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Neurodegeneration in Alzheimer’s disease (AD) has been linked to intracellular accumulation of misfolded proteins and dysregulation of intracellular Ca2+. In the current work, we determined the contribution of specific Ca2+ pathways to an alteration in Ca2+ homeostasis in primary cortical neurons from an adult triple transgenic (3xTg-AD) mouse model of AD that exhibits intraneuronal accumulation of β-amyloid proteins. Resting free Ca2+ concentration ([Ca2+]i), as measured with Ca2+-selective microelectrodes, was greatly elevated in neurons from 3xTg-AD and APPSWE mouse strains when compared with their respective non-transgenic neurons, while there was no alteration in the resting membrane potential. In the absence of the extracellular Ca2+, the [Ca2+]i returned to near normal levels in 3xTg-AD neurons, demonstrating that extracellular Ca2+contributed to elevated [Ca2+]i. Application of nifedipine, or a non-L-type channel blocker, SKF-96365, partially reduced [Ca2+]i. Blocking the ryanodine receptors, with ryanodine or FLA-365 had no effect, suggesting that these channels do not contribute to the elevated [Ca2+]i. Conversely, inhibition of inositol trisphosphate receptors with xestospongin C produced a partial reduction in [Ca2+]i. These results demonstrate that an elevation in resting [Ca2+]i, contributed by aberrant Ca2+entry and release pathways, should be considered a major component of the abnormal Ca2+ homeostasis associated with AD. [ABSTRACT FROM AUTHOR]

Two key models for examining activity-dependent development of primary visual cortex (V1) involve either reduction of activity in both eyes via dark-rearing (DR) or imbalance of activity between the two eyes via monocular deprivation (MD). Combining DNA microarray analysis with computational approaches, RT-PCR, immunohistochemistry and physiological imaging, we find that DR leads to (i) upregulation of genes subserving synaptic transmission and electrical activity, consistent with a coordinated response of cortical neurons to reduction of visual drive, and (ii) downregulation of parvalbumin expression, implicating parvalbumin-expressing interneurons as underlying the delay in cortical maturation after DR. MD partially activates homeostatic mechanisms but differentially upregulates molecular pathways related to growth factors and neuronal degeneration, consistent with reorganization of connections after MD. Expression of a binding protein of insulin-like growth factor-1 (IGF1) is highly upregulated after MD, and exogenous application of IGF1 prevents the physiological effects of MD on ocular dominance plasticity examined in vivo. [ABSTRACT FROM AUTHOR]

Brain-derived neurotrophic factor (BDNF) is a preferred ligand for a member of the tropomyosin-related receptor family, trkB. Activation of trkB is implicated in various activity-independent as well as activity-dependent growth processes in many developing and mature neural systems. In the subcortical visual system, where electrical activity has been implicated in normal development, both differential survival, as well as remodeling of axonal arbors, have been suggested to contribute to eye-specific segregation of retinal ganglion cell inputs. Here, we tested whether BDNF is required for eye-specific segregation of visual inputs to the lateral geniculate nucleus and the superior colliculus, and two other major subcortical target fields in mice. We report that eye-specific patterning is normal in two mutants that lack BDNF expression during the segregation period: a germ-line knockout for BDNF, and a conditional mutant in which BDNF expression is absent or greatly reduced in the central nervous system. We conclude that the availability of BDNF is not necessary for eye-specific segregation in subcortical visual nuclei.

The surgical cross-modal rewiring paradigm is an experimental method for examining the physiological and anatomical consequences of exposing developing cortical subregions to specific types of patterned sensory inputs. Data from these experiments provide strong inferences about the role of extrinsic (subcortical) cortical inputs in shaping the local cortical networks that organize and process sensory information. Behavioral results from this work also suggest that such activity (and activity in general) is a profound organizer of cerebral connectivity. We discuss one future direction of these studies: the implication that extrinsic inputs regulate developmental genes that are responsible for refining the connectivity within local circuits, and a strategy to discover and characterize such genes.