Biology subjects

Scimemi, A.

Publications and source records attributed to Scimemi, A..

10 recordsLinked to original sources

bioRxiv2025

An increased excitation and inhibition onto CA1 pyramidal cells sets the path to Alzheimer s disease

Synapses are critical targets of Alzheimers disease (AD), a highly prevalent neurodegenerative disease associated with accumulation of extracellular amyloid-{beta} peptides. Although amyloidosis and aggregation of the 42-amino acid amyloid-{beta} (A{beta}42) have long been considered pathogenic triggers for AD, clinical evidence linking high levels of A{beta}42 with normal cognition challenges this hypothesis. To resolve this conundrum on the role of A{beta}42 in regulating synaptic activity, we used an adeno-associated viral vector approach that triggers extracellular accumulation of A{beta}42 and spatial memory impairment. We show that A{beta}42 leads to an early increase in excitatory and proximal inhibitory synaptic transmission onto hippocampal CA1 pyramidal cells, and an increased expression of the glutamate transporter GLT-1 in these cells. A{beta}42 accumulation does not cause early cognitive deficits unless accompanied by an increased neuronal GLT-1 expression, suggesting this transporter is a critical mediator of A{beta}42s effects. These findings unveil key molecular and cellular mechanisms implicated with AD pathogenesis.

neuroscience↗

bioRxiv2025

An unsuspected physiological role for mGluRIII glutamate receptors in hippocampal area CA1

Group III metabotropic glutamate receptors (mGluRIII) are expressed broadly throughout the neocortex and hippocampus but are thought to inhibit neurotransmitter release only at a subset of synapses and in a target cell- specific manner. Accordingly, previous slice physiology experiments in hippocampal area CA1 showed that mGluRIII receptors inhibit glutamate and GABA release only at excitatory and inhibitory synapses formed onto GABAergic interneurons, not onto pyramidal cells. Here, we show that the supposed target cell-specific modulation of GABA release only occurs when the extracellular calcium concentration in the recording solution is higher than its physiological concentration in the cerebrospinal fluid. Under more physiological conditions, mGluRIII receptors inhibit GABA release at synapses formed onto both interneurons and pyramidal cells but limit glutamate release only onto interneurons. This previously unrecognized form of mGluRIII-dependent, pre-synaptic modulation of inhibition onto pyramidal cells is accounted for by a reduction in the size of the readily releasable pool, mediated by protein kinase A and its vesicle-associated target proteins, synapsins. Using in vivo whole-cell recordings in behaving mice, we demonstrate that blocking mGluRIII activation in the intact CA1 network results in net effects consistent with decreased inhibition and significantly alters CA1 place cell activity. Together, these findings challenge our current understanding of the role of mGluRIII receptors in the control of synaptic transmission and encoding of spatial information in the hippocampus.

neuroscience↗

bioRxiv2022

NRN-EZ: an application to streamline biophysical modeling of synaptic integration using NEURON

One of the fundamental goals in neuroscience is to determine how the brain processes information and ultimately controls the execution of complex behaviors. Over the past four decades, there has been a steady growth in our knowledge of the morphological and functional diversity of neurons, the building blocks of the brain. These cells clearly differ not only for their anatomy and ion channel distribution, but also for the type, strength, location and temporal pattern of activity of the many synaptic inputs they receive. Compartmental modeling programs like NEURON have become widely used in the neuroscience community to address a broad range of research questions, including how neurons integrate synaptic inputs and propagate information through complex neural networks. One of the main strengths of NEURON is its ability to incorporate user-defined information about the realistic morphology and biophysical properties of different cell types. Although the graphical user interface of the program can be used to run initial exploratory simulations, introducing a stochastic representation of synaptic weights, locations and activation times typically requires users to develop their own codes, a task that can be overwhelming for some beginner users. Here we describe NRN-EZ, an interactive application that allows users to specify complex patterns of synaptic input activity that can be integrated as part of NEURON simulations. Through its graphical user interface, NRN-EZ leverages the learning curve to run computational models in NEURON, for users that do not necessarily have a computer science background.

neuroscience↗

bioRxiv2022

Neuronal glutamate transporters control reciprocal inhibition and gain modulation in D1 medium spiny neurons

Understanding the function of glutamate transporters has broad implications for explaining how neurons integrate information and relay it through complex neuronal circuits. Most of what is currently known about glutamate transporters, specifically their ability to maintain glutamate homeostasis and limit glutamate diffusion away from the synaptic cleft, is based on studies of glial glutamate transporters. By contrast, little is known about the functional implications of neuronal glutamate transporters. The neuronal glutamate transporter EAAC1 is widely expressed throughout the brain, particularly in the striatum, the primary input nucleus of the basal ganglia, a region implicated with movement execution and reward. Here, we show that EAAC1 limits synaptic excitation onto a population of striatal medium spiny neurons identified for their expression of D1 dopamine receptors (D1-MSNs). In these cells, EAAC1 also contributes to strengthen lateral inhibition from other D1-MSNs. Together, these effects contribute to reduce the gain of the input-output relationship and increase the offset at increasing levels of synaptic inhibition in D1-MSNs. By reducing the sensitivity and dynamic range of action potential firing in D1-MSNs, EAAC1 limits the propensity of mice to rapidly switch between behaviors associated with different reward probabilities.

neuroscience↗

bioRxiv2021

Estimating the glutamate transporter surface density in mouse hippocampal astrocytes

Glutamate transporters preserve the spatial specificity of synaptic transmission by limiting glutamate diffusion away from the synaptic cleft, and prevent excitotoxicity by keeping the extracellular concentration of glutamate at low nanomolar levels. Glutamate transporters are abundantly expressed in astrocytes, and previous estimates have been obtained about their surface expression in astrocytes of the rat hippocampus and cerebellum. Analogous estimates for the mouse hippocampus are currently not available. In this work, we derive the surface density of astrocytic glutamate transporters in mice of different ages via quantitative dot blot. We find that the surface density of glial glutamate transporters is similar in 7-8 week old mice and rats. In mice, the levels of glutamate transporters increase until about 6 months of age and then begin to decline slowly. Our data, obtained from a combination of experimental and modeling approaches, show that there are stark differences in the density of expression of glutamate transporters across different sub-cellular compartments, indicating that the extent to which astrocytes limit extrasynaptic glutamate diffusion depends not only on their level of synaptic coverage, but also on the identity of the astrocyte compartment in contact with the synapse. Together, these findings provide information on how heterogeneity in the spatial distribution of glutamate transporters in the plasma membrane of hippocampal astrocytes my alter glutamate receptor activation out of the synaptic cleft. Author summaryIn this work, we use experimental and modeling approaches to estimate the surface density of the glial glutamate transporters GLAST and GLT-1 in mouse hippocampal astrocytes. The results show that the surface density of glutamate transporters in hippocampal astrocytes is similar in 7-8 week old mice and rats. In mice, GLAST and GLT-1 reach their peak expression at ~ 6 months of age. Their expression, however, varies widely across different sub-cellular compartments. These findings indicate that the identity of the sub-cellular compartment of an astrocyte in contact with a glutamatergic synapses, in addition to the extent of its synaptic coverage, is a main factor to limit glutamate spillover and receptor activation at a distance from the release site.

neuroscience↗

bioRxiv2020

Neuromesodermal Progenitors Advance Network Formation of Spinal Neurons and Support Cells in Neural Ribbons In Vitro and Unprotected Survival in a Rat Subacute Contusion Model

Improved human stem cell interventions to treat CNS trauma requires continued expansion of in vitro models and delivery platforms to fill gaps in analysis and treatment. Transplanted neural stem cells (NSCs) face unique, multi-faceted challenges beyond survival that include differentiation, maturation, and integration into a complex cytokine-releasing microenvironment that impinges on a multipotent cell type. Alternate strategies to transplant neurons and neuronal networks deserve reevaluation, particularly since novel differentiation protocols mimicking region-specific developmental and positional cues have recently emerged. To investigate transplantation of neurons and their early networks, we generate in vitro neural ribbons containing spinal neurons and support cells anatomically matched for cervical spinal cord injury (SCI). These glutamate-responsive, electrically-active neural ribbons apply a new hiPSC differentiation strategy transiting through neuromesodermal progenitors (NMps) to derive developmentally relevant spinal motor neurons (SMNs), interneurons (INs), and oligodendrocyte progenitor cells (OPCs). Bioinformatic profiling validates region-specific identities. Neurons and neuronal networks are functionally evaluated for action potential firing, calcium signaling, population activity, and synaptogenesis. NMp-derived neurons survive in vivo within the subacute phase hemi-contusion injury cavity when delivered either as free suspension or as encapsulated networks of pre-formed CNS cytoarchitectures. Delivery as encapsulated networks further supports survival of lower cell numbers and rapid graft penetration into host tissue. Neural network ribbons therefore provide a novel intermediary approach between cell suspensions and complex organoids for investigating network formation and early transplantation events with hiPSC-derived neurons, providing flexibility to rapidly tune cell type(s), cell ratios, and traceable biomarkers. Significance StatementIn the two decades since human stem cell technologies have emerged, the challenge has remained to improve the developmentally relevant derivation of therapeutic cells. The ability to now generate anatomically matched neurons for SCI necessitates a re-evaluation of these cells and their networks in vitro and in vivo. In this study, we apply developmental cues via neuromesodermal progenitors to generate spinal neurons from hiPSCs. Genetic and functional evaluation of these cells as in vitro neuronal networks, due to their capacity to survive and graft effectively within the rat subacute contusion cavity, offer novel approaches for customizing SCI transplantation. This work demonstrates a strategy to develop transplantable, chemically-responsive networks linking in vitro models with injury customization towards improved in vivo outcomes.

neuroscience↗

bioRxiv2020

Late Adolescence Mortality in Mice with Brain-Specific Deletion of the Volume-Regulated Anion Channel Subunit LRRC8A

The leucine-rich repeat-containing family 8 member A (LRRC8A) is an essential subunit of the volume-regulated anion channel (VRAC). VRAC is critical for cell volume control, but its broader physiological functions remain under investigation. Recent studies in the field indicate that Lrrc8a disruption in brain astrocytes reduces neuronal excitability, impairs synaptic plasticity and memory, and protects against cerebral ischemia. In the present work, we generated the brain-wide conditional LRRC8A knock-out mice (LRRC8A bKO) using NestinCre-driven Lrrc8aflox/flox excision in neurons, astrocytes, and oligodendroglia. LRRC8A bKO animals were born close to the expected Mendelian ratio and developed without overt histological abnormalities, but, surprisingly, all died between 5 and 9 weeks of age with a seizure phenotype, which was confirmed by video and EEG recordings. Brain slice electrophysiology detected changes in the excitability of pyramidal cells and modified GABAergic inputs in the hippocampal CA1 region of LRRC8A bKO. LRRC8A-null hippocampi showed increased immunoreactivity of the astrocytic marker GFAP, indicating reactive astrogliosis. We also found decreased whole-brain protein levels of the GABA transporter GAT-1, the glutamate transporter GLT-1, and the astrocytic enzyme glutamine synthetase. Complementary HPLC assays identified reduction in the tissue levels of the glutamate and GABA precursor glutamine. Together, these findings suggest that VRAC provides vital control of brain excitability in mouse adolescence. VRAC deletion leads to a lethal phenotype involving progressive astrogliosis and dysregulation of astrocytic uptake and supply of amino acid neurotransmitters and their precursors.

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bioRxiv2019

Beyond the suprachiasmatic nucleus: circadian rhythmicity shapes astrocyte morphology and neuronal function in hippocampal area CA1

Most animal species operate according to a 24-hour period set by the suprachiasmatic nucleus (SCN) of the hypothalamus. The rhythmic activity of the SCN is known to modulate hippocampal-dependent memory processes, but the molecular and cellular mechanisms that account for this effect remain largely unknown. Here, we show that there are cell-type specific structural and functional changes that occur with circadian rhythmicity in neurons and astrocytes in hippocampal area CA1. Pyramidal neurons change the surface expression of NMDA receptors, whereas astrocytes change their proximity to synapses. Together, these phenomena alter glutamate clearance, receptor activation and integration of temporally clustered excitatory synaptic inputs, ultimately shaping hippocampal-dependent learning in vivo. We identify corticosterone as a key contributor to changes in synaptic strength. These findings identify important mechanisms through which neurons and astrocytes modify the molecular composition and structure of the synaptic environment, contribute to the local storage of information in the hippocampus and alter the temporal dynamics of cognitive processing.

neuroscience↗

bioRxiv2017

Neuronal glutamate transporters control dopaminergic signaling and compulsive behaviors

There is an ongoing debate on the contribution of the neuronal glutamate transporter EAAC1 to the onset of compulsive behaviors. Here we use behavioral, electrophysiological, molecular and viral approaches in male and female mice to identify the molecular and cellular mechanisms by which EAAC1 controls the execution of repeated motor behaviors. Our findings show that in the striatum, a brain region implicated with movement execution, EAAC1 limits group I metabotropic glutamate receptor (mGluRI) activation, facilitates D1 dopamine receptor (D1R) expression and ensures long-term synaptic plasticity. Blocking mGluRI in slices from mice lacking EAAC1 restores D1R expression and synaptic plasticity. Conversely, activation of intracellular signaling pathways coupled to mGluRI in D1R-expressing striatal neurons of mice expressing EAAC1 leads to reduced D1R expression and increased stereotyped movement execution. These findings identify new molecular mechanisms by which EAAC1 can shape glutamatergic and dopaminergic signals and control repeated movement execution.\n\nSIGNIFICANCE STATEMENTGenetic studies implicate Slc1a1, a gene encoding the neuronal glutamate transporter EAAC1, with obsessive-compulsive disorder (OCD). EAAC1 is abundantly expressed in the striatum, a brain region that is hyperactive in OCD. What remains unknown is how EAAC1 shapes synaptic function in the striatum. Our findings show that EAAC1 limits activation of metabotropic glutamate receptors (mGluRI) in the striatum and, by doing so, it promotes D1R expression. Targeted activation of signaling cascades coupled to mGluRI in mice expressing EAAC1 reduces D1R expression and triggers repeated motor behaviors in mice. These findings provide new information on the molecular basis of OCD and suggest new avenues for its treatment.

neuroscience↗

bioRxiv2017

Global and local excitation and inhibition shape the dynamics of the cortico-striatal-thalamo-cortical pathway

The cortico-striatal-thalamo-cortical (CSTC) pathway is a brain circuit that controls movement execution, habit formation and reward. Hyperactivity in the CSTC pathway is involved in obsessive compulsive disorder, a neuropsychiatric disorder characterized by the execution of repetitive involuntary movements. The striatum shapes the activity of the CSTC pathway through the coordinated activation of two classes of medium spiny neurons (MSNs) expressing D1 or D2 dopamine receptors. The exact mechanisms by which balanced excitation/inhibition of these cells controls the network dynamics of the CSTC pathway remain unclear. Here we use non-linear modeling of neuronal activity and bifurcation theory to investigate how global and local changes in excitation/inhibition of MSNs regulate the activity of the CSTC pathway. Our findings indicate that a global and proportionate increase in excitation/inhibition pushes the system to states of generalized hyper-activity throughout the entire CSTC pathway. Certain disproportionate changes in global excitation/inhibition trigger network oscillations. Local changes in the excitation/inhibition of MSNs generate specific oscillatory behaviors in MSNs and in the CSTC pathway. These findings indicate that subtle changes in the relative strength of excitation/inhibition of MSNs can powerfully control the network dynamics of the CSTC pathway in ways that are not easily predicted by its synaptic connections.

neuroscience↗