuronal populations by cell death. In the mouse neocortex, a third of GABAergic interneurons are eliminated by BAX-dependent apoptosis during the first postnatal week. Interneuron cell death is modulated by neural activity and pro-survival pathways but the cell-surface molecules that select interneurons for survival or death are unknown. We demonstrate that members of the cadherin superfamily, the clustered γ-Protocadherins (PCDHGs), regulate the survival of inhibitory interneurons and the balance of cell death. Deletion of the Pcdhgs in mice causes inhibitory interneuron loss in the cortex and cerebellum, and leads to motor deficits and seizures. Our findings provide a molecular basis for controlling inhibitory interneuron population size during circuit formation.

Cone beam CT for perioperative imaging in hearing preservation Cochlear implantation - a human cadaveric study.

BACKGROUND: Knowledge of the cochlear implant array's precise position is important because of the correlation between electrode position and speech understanding. Several groups have provided recent image processing evidence to determine scalar translocation, angular insertion depth, and cochlear duct length (CDL); all of which are being used for patient-specific programming. Cone beam computed tomography (CBCT) is increasingly used in otology due to its superior resolution and low radiation dose. Our objectives are as followed: 1.Validate CBCT by measuring cochlear metrics, including basal turn diameter (A-value) and lateral wall cochlear duct length at different angular intervals and comparing it against microcomputed CT (uCT).2.Explore the relationship between measured lateral wall cochlear duct length at different angular intervals and insertion depth among 3 different length electrodes using CBCT. METHODS: The study was performed using fixed human cadaveric temporal bones in a tertiary academic centre. Ten temporal bones were subjected to the standard facial recess approach for cochlear implantation and imaged by CBCT followed by uCT. Measurements were performed on a three-dimensional reconstructed model of the cochlea. Sequential insertion of 3 electrodes (Med-El Flex24, 28 and Soft) was then performed in 5 bones and reimaged by CBCT. Statistical analysis was performed using Pearson's correlation. RESULTS: There was good agreement between CBCT and uCT for cochlear metrics, validating the precision of CBCT against the current gold standard uCT in imaging. The A-value recorded by both modalities showed a high degree of linear correlation and did not differ by more than 0.23 mm in absolute values. For the measurement of lateral wall CDL at various points along the cochlea, there was a good correlation between both modalities at 360 deg and 720 deg (r = 0.85, p < 0.01 and r = 0.79, p < 0.01). The Flex24 electrode displayed consistent insertion depth across different bones. CONCLUSIONS: CBCT reliably performs cochlear metrics and measures electrode insertion depth. The low radiation dose, fast acquisition time, diminished metallic artifacts and portability of CBCT make it a valid option for imaging in cochlear implant surgery.