Faculty Bibliography

Altered neuronal excitability is one of the hallmarks of fragile X syndrome (FXS), but the mechanisms underlying this critical neuronal dysfunction are poorly understood. Here, we find that pyramidal cells in the entorhinal cortex of Fmr1 KO mice, an established FXS mouse model, display a decreased AP threshold and increased neuronal excitability. The AP threshold changes in Fmr1 KO mice are caused by increased persistent sodium current (INaP). Our results indicate that this abnormal INaP in Fmr1 KO animals is mediated by increased mGluR5-PLC-PKC (metabotropic glutamate receptor 5/phospholipase C/protein kinase C) signaling. These findings identify Na(+) channel dysregulation as a major cause of neuronal hyperexcitability in cortical FXS neurons and uncover a mechanism by which abnormal mGluR5 signaling causes neuronal hyperexcitability in a FXS mouse model.

Although the two pathological hallmarks of Alzheimer's disease (AD), senile plaques composed of amyloid-beta (Abeta) peptides and neurofibrillary tangles (NFTs) consisting of hyperphosphorylated tau, have been studied extensively in postmortem AD and relevant animal and cellular models, the pathogenesis of AD remains unknown, particularly in the early stages of the disease where therapies presumably would be most effective. We and others have demonstrated that Abeta plaques and NFTs are present in varying degrees before the onset and throughout the progression of dementia. In this regard, aged people with no cognitive impairment (NCI), mild cognitive impairment (MCI, a presumed prodromal AD transitional state), and AD all present at autopsy with varying levels of pathological hallmarks. Cognitive decline, a requisite for the clinical diagnosis of dementia associated with AD, generally correlates better with NFTs than Abeta plaques. However, correlations are even higher between cognitive decline and synaptic loss. In this review, we illustrate relevant clinical pathological research in preclinical AD and throughout the progression of dementia in several areas including Abeta and tau pathobiology, single population expression profiling of vulnerable hippocampal and basal forebrain neurons, neuron plasticity, neuroimaging, cerebrospinal fluid (CSF) biomarker studies and their correlation with antemortem cognitive endpoints. In each of these areas, we provide evidence for the importance of studying the pathological hallmarks of AD not in isolation, but rather in conjunction with other molecular, cellular, and imaging markers to provide a more systematic and comprehensive assessment of the multiple changes that occur during the transition from NCI to MCI to frank AD.

Linear-nonlinear (LN) models and their extensions have proven successful in describing transformations from stimuli to spiking responses of neurons in early stages of sensory hierarchies. Neural responses at later stages are highly nonlinear and have generally been better characterized in terms of their decoding performance on prespecified tasks. Here we develop a biologically plausible decoding model for classification tasks, that we refer to as neural quadratic discriminant analysis (nQDA). Specifically, we reformulate an optimal quadratic classifier as an LN-LN computation, analogous to "subunit" encoding models that have been used to describe responses in retina and primary visual cortex. We propose a physiological mechanism by which the parameters of the nQDA classifier could be optimized, using a supervised variant of a Hebbian learning rule. As an example of its applicability, we show that nQDA provides a better account than many comparable alternatives for the transformation between neural representations in two high-level brain areas recorded as monkeys performed a visual delayed-match-to-sample task.

The arrangement of beta cells within islets of Langerhans is critical for insulin release through the generation of rhythmic activity. A privileged role for individual beta cells in orchestrating these responses has long been suspected, but not directly demonstrated. We show here that the beta cell population in situ is operationally heterogeneous. Mapping of islet functional architecture revealed the presence of hub cells with pacemaker properties, which remain stable over recording periods of 2 to 3 hr. Using a dual optogenetic/photopharmacological strategy, silencing of hubs abolished coordinated islet responses to glucose, whereas specific stimulation restored communication patterns. Hubs were metabolically adapted and targeted by both pro-inflammatory and glucolipotoxic insults to induce widespread beta cell dysfunction. Thus, the islet is wired by hubs, whose failure may contribute to type 2 diabetes mellitus.

Jiang et al (Research Article, 27 November 2015, aac9462) describe detailed experiments that substantially add to the knowledge of cortical microcircuitry and are unique in the number of connections reported and the quality of interneuron reconstruction. The work appeals to experts and laypersons because of the notion that it unveils new principles and provides a complete description of cortical circuits. We provide a counterbalance to the authors' claims to give those less familiar with the minutiae of cortical circuits a better sense of the contributions and the limitations of this study.

BACKGROUND:The mouse cerebellum (Cb) has a remarkably complex foliated three-dimensional (3D) structure, but a stereotypical cytoarchitecture and local circuitry. Little is known of the cellular behaviors and genes that function during development to determine the foliation pattern. In the anteroposterior axis the mammalian cerebellum is divided by lobules with distinct sizes, and the foliation pattern differs along the mediolateral axis defining a medial vermis and two lateral hemispheres. In the vermis, lobules are further grouped into four anteroposterior zones (anterior, central, posterior and nodular zones) based on genetic criteria, and each has distinct lobules. Since each cerebellar afferent group projects to particular lobules and zones, it is critical to understand how the 3D structure of the Cb is acquired. During cerebellar development, the production of granule cells (gcs), the most numerous cell type in the brain, is required for foliation. We hypothesized that the timing of gc accumulation is different in the four vermal zones during development and contributes to the distinct lobule morphologies. METHODS AND RESULTS:In order to test this idea, we used genetic inducible fate mapping to quantify accumulation of gcs in each lobule during the first two postnatal weeks in mice. The timing of gc production was found to be particular to each lobule, and delayed in the central zone lobules relative to the other zones. Quantification of gc proliferation and differentiation at three time-points in lobules representing different zones, revealed the delay involves a later onset of maximum differentiation and prolonged proliferation of gc progenitors in the central zone. Similar experiments in Engrailed mutants (En1 (-/+) ;En2 (-/-) ), which have a smaller Cb and altered foliation pattern preferentially outside the central zone, showed that gc production, proliferation and differentiation are altered such that the differences between zones are attenuated compared to wild-type mice. CONCLUSIONS:Our results reveal that gc production is differentially regulated in each zone of the cerebellar vermis, and our mutant analysis indicates that the dynamics of gc production plays a role in determining the 3D structure of the Cb.

In this issue of Neuron, Yuzwa et al. (2016) identify secreted factors that influence the cell fates of embryonic neural progenitor cells. Surprisingly, the major contributors are trophic factors from the GDNF family and a cytokine, interferon-gamma. Advanced analysis of proteomic and transcriptome data discovered ligand receptors that influence cell-cell communication.

The clustering of neurons sharing similar functional properties and connectivity is a common organizational feature of vertebrate nervous systems. Within motor networks, spinal motor neurons (MNs) segregate into longitudinally arrayed subtypes, establishing a central somatotopic map of peripheral target innervation. MN organization and connectivity relies on Hox transcription factors expressed along the rostrocaudal axis; however, the developmental mechanisms governing the orderly arrangement of MNs are largely unknown. We show that Pbx genes, which encode Hox cofactors, are essential for the segregation and clustering of neurons within motor columns. In the absence of Pbx1 and Pbx3 function, Hox-dependent programs are lost and the remaining MN subtypes are unclustered and disordered. Identification of Pbx gene targets revealed an unexpected and apparently Hox-independent role in defining molecular features of dorsally projecting medial motor column (MMC) neurons. These results indicate Pbx genes act in parallel genetic pathways to orchestrate neuronal subtype differentiation, connectivity, and organization.

Aplydactone is an unusual brominated sesquiterpenoid isolated from the sea hare Aplysia dactylomela. Its highly strained skeleton contains two four- and three six-membered rings and features three adjacent quaternary carbon atoms. Although it is most likely of photochemical origin, attempts to generate it from a chamigrane precursor have failed thus far. In this work, we present a total synthesis of aplydactone that relies on two photochemical key steps that are not biomimetic but highly effective in establishing the two cyclobutane rings. Our synthesis also features an unusual Barbier-type cyclization and culminates in new radical conditions to install the sterically hindered secondary bromide of the natural product.

The oligomeric amyloid-beta (Abeta) peptide is thought to contribute to the subtle amnesic changes in Alzheimer's disease (AD) by causing synaptic dysfunction. Here, we examined the time course of synaptic changes in mouse hippocampal neurons following exposure to Abeta42 at picomolar concentrations, mimicking its physiological levels in the brain. We found opposite effects of the peptide with short exposures in the range of minutes enhancing synaptic plasticity, and longer exposures lasting several hours reducing it. The plasticity reduction was concomitant with an increase in the basal frequency of spontaneous neurotransmitter release, a higher basal number of functional presynaptic release sites, and a redistribution of synaptic proteins including the vesicle-associated proteins synapsin I, synaptophysin, and the post-synaptic glutamate receptor I. These synaptic alterations were mediated by cytoskeletal changes involving actin polymerization and p38 mitogen-activated protein kinase. These in vitro findings were confirmed in vivo with short hippocampal infusions of picomolar Abeta enhancing contextual memory and prolonged infusions impairing it. Our findings provide a model for initiation of synaptic dysfunction whereby exposure to physiologic levels of Abeta for a prolonged period of time causes microstructural changes at the synapse which result in increased transmitter release, failure of synaptic plasticity, and memory loss.