Targeting aberrant dendritic integration to treat cognitive comorbidities of epilepsy

AbstractMemory deficits are a debilitating symptom of epilepsy, but little is known about mechanisms underlying cognitive deficits. Here, we describe a Na+ channel-dependent mechanism underlying altered hippocampal dendritic integration, degraded place coding, and deficits in spatial memory.Two-photon glutamate uncaging experiments revealed that the mechanisms constraining the generation of Na+ spikes in hippocampal 1st order pyramidal cell dendrites are profoundly degraded in experimental epilepsy. This phenomenon was reversed by selectively blocking Nav1.3 sodium channels. In-vivo two-photon imaging revealed that hippocampal spatial representations were less precise in epileptic mice. Blocking Nav1.3 channels significantly improved the precision of spatial coding, and reversed hippocampal memory deficits.Thus, a dendritic channelopathy may underlie cognitive deficits in epilepsy and targeting it pharmacologically may constitute a new avenue to enhance cognition.One Sentence SummaryImpaired input computations via aberrant dendritic spikes in chronic epilepsy degrade neuronal place codes and spatial memory

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Electro-acupuncture Alleviates METH Withdrawal-induced Spatial Memory Deficits by Restoring Astrocyte-drived Glutamate Uptake in dCA1

10.1101/2020.05.20.106153 ◽

2020 ◽

Author(s):

Pengbo Shi ◽

Zhaosu Li ◽

Xing Xu ◽

Jiaxun Nie ◽

Dekang Liu ◽

...

Keyword(s):

Spatial Memory ◽

Cognitive Deficits ◽

Glutamate Uptake ◽

Cognitive Disorders ◽

Memory Deficits ◽

Therapeutic Interventions ◽

Therapeutic Effects ◽

Non Invasive ◽

The Brain

ABSTRACTMethamphetamine (METH) is frequently abused drug and produces cognitive deficits. METH could induce hyper-glutamatergic state in the brain, which could partially explain METH-related cognitive deficits, but the synaptic etiology remains incompletely understood. To address this issue, we explored the role of dCA1 tripartite synapses and the potential therapeutic effects of electro-acupuncture (EA) in the development of METH withdrawal-induced spatial memory deficits in mice. We found that METH withdrawal weakened astrocytic capacity of glutamate (Glu) uptake, but failed to change Glu release from dCA3, which lead to hyper-glutamatergic excitotoxicity at dCA1 tripartite synapses. By restoring the astrocytic capacity of Glu uptake, EA treatments suppressed the hyper-glutamatergic state and normalized the excitability of postsynaptic neuron in dCA1, finally alleviated spatial memory deficits in METH withdrawal mice. These findings indicate that astrocyte at tripartite synapses might be a key target for developing therapeutic interventions against METH-associated cognitive disorders, and EA represent a promising non-invasive therapeutic strategy for the management of drugs-caused neurotoxicity.

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Dysregulation of hippocampal adult-born immature neurons disrupts a brain-wide network for spatial memory

10.1101/2020.09.02.273649 ◽

2020 ◽

Author(s):

Hechen Bao ◽

Zhiqiang Hu ◽

Sung-ho Lee ◽

Ramya Kolagani ◽

Tzu-Hao Harry Chao ◽

...

Keyword(s):

Spatial Memory ◽

Cognitive Deficits ◽

Insular Cortex ◽

Brain Regions ◽

Small Population ◽

Dorsal Thalamus ◽

Immature Neurons ◽

Hippocampal Ca3 ◽

Adult Born Neurons

SummaryMounting evidence suggests that cognitive deficits associated with various neurological disorders may arise in part from a small population of dysregulated adult-born neurons in the dentate gyrus (DG). How these dysregulated adult-born neurons contribute to brain-wide network maladaptation and subsequent cognitive deficits remains unknown. Using an established mouse model with a small number of time-stamped dysregulated adult-born immature neurons and spatial memory deficits, we performed resting state functional magnetic resonance imaging and found that approximately 500 deficient immature neurons (<0.1% of total DG granule neurons) are sufficient to induce a significant decrease in the functional connectivity between DG and insular cortex (IC), two brain regions without direct anatomical connections. Furthermore, using a combination of rabies-based retrograde tracing and in vivo fiber photometry recording, we demonstrated that dysregulated adult-born neurons induce aberrant activity and synchrony in local hippocampal CA3 and CA1 regions, as well as distal medial-dorsal thalamus and IC regions during a spatial memory process. These results suggest that a few hundred dysregulated adult-born immature neurons can impact brain-wide network dynamics across several anatomically discrete regions and collectively contribute to impaired cognitive functions.

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Impaired spatial memory codes in a mouse model of Rett syndrome

eLife ◽

10.7554/elife.31451 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 8

Author(s):

Sara E Kee ◽

Xiang Mou ◽

Huda Y Zoghbi ◽

Daoyun Ji

Keyword(s):

Mouse Model ◽

Spatial Memory ◽

Rett Syndrome ◽

Spatial Information ◽

Memory Deficits ◽

Place Cells ◽

Long Time ◽

Spatial Memories ◽

Memory Codes

The Mecp2+/- mouse model recapitulates many phenotypes of patients with Rett syndrome (RTT), including learning and memory deficits. It is unknown, however, how the disease state alters memory circuit functions in vivo in RTT mice. Here we recorded from hippocampal place cells, which are thought to encode spatial memories, in freely moving RTT mice and littermate controls. We found that place cells in RTT mice are impaired in their experience-dependent increase of spatial information. This impairment is accompanied by an enhanced baseline firing synchrony of place cells within ripple oscillations during rest, which consequently occludes the increase in synchrony after a novel experience. Behaviorally, contextual memory is normal at short but not long time scale in RTT mice. Our results suggest that hypersynchrony interferes with memory consolidation and leads to impaired spatial memory codes in RTT mice, providing a possible circuit mechanism for memory deficits in Rett Syndrome.

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Unbalanced dendritic inhibition of CA1 neurons drives spatial-memory deficits in the Ts2Cje Down syndrome model

Nature Communications ◽

10.1038/s41467-019-13004-9 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 6

Author(s):

Sergio Valbuena ◽

Álvaro García ◽

Wilfrid Mazier ◽

Ana V. Paternain ◽

Juan Lerma

Keyword(s):

Down Syndrome ◽

Spatial Memory ◽

Cognitive Deficits ◽

Pyramidal Cells ◽

Memory Deficits ◽

Synaptic Inhibition ◽

Ca1 Neurons ◽

Ca1 Pyramidal Cells ◽

Encoding Gene ◽

Inhibitory Tone

Abstract Overinhibition is assumed one of the main causes of cognitive deficits (e.g. memory impairment) in mouse models of Down syndrome (DS). Yet the mechanisms that drive such exaggerated synaptic inhibition and their behavioral effects remain unclear. Here we report the existence of bidirectional alterations to the synaptic inhibition on CA1 pyramidal cells in the Ts2Cje mouse model of DS which are associated to impaired spatial memory. Furthermore, we identify triplication of the kainate receptor (KAR) encoding gene Grik1 as the cause of these phenotypes. Normalization of Grik1 dosage in Ts2Cje mice specifically restored spatial memory and reversed the bidirectional alterations to CA1 inhibition, but not the changes in synaptic plasticity or the other behavioral modifications observed. We propose that modified information gating caused by disturbed inhibitory tone rather than generalized overinhibition underlies some of the characteristic cognitive deficits in DS.

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Impairments of Synaptic Plasticity Induction Threshold and Network Oscillatory Activity in the Hippocampus Underlie Memory Deficits in a Non-Transgenic Mouse Model of Amyloidosis

Biology ◽

10.3390/biology9070175 ◽

2020 ◽

Vol 9 (7) ◽

pp. 175

Author(s):

Jennifer Mayordomo-Cava ◽

Guillermo Iborra-Lázaro ◽

Souhail Djebari ◽

Sara Temprano-Carazo ◽

Irene Sánchez-Rodríguez ◽

...

Keyword(s):

Cognitive Deficits ◽

Amyloid Β ◽

Memory Deficits ◽

Long Term Potentiation ◽

Biologically Active ◽

Network Activity ◽

Oscillatory Activity ◽

In Vivo Model

In early Alzheimer disease (AD) models synaptic failures and upstreaming aberrant patterns of network synchronous activity result in hippocampal-dependent memory deficits. In such initial stage, soluble forms of Amyloid-β (Aβ) peptides have been shown to play a causal role. Among different Aβ species, Aβ25–35 has been identified as the biologically active fragment, as induces major neuropathological signs related to early AD stages. Consequently, it has been extensively used to acutely explore the pathophysiological events related with neuronal dysfunction induced by soluble Aβ forms. However, the synaptic mechanisms underlying its toxic effects on hippocampal-dependent memory remain unresolved. Here, in an in vivo model of amyloidosis generated by intracerebroventricular injections of Aβ25–35 we studied the synaptic dysfunction mechanisms underlying hippocampal cognitive deficits. At the synaptic level, long-term potentiation (LTP) of synaptic excitation and inhibition was induced in CA1 region by high frequency simulation (HFS) applied to Schaffer collaterals. Aβ25–35 was found to alter metaplastic mechanisms of plasticity, facilitating long-term depression (LTD) of both types of LTP. In addition, aberrant synchronization of hippocampal network activity was found while at the behavioral level, deficits in hippocampal-dependent habituation and recognition memories emerged. Together, our results provide a substrate for synaptic disruption mechanism underlying hippocampal cognitive deficits present in Aβ25–35 amyloidosis model.

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When the air hits your brain: decreased arterial pulsatility after craniectomy leading to impaired glymphatic flow

Journal of Neurosurgery ◽

10.3171/2019.2.jns182675 ◽

2020 ◽

Vol 133 (1) ◽

pp. 210-223 ◽

Cited By ~ 7

Author(s):

Benjamin A. Plog ◽

Nanhong Lou ◽

Clifford A. Pierre ◽

Alex Cove ◽

H. Mark Kenney ◽

...

Keyword(s):

Cognitive Deficits ◽

Brain Function ◽

Microglial Activation ◽

Ex Vivo ◽

Brain Parenchyma ◽

Neurological Function ◽

Neurosurgical Procedures ◽

Two Photon ◽

Syndrome Of The Trephined

OBJECTIVECranial neurosurgical procedures can cause changes in brain function. There are many potential explanations, but the effect of simply opening the skull has not been addressed, except for research into syndrome of the trephined. The glymphatic circulation, by which CSF and interstitial fluid circulate through periarterial spaces, brain parenchyma, and perivenous spaces, depends on arterial pulsations to provide the driving force for bulk flow; opening the cranial cavity could dampen this force. The authors hypothesized that a craniectomy, without any other pathological insult, is sufficient to alter brain function due to reduced arterial pulsatility and decreased glymphatic flow. Furthermore, they postulated that glymphatic impairment would produce activation of astrocytes and microglia; with the reestablishment of a closed cranial compartment, the glymphatic impairment, astrocytic/microglial activation, and neurobehavioral decline caused by opening the cranial compartment might be reversed.METHODSUsing two-photon in vivo microscopy, the pulsatility index of cortical vessels was quantified through a thinned murine skull and then again after craniectomy. Glymphatic influx was determined with ex vivo fluorescence microscopy of mice 0, 14, 28, and 56 days following craniectomy or cranioplasty; brain sections were immunohistochemically labeled for GFAP and CD68. Motor and cognitive performance was quantified with rotarod and novel object recognition tests at baseline and 14, 21, and 28 days following craniectomy or cranioplasty.RESULTSPenetrating arterial pulsatility decreased significantly and bilaterally following unilateral craniectomy, producing immediate and chronic impairment of glymphatic CSF influx in the ipsilateral and contralateral brain parenchyma. Craniectomy-related glymphatic dysfunction was associated with an astrocytic and microglial inflammatory response, as well as with the development of motor and cognitive deficits. Recovery of glymphatic flow preceded reduced gliosis and return of normal neurological function, and cranioplasty accelerated this recovery.CONCLUSIONSCraniectomy causes glymphatic dysfunction, gliosis, and changes in neurological function in this murine model of syndrome of the trephined.

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Interplay of miR-137 and EZH2 contributes to the genome-wide redistribution of H3K27me3 underlying the Pb-induced memory impairment

Cell Death and Disease ◽

10.1038/s41419-019-1912-7 ◽

2019 ◽

Vol 10 (9) ◽

Cited By ~ 9

Author(s):

Xiaozhen Gu ◽

Yi Xu ◽

Wei-Zhen Xue ◽

Yulan Wu ◽

Zi Ye ◽

...

Keyword(s):

Spatial Memory ◽

Memory Impairment ◽

Early Stage ◽

Memory Deficits ◽

Wide Distribution ◽

Morris Water Maze Test ◽

Molecular Change ◽

Genome Wide ◽

Pb Exposure

Abstract Compromised learning and memory is a common feature of multiple neurodegenerative disorders. A paradigm spatial memory impairment could be caused by developmental lead (Pb) exposure. Growing evidence implicates epigenetic modifications in the Pb-mediated memory deficits; however, how histone modifications exemplified by H3K27me3 (H3 Lys27 trimethylation) contribute to this pathogenesis remains poorly understood. Here we found that Pb exposure diminished H3K27me3 levels in vivo by suppressing EZH2 (enhancer of zeste homolog 2) expression at an early stage. EZH2 overexpression in Pb-treated rats rescued the H3K27me3 abundance and partially restored the normal spatial memory, as manifested by the rat performance in a Morris water maze test, and structural analysis of hippocampal spine densities. Furthermore, miR-137 and EZH2 constitute mutually inhibitory loop to regulate the H3K27me3 level, and this feedback regulation could be specifically activated by Pb treatment. Considering genes targeted by H3K27me3, ChIP-chip (chromatin immunoprecipitation on chip) studies revealed that Pb could remodel the genome-wide distribution of H3K27me3, represented by pathways like transcriptional regulation, developmental regulation, cell motion, and apoptosis, as well as a novel Wnt9b locus. As a Wnt isoform associated with canonical and noncanonical signaling, Wnt9b was regulated by the opposite modifications of H3K4me3 (H3 Lys4 trimethylation) and H3K27me3 in Pb-exposed neurons. Rescue trials further validated the contribution of Wnt9b to Pb-induced neuronal impairments, wherein canonical or noncanonical Wnt signaling potentially exhibited destructive or protective roles, respectively. In summary, the study reveals an epigenetic-based molecular change underlying Pb-triggered spatial memory deficits, and provides new potential avenues for our understanding of neurodegenerative diseases with environmental etiology.

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Lupus auto-antibodies act as positive allosteric modulators at NMDA receptors and induce spatial memory deficits

10.1101/791715 ◽

2019 ◽

Author(s):

Kelvin Chan ◽

Jacquelyn Nestor ◽

Tomás S. Huerta ◽

Noele Certain ◽

Gabrielle Moody ◽

...

Keyword(s):

Cell Death ◽

Nervous System ◽

Spatial Memory ◽

Lupus Erythematosus ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Memory Deficits ◽

Allosteric Modulators ◽

Positive Allosteric Modulators

ABSTRACTPatients with Systemic lupus erythematosus (SLE) experience various peripheral and central nervous system manifestations including spatial memory impairment. A subset of auto-antibodies (DNRAbs) cross-react with the GluN2A and GluN2B subunits of the NMDA receptor (NMDAR). We find that these DNRAbs act as positive allosteric modulators on NMDARs with GluN2A-containing NMDARs, even those containing a single GluN2A subunit, exhibiting a much greater sensitivity to DNRAbs than those with exclusively GluN2B. Accordingly, GluN2A-specific antagonists provide greater protection from DNRAb-mediated neuronal cell death than GluN2B antagonists. Using transgenic mice to perturb expression of either GluN2A or GluN2B in vivo, we find that DNRAb-mediated disruption of spatial memory characterized by early neuronal cell death and subsequent microglia-dependent pathologies requires GluN2A-containing NMDARs. Our results indicate that GluN2A-specific antagonists or negative allosteric modulators are strong candidates to treat SLE patients with nervous system dysfunction.

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Increasing dietary choline attenuates spatial memory deficits resulting from exposure to the chemotherapeutic agents cyclophosphamide and doxorubicin

Journal of Psychopharmacology ◽

10.1177/02698811211029752 ◽

2021 ◽

pp. 026988112110297

Author(s):

Bethany E Johns ◽

Melissa Ficken ◽

Melanie E Engberg ◽

Lynn Wecker ◽

Rex M Philpot

Keyword(s):

Spatial Memory ◽

Cognitive Deficits ◽

Memory Deficits ◽

Chemotherapeutic Agents ◽

Standard Diet ◽

Cognitive Domains ◽

Intravenous Injections ◽

Impaired Memory ◽

Dietary Choline

Background: Choline supplementation (+Ch) improves cognitive function in impaired animals and humans. Chemotherapy-related cognitive deficits (CRCDs) occur in cancer patients, and these deficits persist following treatment, adversely impacting quality of life. To date, there are no approved treatments for this condition. Aim: Because +Ch improves impaired memory, it was of interest to determine whether +Ch can attenuate spatial memory deficits induced by the chemotherapeutic agents doxorubicin (DOX) and cyclophosphamide (CYP). Methods: Female BALB/C mice, 64 days of age, were trained in the Morris water maze and baseline performance determined on day 15. Following baseline assessment, mice were placed on +Ch diet (2.0% Ch) or remained on standard diet (0.12% Ch). Mice received intravenous injections of DOX (2.5 mg/kg) and CYP (25 mg/kg), or equivalent volumes of saline (0.9% NaCl), on days 16, 23, 30, and 37, and spatial memory was assessed weekly from day 22 to 71. Results: DOX and CYP produced a prolonged impairment in spatial memory as indicated by an increased latency to the correct zone ( p < 0.05), and a decrease in time in the correct zone ( p < 0.05), % of total swim distance in the correct zone ( p < 0.05) and % entries to the correct zone ( p < 0.05). These effects were attenuated by +Ch. Conclusion: Although it remains to be determined whether this effect extends to other cognitive domains and whether +Ch is prophylactic or therapeutic, these findings suggest that +Ch may be an effective intervention for CRCDs.

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