Integrated multimodal cell atlas of Alzheimer's disease.

Alzheimer's disease (AD) is the most common cause of dementia in older adults. Neuropathological and imaging studies have demonstrated a progressive and stereotyped accumulation of protein aggregates, but the underlying molecular and cellular mechanisms driving AD progression and vulnerable cell populations affected by disease remain coarsely understood. The current study harnesses single cell and spatial genomics tools and knowledge from the BRAIN Initiative Cell Census Network to understand the impact of disease progression on middle temporal gyrus cell types. We used image-based quantitative neuropathology to place 84 donors spanning the spectrum of AD pathology along a continuous disease pseudoprogression score and multiomic technologies to profile single nuclei from each donor, mapping their transcriptomes, epigenomes, and spatial coordinates to a common cell type reference with unprecedented resolution. Temporal analysis of cell-type proportions indicated an early reduction of Somatostatin-expressing neuronal subtypes and a late decrease of supragranular intratelencephalic-projecting excitatory and Parvalbumin-expressing neurons, with increases in disease-associated microglial and astrocytic states. We found complex gene expression differences, ranging from global to cell type-specific effects. These effects showed different temporal patterns indicating diverse cellular perturbations as a function of disease progression. A subset of donors showed a particularly severe cellular and molecular phenotype, which correlated with steeper cognitive decline. We have created a freely available public resource to explore these data and to accelerate progress in AD research at SEA-AD.org.

Cell-type specific molecular signatures of aging revealed in a brain-wide transcriptomic cell-type atlas.

Biological aging can be defined as a gradual loss of homeostasis across various aspects of molecular and cellular function. Aging is a complex and dynamic process which influences distinct cell types in a myriad of ways. The cellular architecture of the mammalian brain is heterogeneous and diverse, making it challenging to identify precise areas and cell types of the brain that are more susceptible to aging than others. Here, we present a high-resolution single-cell RNA sequencing dataset containing ~1.2 million high-quality single-cell transcriptomic profiles of brain cells from young adult and aged mice across both sexes, including areas spanning the forebrain, midbrain, and hindbrain. We find age-associated gene expression signatures across nearly all 130+ neuronal and non-neuronal cell subclasses we identified. We detect the greatest gene expression changes in non-neuronal cell types, suggesting that different cell types in the brain vary in their susceptibility to aging. We identify specific, age-enriched clusters within specific glial, vascular, and immune cell types from both cortical and subcortical regions of the brain, and specific gene expression changes associated with cell senescence, inflammation, decrease in new myelination, and decreased vasculature integrity. We also identify genes with expression changes across multiple cell subclasses, pointing to certain mechanisms of aging that may occur across wide regions or broad cell types of the brain. Finally, we discover the greatest gene expression changes in cell types localized to the third ventricle of the hypothalamus, including tanycytes, ependymal cells, and Tbx3+ neurons found in the arcuate nucleus that are part of the neuronal circuits regulating food intake and energy homeostasis. These findings suggest that the area surrounding the third ventricle in the hypothalamus may be a hub for aging in the mouse brain. Overall, we reveal a dynamic landscape of cell-type-specific transcriptomic changes in the brain associated with normal aging that will serve as a foundation for the investigation of functional changes in the aging process and the interaction of aging and diseases.

De novo TBR1 variants cause a neurocognitive phenotype with ID and autistic traits: report of 25 new individuals and review of the literature.

TBR1, a T-box transcription factor expressed in the cerebral cortex, regulates the expression of several candidate genes for autism spectrum disorders (ASD). Although TBR1 has been reported as a high-confidence risk gene for ASD and intellectual disability (ID) in functional and clinical reports since 2011, TBR1 has only recently been recorded as a human disease gene in the OMIM database. Currently, the neurodevelopmental disorders and structural brain anomalies associated with TBR1 variants are not well characterized. Through international data sharing, we collected data from 25 unreported individuals and compared them with data from the literature. We evaluated structural brain anomalies in seven individuals by analysis of MRI images, and compared these with anomalies observed in TBR1 mutant mice. The phenotype included ID in all individuals, associated to autistic traits in 76% of them. No recognizable facial phenotype could be identified. MRI analysis revealed a reduction of the anterior commissure and suggested new features including dysplastic hippocampus and subtle neocortical dysgenesis. This report supports the role of TBR1 in ID associated with autistic traits and suggests new structural brain malformations in humans. We hope this work will help geneticists to interpret TBR1 variants and diagnose ASD probands.

Distinct Laminar Requirements for NMDA Receptors in Experience-Dependent Visual Cortical Plasticity.

Primary visual cortex (V1) is the locus of numerous forms of experience-dependent plasticity. Restricting visual stimulation to one eye at a time has revealed that many such forms of plasticity are eye-specific, indicating that synaptic modification occurs prior to binocular integration of thalamocortical inputs. A common feature of these forms of plasticity is the requirement for NMDA receptor (NMDAR) activation in V1. We therefore hypothesized that NMDARs in cortical layer 4 (L4), which receives the densest thalamocortical input, would be necessary for all forms of NMDAR-dependent and input-specific V1 plasticity. We tested this hypothesis in awake mice using a genetic approach to selectively delete NMDARs from L4 principal cells. We found, unexpectedly, that both stimulus-selective response potentiation and potentiation of open-eye responses following monocular deprivation (MD) persist in the absence of L4 NMDARs. In contrast, MD-driven depression of deprived-eye responses was impaired in mice lacking L4 NMDARs, as was L4 long-term depression in V1 slices. Our findings reveal a crucial requirement for L4 NMDARs in visual cortical synaptic depression, and a surprisingly negligible role for them in cortical response potentiation. These results demonstrate that NMDARs within distinct cellular subpopulations support different forms of experience-dependent plasticity.

Contrasting roles for parvalbumin-expressing inhibitory neurons in two forms of adult visual cortical plasticity.

The roles played by cortical inhibitory neurons in experience-dependent plasticity are not well understood. Here we evaluate the participation of parvalbumin-expressing (PV+) GABAergic neurons in two forms of experience-dependent modification of primary visual cortex (V1) in adult mice: ocular dominance (OD) plasticity resulting from monocular deprivation and stimulus-selective response potentiation (SRP) resulting from enriched visual experience. These two forms of plasticity are triggered by different events but lead to a similar increase in visual cortical response. Both also require the NMDA class of glutamate receptor (NMDAR). However, we find that PV+ inhibitory neurons in V1 play a critical role in the expression of SRP and its behavioral correlate of familiarity recognition, but not in the expression of OD plasticity. Furthermore, NMDARs expressed within PV+ cells, reversibly inhibited by the psychotomimetic drug ketamine, play a critical role in SRP, but not in the induction or expression of adult OD plasticity.

Metabotropic glutamate receptor signaling is required for NMDA receptor-dependent ocular dominance plasticity and LTD in visual cortex.

A feature of early postnatal neocortical development is a transient peak in signaling via metabotropic glutamate receptor 5 (mGluR5). In visual cortex, this change coincides with increased sensitivity of excitatory synapses to monocular deprivation (MD). However, loss of visual responsiveness after MD occurs via mechanisms revealed by the study of long-term depression (LTD) of synaptic transmission, which in layer 4 is induced by acute activation of NMDA receptors (NMDARs) rather than mGluR5. Here we report that chronic postnatal down-regulation of mGluR5 signaling produces coordinated impairments in both NMDAR-dependent LTD in vitro and ocular dominance plasticity in vivo. The data suggest that ongoing mGluR5 signaling during a critical period of postnatal development establishes the biochemical conditions that are permissive for activity-dependent sculpting of excitatory synapses via the mechanism of NMDAR-dependent LTD.

Visual recognition memory, manifested as long-term habituation, requires synaptic plasticity in V1.

Familiarity with stimuli that bring neither reward nor punishment, manifested through behavioral habituation, enables organisms to detect novelty and devote cognition to important elements of the environment. Here we describe in mice a form of long-term behavioral habituation to visual grating stimuli that is selective for stimulus orientation. Orientation-selective habituation (OSH) can be observed both in exploratory behavior in an open arena and in a stereotyped motor response to visual stimuli in head-restrained mice. We found that the latter behavioral response, termed a 'vidget', requires V1. Parallel electrophysiological recordings in V1 revealed that plasticity, in the form of stimulus-selective response potentiation (SRP), occurred in layer 4 of V1 as OSH developed. Local manipulations of V1 that prevented and reversed electrophysiological modifications likewise prevented and reversed memory demonstrated behaviorally. These findings suggest that a form of long-term visual recognition memory is stored via synaptic plasticity in primary sensory cortex.

Early mitochondrial abnormalities in hippocampal neurons cultured from Fmr1 pre-mutation mouse model.

Pre-mutation CGG repeat expansions (55-200 CGG repeats; pre-CGG) within the fragile-X mental retardation 1 (FMR1) gene cause fragile-X-associated tremor/ataxia syndrome in humans. Defects in neuronal morphology, early migration, and electrophysiological activity have been described despite appreciable expression of fragile-X mental retardation protein (FMRP) in a pre-CGG knock-in (KI) mouse model. The triggers that initiate and promote pre-CGG neuronal dysfunction are not understood. The absence of FMRP in a Drosophila model of fragile-X syndrome was shown to increase axonal transport of mitochondria. In this study, we show that dissociated hippocampal neuronal culture from pre-CGG KI mice (average 170 CGG repeats) express 42.6% of the FMRP levels and 3.8-fold higher Fmr1 mRNA than that measured in wild-type neurons at 4 days in vitro. Pre-CGG hippocampal neurons show abnormalities in the number, mobility, and metabolic function of mitochondria at this early stage of differentiation. Pre-CGG hippocampal neurites contained significantly fewer mitochondria and greatly reduced mitochondria mobility. In addition, pre-CGG neurons had higher rates of basal oxygen consumption and proton leak. We conclude that deficits in mitochondrial trafficking and metabolic function occur despite the presence of appreciable FMRP expression and may contribute to the early pathophysiology in pre-CGG carriers and to the risk of developing clinical fragile-X-associated tremor/ataxia syndrome.