Adult trkB signaling in parvalbumin interneurons is essential to prefrontal network dynamics

Inhibitory interneurons expressing parvalbumin (PV) are central to cortical network dynamics, generation of c oscillations, and cognition. Dysfunction of PV interneurons disrupts cortical information processing and cognitive behavior. Brain-derived neurotrophic factor (BDNF)/tyrosine receptor kinase B (trkB) signaling regulates the maturation of cortical PV interneurons but is also implicated in their adult multidimensional functions. Using a novel viral strategy for cell-type-specific and spatially restricted expression of a dominant-negative trkB (trkB.DN), we show that BDNF/trkB signaling is essential to the integrity and maintenance of prefrontal PV interneurons in adult male and female mice. Reduced BDNF/trkB signaling in PV interneurons in the medial prefrontal cortex (mPFC) resulted in deficient PV inhibition and increased baseline local field potential (LFP) activity in a broad frequency band. The altered network activity was particularly pronounced during increased activation of the prefrontal network and was associated with changed dynamics of local excitatory neurons, as well as decreased modulation of the LFP, abnormalities that appeared to generalize across stimuli and brain states. In addition, our findings link reduced BDNF/trkB signaling in prefrontal PV interneurons to increased aggression. Together our investigations demonstrate that BDNF/trkB signaling in PV interneurons in the adult mPFC is essential to local network dynamics and cognitive behavior. Our data provide direct support for the suggested association between decreased trkB signaling, deficient PV inhibition, and altered prefrontal circuitry.ERCSwedish Research CouncilCAPES-STINT Program GrantKarolinska InstitutetKnut and Alice Wallenberg FoundationSTINT Program Joint Brazilian-Swedish Research Collaboration GrantPublishe

Synaptic plasticity in local networks of neocortical layer 2/3

The neocortex is a hierarchal organ in which information processing takes on place on many levels, from subcellular signalling all the way to neural networks. Neocortical local neuronal networks (microcircuits), composed of interconnected neurons, form elementary information processing units within the cortex. Pyramidal cells, the primary glutamatergic cells in the cortex, receive synaptic input both from within the neocortex and from more distant cortical and sub-cortical regions. The strength of these inputs can be modified on various time scales. The strength of pyramidal-pyramidal (P-P) cell unitary connections can be modified long-term, depending on the timing of action potentials (APs) in the pre- and post-synaptic cells (spike-timing dependent plasticity, STDP). We reported that the learning rule governing STDP modification is regulated by preceding activity in a postsynaptic neuron. Moreover, we have shown that the difference between STDP observed at layer 2/3 (L2/3) P-P cell connections and STDP studied at other excitatory connections in the neocortex is attributed to a fundamental difference in synaptic properties, suggesting that a L2/3 pyramidal cell is able to recognize its presynaptic partner and form physiologically distinct synapses based on the origin of input. Additionally, the time-window for the induction phase of spike timing- dependent long-term potentiation (STD-LTP) and depression (LTD) at L2/3 P-P connections and its dependence on post-synaptic cell spine calcium concentrations was further examined using data-based computational modelling. We have shown that the resulting synaptic gain change depends on a 15 ms window following synaptic activation. Our data suggested a theoretical enzyme-like Ca2+ sensor that could account for the observed synaptic gain changes in L2/3 P-P connections. Synaptic LTP is thought to be a crucial component underlying learning and memory. Neurodegenerative disorders, such as the Alzheimer s disease (AD) are commonly associated with cognitive impairment and memory loss. We reported that STD-LTP induction at excitatory inputs onto L2/3 pyramidal cells in a mouse model of Alzheimer s disease was impaired as early as at 3.5 months of age, at the very onset of AD-like pathology and prior to amyloid plaque formation. STD-LTP was also abolished at L2/3 P-P connections in wild-type brain slices after soluble non-fibrillar Abeta(25-35) application. The underlying mechanism was the selective Abeta-induced reduction of AMPAR-mediated currents. Meanwhile, STD-LTP induction could be rescued by application of AMPAR desensitization antagonist, cyclothiazide. Thus, we have demonstrated a novel target for AD pathology as well as a means of rescuing STDP under AD s neurodegenerative conditions. Synaptic plasticity consists of multiple variations in synaptic gain taking place over different time scales and between different cell types. In another instance, inhibitory connections from FSN interneuron onto the pyramidal cell can undergo short-term changes in synaptic gain following a postsynaptic AP burst. Previous studies suggested that retrograde dendritic release of glutamate regulates such short-term changes. We further clarified the molecular mechanism of retrograde signalling by showing the SAT2-mediated glutamine transport to be is a necessary precursor for retrograde signalling at FSN-pyramidal cell connections, substantiating the role of glutamate as a retrograde messenger at this synapse

Unifying mechanism behind the onset of acquired epilepsy

International audienceAcquired epilepsy (AE) can result from a number of brain insults and neurological diseases with wide etiological diversity sharing one common outcome of brain epileptiform activity. This implies that despite their disparity, all these initiating pathologies affect the same fundamental brain functions underlying network excitability. Identifying such mechanisms and their availability as therapeutic targets would help develop an effective strategy for epileptogenesis prevention. In this opinion article, we propose that the vicious cycle of NADPH oxidase (NOX)-mediated oxidative stress and glucose hypometabolism is the underlying cause of AE, as available data reveal a critical role for both pathologies in epileptogenesis and the process of seizure initiation. Altogether, here we present a novel view on the mechanisms behind the onset of AE and identify therapeutic targets for potential clinical applications

Activation of NADPH oxidase is the primary trigger of epileptic seizures in rodent models

International audienceObjective: ​ Despite decades of epilepsy research, 30% of focal epilepsies remain resistant to anti-seizure drugs, with effective drug development impeded by lack of understanding on how seizures are initiated. Here we report the mechanism of seizure onset relevant to most seizures characteristic for focal epilepsies.Methods: ​ Electric and metabolic network parameters were measured using several seizure models in mouse hippocampal slices and acutely-induced seizures in rats ​ in-vivo ​ to determine metabolic events occuring at seizure onset.Results: ​ We show that the seizure onset is associated with a rapid release of H​ 2​ O​ 2​ resulting from NMDA receptor-mediated activation of NADPH oxidase (NOX). NOX blockade prevented the fast H​ 2​ O​ 2​ release as well as the DC shift and seizure-like event induction in slices. Similarly, intracerebroventricular injection of NOX antagonists prevented acutely induced seizures in rats.Interpretation: ​ Our results show that seizures are initiated by NMDA receptor-mediated NOX-induced oxidative stress and can be arrested by NOX inhibition. We introduce a novel use for blood-brain barrier-permeable NOX inhibitor with a significant potential to become the first seizure-specific medication. Thus, targeting NOX may provide a breakthrough treatment for focal epilepsies

Dietary energy substrates reverse early neuronal hyperactivity in a mouse model of Alzheimer's disease

Deficient energy metabolism and network hyperactivity are the early symptoms of Alzheimer's disease (AD). In this study, we show that administration of exogenous oxidative energy substrates (OES) corrects neuronal energy supply deficiency that reduces the amyloid-beta-induced abnormal neuronal activity in vitro and the epileptic phenotype in AD model in vivo. In vitro, acute application of protofibrillar amyloid-142 (A142) induced aberrant network activity in wild-type hippocampal slices that was underlain by depolarization of both the neuronal resting membrane potential and GABA-mediated current reversal potential. A142 also impaired synaptic function and long-term potentiation. These changes were paralleled by clear indications of impaired energy metabolism, as indicated by abnormal NAD(P)H signaling induced by network activity. However, when glucose was supplemented with OES pyruvate and 3-beta-hydroxybutyrate, A142 failed to induce detrimental changes in any of the above parameters. We administered the same OES as chronic supplementation to a standard diet to APPswe/PS1dE9 transgenic mice displaying AD-related epilepsy phenotype. In the ex-vivo slices, we found neuronal subpopulations with significantly depolarized resting and GABA-mediated current reversal potentials, mirroring abnormalities we observed under acute A1-42 application. Ex-vivo cortex of transgenic mice fed with standard diet displayed signs of impaired energy metabolism, such as abnormal NAD(P)H signaling and strongly reduced tolerance to hypoglycemia. Transgenic mice also possessed brain glycogen levels twofold lower than those of wild-type mice. However, none of the above neuronal and metabolic dysfunctions were observed in transgenic mice fed with the OES-enriched diet. In vivo, dietary OES supplementation abated neuronal hyperexcitability, as the frequency of both epileptiform discharges and spikes was strongly decreased in the APPswe/PS1dE9 mice placed on the diet. Altogether, our results suggest that early AD-related neuronal malfunctions underlying hyperexcitability and energy metabolism deficiency can be prevented by dietary supplementation with native energy substrates. Read the Editorial Highlight for this article on doi: 10.1111/jnc.12138.</p

Secretagogin is a Ca2+-binding protein specifying subpopulations of telencephalic neurons

The Ca2+-binding proteins (CBPs) parvalbumin, calbindin, and calretinin are phenotypic markers of terminally differentiated neurons in the adult brain. Although subtle phylogenetic variations in the neuronal distribution of these CBPs may occur, morphologically and functionally diverse subclasses of interneurons harbor these proteins in olfactory and corticolimbic areas. Secretagogin (scgn) is a recently cloned CBP from pancreatic β and neuroendocrine cells. We hypothesized that scgn is expressed in the mammalian brain. We find that scgn is a marker of neuroblasts commuting in the rostral migratory stream. Terminally differentiated neurons in the olfactory bulb retain scgn expression, with scgn being present in periglomerular cells and granular layer interneurons. In the corticolimbic system, scgn identifies granule cells distributed along the dentate gyrus, indusium griseum, and anterior hippocampal continuation emphasizing the shared developmental origins, and cytoarchitectural and functional similarities of these neurons. We also uncover unexpected phylogenetic differences in scgn expression, since this CBP is restricted to primate cholinergic basal forebrain neurons. Overall, we characterize scgn as a neuron-specific CBP whose distribution identifies neuronal subtypes and hierarchical organizing principles in the mammalian brain

In&nbsp;Vivo Chimeric Alzheimer’s Disease Modeling of Apolipoprotein E4 Toxicity in Human Neurons

Despite its clear impact on Alzheimer's disease (AD) risk, apolipoprotein (apo) E4's contributions to AD etiology remain poorly understood. Progress in answering this and other questions in AD research has been limited by an inability to model human-specific phenotypes in an in&nbsp;vivo environment. Here we transplant human induced pluripotent stem cell (hiPSC)-derived neurons carrying normal apoE3 or pathogenic apoE4 into human apoE3 or apoE4 knockin mouse hippocampi, enabling us to disentangle the effects of apoE4 produced in human neurons and in the brain environment. Using single-nucleus RNA sequencing (snRNA-seq), we identify key transcriptional changes specific to human neuron subtypes in response to endogenous or exogenous apoE4. We also find that Aβ from transplanted human neurons forms plaque-like aggregates, with differences in localization and interaction with microglia depending on the transplant and host apoE genotype. These findings highlight the power of in&nbsp;vivo chimeric disease modeling for studying AD

Neuronal APOE4 removal protects against tau-mediated gliosis, neurodegeneration and myelin deficits

Apolipoprotein E4 (APOE4) is the strongest known genetic risk factor for late-onset Alzheimer's disease (AD). Conditions of stress or injury induce APOE expression within neurons, but the role of neuronal APOE4 in AD pathogenesis is still unclear. Here we report the characterization of neuronal APOE4 effects on AD-related pathologies in an APOE4-expressing tauopathy mouse model. The selective genetic removal of APOE4 from neurons led to a significant reduction in tau pathology, gliosis, neurodegeneration, neuronal hyperexcitability and myelin deficits. Single-nucleus RNA-sequencing revealed that the removal of neuronal APOE4 greatly diminished neurodegenerative disease-associated subpopulations of neurons, oligodendrocytes, astrocytes and microglia whose accumulation correlated to the severity of tau pathology, neurodegeneration and myelin deficits. Thus, neuronal APOE4 plays a central role in promoting the development of major AD pathologies and its removal can mitigate the progressive cellular and tissue alterations occurring in this model of APOE4-driven tauopathy

Dentate gyrus and CA3 GABAergic interneurons bidirectionally modulate signatures of internal and external drive to CA1

Specific classes of GABAergic neurons play specific roles in regulating information processing in the brain. In the hippocampus, two major classes, parvalbumin-expressing (PV+) and somatostatin-expressing (SST+), differentially regulate endogenous firing patterns and target subcellular compartments of principal cells. How these classes regulate the flow of information throughout the hippocampus is poorly understood. We hypothesize that PV+ and SST+ interneurons in the dentate gyrus (DG) and CA3 differentially modulate CA3 patterns of output, thereby altering the influence of CA3 on CA1. We find that while suppressing either interneuron class increases DG and CA3 output, the effects on CA1 were very different. Suppressing PV+ interneurons increases local field potential signatures of coupling from CA3 to CA1 and decreases signatures of coupling from entorhinal cortex to CA1; suppressing SST+ interneurons has the opposite effect. Thus, DG and CA3 PV+ and SST+ interneurons bidirectionally modulate the flow of information through the hippocampal circuit