SynaptoPAC, an optogenetic tool for induction of presynaptic plasticity

Optogenetic manipulations have transformed neuroscience in recent years. While sophisticated tools now exist for controlling the firing patterns of neurons, it remains challenging to optogenetically define the plasticity state of individual synapses. A variety of synapses in the mammalian brain express presynaptic long-term potentiation (LTP) upon elevation of presynaptic cyclic adenosine monophosphate (cAMP), but the molecular expression mechanisms as well as the impact of presynaptic LTP on network activity and behavior are not fully understood. In order to establish optogenetic control of presynaptic cAMP levels and thereby presynaptic potentiation, we developed synaptoPAC, a presynaptically targeted version of the photoactivated adenylyl cyclase bPAC. In cultures of hippocampal granule cells, activation of synaptoPAC with blue light increases action potential-evoked transmission, an effect not seen in hippocampal cultures of non-granule cells. In acute brain slices, synaptoPAC activation immediately triggers a strong presynaptic potentiation at mossy fiber terminals in CA3, but not at Schaffer collateral synapse in CA1. Following light-triggered potentiation, mossy fiber transmission decreases within 20 minutes, but remains enhanced still after 30 min. Optogenetic potentiation alters the short-term plasticity dynamics of release, reminiscent of presynaptic LTP. SynaptoPAC is the first optogenetic tool that allows acute light-controlled potentiation of transmitter release at specific synapses of the brain, and will enable to investigate the role of presynaptic potentiation in network function and the animal’s behavior in an unprecedented manner. SIGNIFICANCE STATEMENT: SynaptoPAC is a novel optogenetic tool that allows increasing synaptic transmission by light-controlled induction of presynaptic plasticity

Circuit-specific dendritic development in the piriform cortex

Dendritic geometry is largely determined during postnatal development and has a substantial impact on neural function. In sensory processing, postnatal development of the dendritic tree is affected by two dominant circuit motifs, ascending sensory feedforward inputs and descending and local recurrent connections. Two subtypes of layer 2 neurons in the three-layered anterior piriform cortex, layer 2a and layer 2b neurons, display a clear vertical segregation of these two circuit motifs. Here, we combined electrophysiology, detailed morphometry and Ca(2+) imaging-both of neuronal networks as well as of subcellular structures-in acute mouse brain slices and modeling. This allowed us to compare the functional implications of distinct circuit-specific postnatal dendritic growth patterns in these two neuronal subtypes. We observed that determination of branching complexity, dendritic length increases and pruning occurred in distinct growth phases. Layer 2a and layer 2b neurons displayed growth phase specific developmental differences between their apical and basal dendritic trees. This was reflected by compartment-specific differences in Ca(2+) signaling. The morphological and functional developmental pattern differences between layer 2a and layer 2b neurons dendrites provide further evidence that they constitute two functionally distinct streams of olfactory information processing

SynaptoPAC, an optogenetic tool for induction of presynaptic plasticity

Optogenetic manipulations have transformed neuroscience in recent years. While sophisticated tools now exist for controlling the firing patterns of neurons, it remains challenging to optogenetically define the plasticity state of individual synapses. A variety of synapses in the mammalian brain express presynaptic long-term potentiation (LTP) upon elevation of presynaptic cyclic adenosine monophosphate (cAMP), but the molecular expression mechanisms as well as the impact of presynaptic LTP on network activity and behavior are not fully understood. In order to establish optogenetic control of presynaptic cAMP levels and thereby presynaptic potentiation, we developed synaptoPAC, a presynaptically targeted version of the photoactivated adenylyl cyclase bPAC. In cultures of hippocampal granule cells of Wistar rats, activation of synaptoPAC with blue light increased action potential-evoked transmission, an effect not seen in hippocampal cultures of non-granule cells. In acute brain slices of C57BL/6N mice, synaptoPAC activation immediately triggered a strong presynaptic potentiation at mossy fiber synapses in CA3, but not at Schaffer collateral synapses in CA1. Following light-triggered potentiation, mossy fiber transmission decreased within 20 minutes, but remained enhanced still after 30 min. The optogenetic potentiation altered the short-term plasticity dynamics of release, reminiscent of presynaptic LTP. Our work establishes synaptoPAC as an optogenetic tool that enables acute light-controlled potentiation of transmitter release at specific synapses in the brain, facilitating studies of the role of presynaptic potentiation in network function and animal behavior in an unprecedented manner. SIGNIFICANCE STATEMENT: SynaptoPAC is a novel optogenetic tool that allows increasing synaptic transmission by light-controlled induction of presynaptic plasticity

Conscious mobility for urban spaces: case studies review and indicator framework design

A lack of data collection on conscious mobility behaviors has been identified in current sustainable and smart mobility planning, development and implementation strategies. This leads to technocentric solutions that do not place people and their behavior at the center of new mobility solutions in urban centers around the globe. This paper introduces the concept of conscious mobility to link techno-economic analyses with user awareness on the impact of their travel decisions on other people, local urban infrastructure and the environment through systematic big data collection. A preliminary conscious mobility indicator framework is presented to leverage behavioral considerations to enhance urban-community mobility systems. Key factors for conscious mobility analysis have been derived from five case studies. The sample offers regional diversity (i.e., local, regional and the global urban contexts), as well as different goals in the transformation of conventional urban transport systems, from improving public transport efficiency and equipment electrification to mitigate pollution and climate risks, to focusing on equity, access and people safety. The case studies selected provide useful metrics on the adoption of cleaner, smarter, safer and more autonomous mobility technologies, along with novel people-centric program designs to build an initial set of conscious mobility indicators frameworks. The parameters were applied to the city of Monterrey, Nuevo Leon in Mexico focusing on the needs of the communities that work, study and live around the local urban campus of the Tecnologico de Monterrey’s Distrito Tec. This case study, served as an example of how conscious mobility indicators could be applied and customized to a community and region of interest. This paper introduces the first application of the conscious mobility framework for urban communities’ mobility system analysis. This more holistic assessment approach includes dimensions such as society and culture, infrastructure and urban spaces, technology, government, normativity, economy and politics, and the environment. The expectation is that the conscious mobility framework of analysis will become a useful tool for smarter and sustainable urban and mobility problem solving and decision making to enhance the quality of life all living in urban communities

Spermidine protects from age-related synaptic alterations at hippocampal mossy fiber-CA3 synapses

Aging is associated with functional alterations of synapses thought to contribute to age-dependent memory impairment (AMI). While therapeutic avenues to protect from AMI are largely elusive, supplementation of spermidine, a polyamine normally declining with age, has been shown to restore defective proteostasis and to protect from AMI in Drosophila. Here we demonstrate that dietary spermidine protects from age-related synaptic alterations at hippocampal mossy fiber (MF)-CA3 synapses and prevents the aging-induced loss of neuronal mitochondria. Dietary spermidine rescued age-dependent decreases in synaptic vesicle density and largely restored defective presynaptic MF-CA3 long-term potentiation (LTP) at MF-CA3 synapses (MF-CA3) in aged animals. In contrast, spermidine failed to protect CA3-CA1 hippocampal synapses characterized by postsynaptic LTP from age-related changes in function and morphology. Our data demonstrate that dietary spermidine attenuates age-associated deterioration of MF-CA3 synaptic transmission and plasticity. These findings provide a physiological and molecular basis for the future therapeutic usage of spermidine

Evidence of beta amyloid independent small vessel disease in familial Alzheimer\u27s disease

\ua9 2022 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology. We studied small vessel disease (SVD) pathology in Familial Alzheimer\u27s disease (FAD) subjects carrying the presenilin 1 (PSEN1) p.Glu280Ala mutation in comparison to those with sporadic Alzheimer\u27s disease (SAD) as a positive control for Alzheimer\u27s pathology and Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) bearing different NOTCH3 mutations, as positive controls for SVD pathology. Upon magnetic resonance imaging (MRI) in life, some FAD showed mild white matter hyperintensities and no further radiologic evidence of SVD. In post-mortem studies, total SVD pathology in cortical areas and basal ganglia was similar in PSEN1 FAD and CADASIL subjects, except for the feature of arteriosclerosis which was higher in CADASIL subjects than in PSEN1 FAD subjects. Further only a few SAD subjects showed a similar degree of SVD pathology as observed in CADASIL. Furthermore, we found significantly enlarged perivascular spaces in vessels devoid of cerebral amyloid angiopathy in FAD compared with SAD and CADASIL subjects. As expected, there was greater fibrinogen-positive perivascular reactivity in CADASIL but similar reactivity in PSEN1 FAD and SAD groups. Fibrinogen immunoreactivity correlated with onset age in the PSEN1 FAD cases, suggesting increased vascular permeability may contribute to cognitive decline. Additionally, we found reduced perivascular expression of PDGFRβ AQP4 in microvessels with enlarged PVS in PSEN1 FAD cases. We demonstrate that there is Aβ-independent SVD pathology in PSEN1 FAD, that was marginally lower than that in CADASIL subjects although not evident by MRI. These observations suggest presence of covert SVD even in PSEN1, contributing to disease progression. As is the case in SAD, these consequences may be preventable by early recognition and actively controlling vascular disease risk, even in familial forms of dementia

Publisher Correction: ZnO nucleation into trititanate nanotubes by ALD equipment techniques, a new way to functionalize layered metal oxides

In this contribution, we explore the potential of atomic layer deposition (ALD) techniques for developing new semiconductor metal oxide composites. Specifically, we investigate the functionalization of multi-wall trititanate nanotubes, H2Ti3O7 NTs (sample T1) with zinc oxide employing two different ALD approaches: vapor phase metalation (VPM) using diethylzinc (Zn(C2H5)2, DEZ) as a unique ALD precursor, and multiple pulsed vapor phase infiltration (MPI) using DEZ and water as precursors. We obtained two different types of tubular H2Ti3O7 species containing ZnO in their structures. Multi-wall trititanate nanotubes with ZnO intercalated inside the tube wall sheets were the main products from the VPM infiltration (sample T2). On the other hand, MPI (sample T3) principally leads to single-wall nanotubes with a ZnO hierarchical bi-modal functionalization, thin film coating, and surface decorated with ZnO particles. The products were mainly characterized by electron microscopy, energy dispersive X-ray, powder X-ray diffraction, Fourier transform infrared spectroscopy, and X-ray photoelectron spectroscopy. An initial evaluation of the optical characteristics of the products demonstrated that they behaved as semiconductors. The IR study revealed the role of water, endogenous and/or exogenous, in determining the structure and properties of the products. The results confirm that ALD is a versatile tool, promising for developing tailor-made semiconductor materials

Branch point strength controls species-specific CAMK2B alternative splicing and regulates LTP

Regulation and functionality of species-specific alternative splicing has remained enigmatic to the present date. Calcium/calmodulin-dependent protein kinase IIβ (CaMKIIβ) is expressed in several splice variants and plays a key role in learning and memory. Here, we identify and characterize several primate-specific CAMK2B splice isoforms, which show altered kinetic properties and changes in substrate specificity. Furthermore, we demonstrate that primate-specific CAMK2B alternative splicing is achieved through branch point weakening during evolution. We show that reducing branch point and splice site strengths during evolution globally renders constitutive exons alternative, thus providing novel mechanistic insight into cis-directed species-specific alternative splicing regulation. Using CRISPR/Cas9, we introduce a weaker, human branch point sequence into the mouse genome, resulting in strongly altered Camk2b splicing in the brains of mutant mice. We observe a strong impairment of long-term potentiation in CA3-CA1 synapses of mutant mice, thus connecting branch point-controlled CAMK2B alternative splicing with a fundamental function in learning and memory