Faculty Bibliography

Growth of axons and dendrites is a dynamic process that involves guidance molecules, adhesion proteins, and neurotrophic factors. Although neurite extension is stimulated by the neurotrophin nerve growth factor (NGF), we found that the precursor of NGF, proNGF, induced acute collapse of growth cones of cultured hippocampal neurons. This retraction was initiated by an interaction between the p75 neurotrophin receptor (p75(NTR)) and the sortilin family member SorCS2 (sortilin-related VPS10 domain-containing receptor 2). Binding of proNGF to the p75(NTR)-SorCS2 complex induced growth cone retraction by initiating the dissociation of the guanine nucleotide exchange factor Trio from the p75(NTR)-SorCS2 complex, resulting in decreased Rac activity and, consequently, growth cone collapse. The actin-bundling protein fascin was also inactivated, contributing to the destabilization and collapse of actin filaments. These results identify a bifunctional signaling mechanism by which proNGF regulates actin dynamics to acutely modulate neuronal morphology

Carefully designed animal models of genetic risk factors are likely to aid our understanding of the pathogenesis of schizophrenia. Here, we study a mouse strain with a truncating lesion in the endogenous Disc1 ortholog designed to model the effects of a schizophrenia-predisposing mutation and offer a detailed account of the consequences that this mutation has on the development and function of a hippocampal circuit. We uncover widespread and cumulative cytoarchitectural alterations in the dentate gyrus during neonatal and adult neurogenesis, which include errors in axonal targeting and are accompanied by changes in short-term plasticity at the mossy fiber/CA3 circuit. We also provide evidence that cAMP levels are elevated as a result of the Disc1 mutation, leading to altered axonal targeting and dendritic growth. The identified structural alterations are, for the most part, not consistent with the growth-promoting and premature maturation effects inferred from previous RNAi-based Disc1 knockdown. Our results provide support to the notion that modest disturbances of neuronal connectivity and accompanying deficits in short-term synaptic dynamics is a general feature of schizophrenia-predisposing mutations

Wiring economy has successfully explained the individual placement of neurons in simple nervous systems like that of Caenorhabditis elegans [1-3] and the locations of coarser structures like cortical areas in complex vertebrate brains [4]. However, it remains unclear whether wiring economy can explain the placement of individual neurons in brains larger than that of C. elegans. Indeed, given the greater number of neuronal interconnections in larger brains, simply minimizing the length of connections results in unrealistic configurations, with multiple neurons occupying the same position in space. Avoiding such configurations, or volume exclusion, repels neurons from each other, thus counteracting wiring economy. Here we test whether wiring economy together with volume exclusion can explain the placement of neurons in a module of the Drosophila melanogaster brain known as lamina cartridge [5-13]. We used newly developed techniques for semiautomated reconstruction from serial electron microscopy (EM) [14] to obtain the shapes of neurons, the location of synapses, and the resultant synaptic connectivity. We show that wiring length minimization and volume exclusion together can explain the structure of the lamina microcircuit. Therefore, even in brains larger than that of C. elegans, at least for some circuits, optimization can play an important role in individual neuron placement.

Most neurons in cortical area MT (V5) are strongly direction selective, and their activity is closely associated with the perception of visual motion. These neurons have large receptive fields built by combining inputs with smaller receptive fields that respond to local motion. Humans integrate motion over large areas and can perceive what has been referred to as global motion. The large size and direction selectivity of MT receptive fields suggests that MT neurons may represent global motion. We have explored this possibility by measuring responses to a stimulus in which the directions of simultaneously presented local and global motion are independently controlled. Surprisingly, MT responses depended only on the local motion and were unaffected by the global motion. Yet, under similar conditions, human observers perceive global motion and are impaired in discriminating local motion. Although local motion perception might depend on MT signals, global motion perception depends on mechanisms qualitatively different from those in MT. Motion perception therefore does not depend on a single cortical area but reflects the action and interaction of multiple brain systems

The cardiovascular system operates under demands ranging from conditions of rest to extreme stress. One mechanism of cardiac stress tolerance is action potential duration shortening driven by ATP-sensitive potassium (K(ATP)) channels. K(ATP) channel expression has a significant physiologic impact on action potential duration shortening and myocardial energy consumption in response to physiologic heart rate acceleration. However, the effect of reduced channel expression on action potential duration shortening in response to severe metabolic stress is yet to be established. Here, transgenic mice with myocardium-specific expression of a dominant negative K(ATP) channel subunit were compared with littermate controls. Evaluation of K(ATP) channel whole cell current and channel number/patch was assessed by patch clamp in isolated ventricular cardiomyocytes. Monophasic action potentials were monitored in retrogradely perfused, isolated hearts during the transition to hypoxic perfusate. An 80-85% reduction in cardiac K(ATP) channel current density results in a similar magnitude, but significantly slower rate, of shortening of the ventricular action potential duration in response to severe hypoxia, despite no significant difference in coronary flow. Therefore, the number of functional cardiac sarcolemmal K(ATP) channels is a critical determinant of the rate of adaptation of myocardial membrane excitability, with implications for optimization of cardiac energy consumption and consequent cardioprotection under conditions of severe metabolic stress.

Food restriction (FR) decreases brain-derived neurotrophic factor (BDNF) expression in hypothalamic and hindbrain regions that regulate feeding and metabolic efficiency, while increasing expression in hippocampal and neocortical regions. Drugs of abuse alter BDNF expression within the mesocorticolimbic dopamine (DA) pathway, and modifications of BDNF expression within this pathway alter drug-directed behavior. Although FR produces a variety of striatal neuroadaptations and potentiates the rewarding effects of abused drugs, the effects of FR on BDNF expression and function within the DA pathway are unknown. The primary purpose of the present study was to examine the effect of FR on protein levels of BDNF and its tropomyosin receptor kinase B (TrkB) receptor in component structures of the mesocorticolimbic pathway. Three to four weeks of FR, with stabilization of rats at 80% of initial body weight, did not alter BDNF or TrkB levels in nucleus accumbens, caudate-putamen, or medial prefrontal cortex. However, FR decreased TrkB levels in the ventral tegmental area (VTA), without change in levels of BDNF protein or mRNA. The finding that FR also decreased TrkB levels in substantia nigra, with elevation of BDNF protein, suggests that decreased TrkB in VTA could be a residual effect of increased BDNF during an earlier phase of FR. Voltage-clamp recordings in VTA DA neurons indicated decreased glutamate receptor transmission. These data might predict lower average firing rates in FR relative to ad libitum fed subjects, which would be consistent with previous evidence of decreased striatal DA transmission and upregulation of postsynaptic DA receptor signaling. However, FR subjects also displayed elevated VTA levels of phospho-ERK1/2, which is an established mediator of synaptic plasticity. Because VTA neurons are heterogeneous with regard to neurochemistry, function, and target projections, the relationship(s) between the three changes observed in VTA, and their involvement in the augmented striatal and behavioral responsiveness of FR subjects to drugs of abuse, remains speculative