scholarly journals Medial prefrontal cortical NMDA receptors regulate depression-like behavior and dictate limbic thalamus innervation

2017 ◽  
Author(s):  
Oliver H. Miller ◽  
Andreas Bruns ◽  
Imen Ben Ammar ◽  
Thomas Mueggler ◽  
Benjamin J. Hall
Keyword(s):  
Viral Vectors ◽  
Pyramidal Neurons ◽  
Synaptic Activity ◽  
Dependent Manner ◽  
Prefrontal Cortical ◽  
Limbic Thalamus ◽  
Level Function ◽  
Nmdar Subunit ◽  
Circuit Function ◽  
Activity Dependent

AbstractDepression is a pervasive and debilitating neuropsychiatric disorder. A single, low dose of the NMDA receptor (NMDAR) antagonist ketamine elicits a long-lasting antidepressant response in patients with treatment-resistant major depressive disorder. Developing mechanistic understanding of how NMDAR antagonism alters synapse and circuit function is pivotal to developing translatable, circuit-based therapies for depression. Here using viral vectors, anatomical tracing, fMRI, and optogenetic-assisted circuit analysis, we assessed the role of the NMDAR subunit GluN2B in regulating cellular, synaptic, and circuit-level function and depression-related behavior. We demonstrate that post-developmental deletion of GluN2B from pyramidal neurons in medial prefrontal cortex enhances action potential output in a synaptic activity-dependent manner. GluN2B deletion dictates functional connectivity between mPFC and limbic thalamus but not ventral hippocampus and elicits antidepressant-like behavior. Our findings demonstrate that postsynaptic GluN2B exerts input-specific control of pyramidal neuron innervation, and identify a novel circuit for regulating depression-like behaviors in mice.

scholarly journals Neuroligin3 splice isoforms shape inhibitory synaptic function in the mouse hippocampus

2020 ◽  
Vol 295 (25) ◽  
pp. 8589-8595 ◽  
Author(s):  
Motokazu Uchigashima ◽  
Ming Leung ◽  
Takuya Watanabe ◽  
Amy Cheung ◽  
Timmy Le ◽  
...  
Keyword(s):  
Synaptic Transmission ◽  
Single Cell ◽  
Pyramidal Neurons ◽  
Autism Spectrum ◽  
Synaptic Function ◽  
Synaptic Activity ◽  
Dependent Manner ◽  
Splice Isoforms ◽  
Inhibitory Synaptic Transmission ◽  
Ca1 Pyramidal Neurons

Synapse formation is a dynamic process essential for the development and maturation of the neuronal circuitry in the brain. At the synaptic cleft, trans-synaptic protein–protein interactions are major biological determinants of proper synapse efficacy. The balance of excitatory and inhibitory synaptic transmission (E-I balance) stabilizes synaptic activity, and dysregulation of the E-I balance has been implicated in neurodevelopmental disorders, including autism spectrum disorders. However, the molecular mechanisms underlying the E-I balance remain to be elucidated. Here, using single-cell transcriptomics, immunohistochemistry, and electrophysiology approaches to murine CA1 pyramidal neurons obtained from organotypic hippocampal slice cultures, we investigate neuroligin (Nlgn) genes that encode a family of postsynaptic adhesion molecules known to shape excitatory and inhibitory synaptic function. We demonstrate that the NLGN3 protein differentially regulates inhibitory synaptic transmission in a splice isoform–dependent manner at hippocampal CA1 synapses. We also found that distinct subcellular localizations of the NLGN3 isoforms contribute to the functional differences observed among these isoforms. Finally, results from single-cell RNA-Seq analyses revealed that Nlgn1 and Nlgn3 are the major murine Nlgn genes and that the expression levels of the Nlgn splice isoforms are highly diverse in CA1 pyramidal neurons. Our results delineate isoform-specific effects of Nlgn genes on the E-I balance in the murine hippocampus.

Early NMDA Receptor Ablation in Interneurons Causes an Activity-Dependent E/I Imbalance in vivo in Prefrontal Cortex Pyramidal Neurons of a Mouse Model Useful for the Study of Schizophrenia

2021 ◽  
Author(s):  
Diego E Pafundo ◽  
Carlos A Pretell Annan ◽  
Nicolas M Fulginiti ◽  
Juan E Belforte
Keyword(s):  
Prefrontal Cortex ◽  
Mouse Model ◽  
Pyramidal Neurons ◽  
Gamma Oscillations ◽  
Dependent Manner ◽  
Early Postnatal Development ◽  
Synaptic Inputs ◽  
Selective Ablation ◽  
Activity Dependent

Abstract Altered Excitatory/Inhibitory (E/I) balance of cortical synaptic inputs has been proposed as a central pathophysiological factor for psychiatric neurodevelopmental disorders, including schizophrenia (SZ). However, direct measurement of E/I synaptic balance have not been assessed in vivo for any validated SZ animal model. Using a mouse model useful for the study of SZ we show that a selective ablation of NMDA receptors (NMDAr) in cortical and hippocampal interneurons during early postnatal development results in an E/I imbalance in vivo, with synaptic inputs to pyramidal neurons shifted towards excitation in the adult mutant medial prefrontal cortex (mPFC). Remarkably, this imbalance depends on the cortical state, only emerging when theta and gamma oscillations are predominant in the network. Additional brain slice recordings and subsequent 3D morphological reconstruction showed that E/I imbalance emerges after adolescence concomitantly with significant dendritic retraction and dendritic spine re-localization in pyramidal neurons. Therefore, early postnatal ablation of NMDAr in cortical and hippocampal interneurons developmentally impacts on E/I imbalance in vivo in an activity-dependent manner.

scholarly journals Astrocyte Networks and Epilepsy: When Stars Collide

2009 ◽  
Vol 9 (4) ◽  
pp. 113-115 ◽  
Author(s):  
Michael Wong
Keyword(s):  
Synaptic Transmission ◽  
Gap Junctions ◽  
Connexin 43 ◽  
Molecular Mechanisms ◽  
Epileptiform Activity ◽  
Synaptic Activity ◽  
Structural Basis ◽  
Dependent Manner ◽  
Domain Organization ◽  
Activity Dependent

Loss of Astrocytic Domain Organization in the Epileptic Brain. Oberheim NA, Tian GF, Han X, Peng W, Takano T, Ransom B, Nedergaard M. J Neurosci 2008;28(13):3264–3276. Gliosis is a pathological hallmark of posttraumatic epileptic foci, but little is known about these reactive astrocytes beyond their high glial fibrillary acidic protein (GFAP) expression. Using diolistic labeling, we show that cortical astrocytes lost their nonoverlapping domain organization in three mouse models of epilepsy: posttraumatic injury, genetic susceptibility, and systemic kainate exposure. Neighboring astrocytes in epileptic mice showed a 10-fold increase in overlap of processes. Concurrently, spine density was increased on dendrites of excitatory neurons. Suppression of seizures by the common antiepileptic, valproate, reduced the overlap of astrocytic processes. Astrocytic domain organization was also preserved in APP transgenic mice expressing a mutant variant of human amyloid precursor protein despite a marked upregulation of GFAP. Our data suggest that loss of astrocytic domains was not universally associated with gliosis, but restricted to seizure pathologies. Reorganization of astrocytes may, in concert with dendritic sprouting and new synapse formation, form the structural basis for recurrent excitation in the epileptic brain. Astroglial Metabolic Networks Sustain Hippocampal Synaptic Transmission. Rouach N, Koulakoff A, Abudara V, Willecke K, Giaume C. Science 2008;322(5907):1551–1555. Astrocytes provide metabolic substrates to neurons in an activity-dependent manner. However, the molecular mechanisms involved in this function, as well as its role in synaptic transmission, remain unclear. Here, we show that the gap-junction subunit proteins connexin 43 and 30 allow intercellular trafficking of glucose and its metabolites through astroglial networks. This trafficking is regulated by glutamatergic synaptic activity mediated by AMPA receptors. In the absence of extracellular glucose, the delivery of glucose or lactate to astrocytes sustains glutamatergic synaptic transmission and epileptiform activity only when they are connected by gap junctions. These results indicate that astroglial gap junctions provide an activity-dependent intercellular pathway for the delivery of energetic metabolites from blood vessels to distal neurons.

scholarly journals Common synaptic phenotypes arising from diverse mutations in the human NMDA receptor subunit GluN2A

2020 ◽  
Author(s):  
M. Elmasri ◽  
D. Hunter ◽  
G. Winchester ◽  
W. Aziz ◽  
E. Bates ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Pyramidal Neurons ◽  
Single Gene ◽  
Synaptic Activity ◽  
Molecular Defect ◽  
Loss Of Function ◽  
Nmda Receptor Subunit ◽  
Ca1 Neurons ◽  
Current Decay ◽  
Nmdar Subunit

Dominant mutations in the human gene GRIN2A, encoding NMDA receptor (NMDAR) subunit GluN2A, make a significant and growing contribution to the catalogue of published single-gene epilepsies. Understanding the disease mechanism in these epilepsy patients is complicated by the surprising diversity of effects that the mutations have on NMDARs. We have examined the cell-autonomous impact of 5 severe GluN2A mutations by measuring NMDAR-mediated synaptic currents (NMDAR-EPSCs) in CA1 pyramidal neurons following rescue with human GluN2A mutants. Surprisingly, prolonged NMDAR-EPSC current decay and smaller peak amplitudes were common features of both gain- and loss-of-function mutants despite there being drastic differences between their effects on receptor function and enrichment at synapses. Modelling of NMDARs with mutant properties in CA1 neurons indicates that mutant NMDARs may contribute to broadening of depolarizations during bursts of high-frequency synaptic activity. Overall, the implication is that similar therapeutic approaches may be more widely applicable to patients with GRIN2A-related disorders irrespective of their molecular defect.

scholarly journals Local autocrine signaling of IGF1 synthesized and released by CA1 pyramidal neurons regulates plasticity of dendritic spines

2021 ◽  
Author(s):  
Xun Tu ◽  
Anant Jain ◽  
Helena Decker ◽  
Ryohei Yasuda
Keyword(s):  
Synaptic Plasticity ◽  
Dendritic Spines ◽  
Pyramidal Neurons ◽  
Receptor Activation ◽  
Brain Regions ◽  
Dependent Manner ◽  
Autocrine Signaling ◽  
Ca1 Pyramidal Neurons ◽  
Igf1 Receptor ◽  
Activity Dependent

Insulin-like growth factor 1 (IGF1) regulates hippocampal plasticity, learning, and memory. While circulating, liver-derived IGF1 is known to play an essential role in hippocampal function and plasticity, IGF1 is also synthesized in multiple brain regions, including the hippocampus. However, little is known about the role of hippocampus-derived IGF1 in synaptic plasticity, the type of cells that may provide relevant IGF1, and the spatiotemporal dynamics of IGF1 signaling. Here, using a new FRET sensor for IGF1 signaling, we show that IGF1 in the hippocampus is primarily synthesized in CA1 pyramidal neurons and released in an activity-dependent manner in mice. The local IGF1 release from dendritic spines triggers local autocrine IGF1 receptor activation on the same spine, regulating structural and electrophysiological plasticity of the activated spine. Thus, our study demonstrates a novel mechanism underlying synaptic plasticity by the synthesis and autocrine signaling of IGF1 specific to CA1 pyramidal neurons.

scholarly journals Inhibitory regulation of calcium transients in prefrontal dendritic spines is compromised by a nonsense Shank3 mutation

2020 ◽  
Author(s):  
Farhan Ali ◽  
Ling-Xiao Shao ◽  
Danielle M. Gerhard ◽  
Katherine Sweasy ◽  
Santosh Pothula ◽  
...  
Keyword(s):  
Dendritic Spines ◽  
Pyramidal Neurons ◽  
Autism Spectrum ◽  
Calcium Transients ◽  
Gabaergic Interneurons ◽  
Calcium Dysregulation ◽  
Two Photon Microscopy ◽  
Prefrontal Cortical ◽  
Nmdar Subunit ◽  
Subcellular Resolution

AbstractThe SHANK3 gene encodes a postsynaptic scaffold protein in excitatory synapses, and its disruption is implicated in neurodevelopmental disorders such as Phelan-McDermid syndrome, autism spectrum disorder, and schizophrenia. Most studies of SHANK3 in the neocortex and hippocampus have focused on disturbances in pyramidal neurons. However, GABAergic interneurons likewise receive excitatory inputs and presumably would also be a target of constitutive SHANK3 perturbations. In this study, we characterize the prefrontal cortical microcircuit in awake mice using subcellular-resolution two-photon microscopy. We focused on a nonsense R1117X mutation, which leads to truncated SHANK3 and has been linked previously to cortical dysfunction. We find that R1117X mutants have abnormally elevated calcium transients in apical dendritic spines. The synaptic calcium dysregulation is due to a loss of dendritic inhibition via decreased NMDAR currents and reduced firing of dendrite-targeting somatostatin-expressing (SST) GABAergic interneurons. Notably, upregulation of the NMDAR subunit GluN2B in SST interneurons corrects the excessive synaptic calcium signals and ameliorates learning deficits in R1117X mutants. These findings reveal dendrite-targeting interneurons, and more broadly the inhibitory control of dendritic spines, as a key microcircuit mechanism compromised by the SHANK3 dysfunction.

scholarly journals Activity-dependent trafficking of lysosomes in dendrites and dendritic spines

2017 ◽  
Vol 216 (8) ◽  
pp. 2499-2513 ◽  
Author(s):  
Marisa S. Goo ◽  
Laura Sancho ◽  
Natalia Slepak ◽  
Daniela Boassa ◽  
Thomas J. Deerinck ◽  
...  
Keyword(s):  
Dendritic Spines ◽  
Synaptic Activity ◽  
Synaptic Membrane ◽  
Dependent Manner ◽  
Two Photon ◽  
Acid Type ◽  
Cytoskeletal Dynamics ◽  
And Function ◽  
Actin Cytoskeletal Dynamics ◽  
Activity Dependent

In neurons, lysosomes, which degrade membrane and cytoplasmic components, are thought to primarily reside in somatic and axonal compartments, but there is little understanding of their distribution and function in dendrites. Here, we used conventional and two-photon imaging and electron microscopy to show that lysosomes traffic bidirectionally in dendrites and are present in dendritic spines. We find that lysosome inhibition alters their mobility and also decreases dendritic spine number. Furthermore, perturbing microtubule and actin cytoskeletal dynamics has an inverse relationship on the distribution and motility of lysosomes in dendrites. We also find trafficking of lysosomes is correlated with synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid–type glutamate receptors. Strikingly, lysosomes traffic to dendritic spines in an activity-dependent manner and can be recruited to individual spines in response to local activation. These data indicate the position of lysosomes is regulated by synaptic activity and thus plays an instructive role in the turnover of synaptic membrane proteins.

scholarly journals Activity-dependent modulation of NMDA receptors by endogenous zinc shapes dendritic function in cortical neurons.

2021 ◽  
Author(s):  
Annunziato Morabito ◽  
Yann Zerlaut ◽  
Benjamin Serraz ◽  
Romain Sala ◽  
Pierre Paoletti ◽  
...  
Keyword(s):  
Nmda Receptors ◽  
Cortical Neurons ◽  
Single Neuron ◽  
Pyramidal Neurons ◽  
Synaptic Activity ◽  
Cortical Circuits ◽  
New Perspective ◽  
Activity Dependent

Activation of NMDA receptors (NMDARs) has been proposed to be a key component of single neuron computations in vivo. However is unknown if specific mechanisms control the function of such receptors and modulate input-output transformations performed by cortical neurons under in vivo-like conditions. Here we found that in layer 2/3 pyramidal neurons (L2/3 PNs), repeated synaptic stimulation results in an activity-dependent decrease in NMDARs activity by vesicular zinc. Such a mechanism shifted the threshold for dendritic non-linearities and strongly reduced LTP induction. Modulation of NMDARs was cell- and pathway-specific, being present selectively in L2/3-L2/3 connections but absent in ascending bottom-up inputs originating from L4 neurons. Numerical simulations highlighted that activity-dependent modulation of NMDARs has an important influence in dendritic computations endowing L2/3 PN dendrites with the ability to sustain dendritic non-linear integrations constant across different regimes of synaptic activity like those found in vivo. The present results therefore provide a new perspective on the action of vesicular zinc in cortical circuits by highlighting the role of this endogenous ion in normalizing dendritic integration of PNs during a constantly changing synaptic input pattern.

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