Subanesthetic Ketamine Reactivates Adult Cortical Plasticity to Restore Vision from Amblyopia

Grieco, Steven F.; Qiao, Xin; Zheng, Xiaoting; Liu, Yong-Jun; Chen, Lujia; Hai, Zhang; Yu, Zhaoxia; Gavornik, Jeffrey P.; Lai, Cary; Gandhi, Sunil; Holmes, Todd C.; Xu, Xiangmin

doi:10.1016/j.cub.2020.07.008

Cited by 43 publications

(49 citation statements)

References 81 publications

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“…A small metal baseplate is glued around the lens, and the headmounted miniscope is magnetically attached to the baseplate. As established in our published studies (Grieco et al, 2021;Grieco et al, 2020;Sun et al, 2019;Wong et al, 2021), GRIN lens implants and the stability of the miniscope attachment permit longitudinal dynamic imaging results to be aligned across sessions and multiple days due to stable registration. Hundreds of neurons can be captured simultaneously in a 700 μm x 450 μm field of view, with a resolution of ~0.9 μm per pixel (Fig.…”

Section: Miniscope Imaging Of Neural Population Activities In 3xtg-ad Hippocampal Ca1mentioning

confidence: 86%

Spatial coding defects of hippocampal neural ensemble calcium activities in the 3xTg-AD Alzheimer’s disease mouse model

Lin

Chen

Baglietto‐Vargas

et al. 2021

Preprint

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Background Alzheimer’s disease (AD) causes progressive age-related defects in memory and cognitive function, and has emerged as a major health and socio-economic concern in the US and worldwide. To develop effective therapeutic treatments for AD, we need to better understand the neural mechanisms by which AD causes memory loss and cognitive deficits. Methods Here we examine large scale hippocampal neural population calcium activities imaged at single cell resolution in a triple-transgenic Alzheimer’s disease mouse model (3xTg-AD) that presents both amyloid plaque and neurofibrillary pathological features along with age-related behavioral defects. To measure encoding of environmental location in hippocampal neural ensembles in the 3xTg-AD mice in vivo, we performed GCaMP6-based calcium imaging using head-mounted, miniature fluorescent microscopes (“miniscopes”) on freely moving animals. We compared hippocampal CA1 excitatory neural ensemble activities during open-field exploration and track-based route-running behaviors in age-matched AD and control mice at young (3–6.5 months old) and old (18–21 months old) animals. Results 3xTg-AD CA1 excitatory cells display significantly higher calcium activity rates compared with Non-Tg controls for both the young and old age groups during spatial exploration, suggesting that in vivo enhanced neuronal calcium ensemble activity is a disease feature. Increased ages are correlated with decreased neural calcium activity rates across genotypes. CA1 neuronal populations of 3xTg-AD mice show lower spatial information scores compared with control mice. Spatial firing of CA1 neurons of old 3xTg-AD mice also displays higher sparsity and spatial coherence, indicating less place specificity for spatial representation. We find locomotion significantly modulates the amplitude of hippocampal neural calcium ensemble activities in 3xTg-AD mice, but not in non-transgenic controls during open field ambulatory movements. Conclusions Our data offers new and comprehensive information about age-dependent neural circuit activity changes in this important AD mouse model, and provides strong evidence that spatial coding defects in the neuronal population activities are associated with AD pathology and AD-related memory behavioral deficits.

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Section: Miniscope Imaging Of Neural Population Activities In 3xtg-ad Hippocampal Ca1mentioning

confidence: 86%

Spatial coding defects of hippocampal neural ensemble calcium activities in the 3xTg-AD Alzheimer’s disease mouse model

Lin

Chen

Baglietto‐Vargas

et al. 2021

Preprint

Self Cite

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“…By contrast, the excitability of FS-GABAergic interneuron was not reduced in ctoNrg1 mice where Nrg1 was overexpressed in excitatory pyramidal neurons 26 . Recent studies indicated that NRG1 was highly expressed in PV-positive GABAergic interneurons and was important for the plasticity of the visual cortex 56,57 . Together, these results demonstrated the function of NRG1 in GABAergic interneurons.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of neuregulin 1 in GABAergic interneurons results in reversible cortical disinhibition

Wang

Zhao

et al. 2021

Nat Commun

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Cortical disinhibition is a common feature of several neuropsychiatric diseases such as schizophrenia, autism and intellectual disabilities. However, the underlying mechanisms are not fully understood. To mimic increased expression of Nrg1, a schizophrenia susceptibility gene in GABAergic interneurons from patients with schizophrenia, we generated gtoNrg1 mice with overexpression of Nrg1 in GABAergic interneurons. gtoNrg1 mice showed cortical disinhibition at the cellular, synaptic, neural network and behavioral levels. We revealed that the intracellular domain of NRG1 interacts with the cytoplasmic loop 1 of Nav1.1, a sodium channel critical for the excitability of GABAergic interneurons, and inhibits Nav currents. Intriguingly, activation of GABAergic interneurons or restoring NRG1 expression in adulthood could rescue the hyperactivity and impaired social novelty in gtoNrg1 mice. These results identify mechanisms underlying cortical disinhibition related to schizophrenia and raise the possibility that restoration of NRG1 signaling and GABAergic function is beneficial in certain neuropsychiatric disorders.

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“…Furthermore, the highly-selective NMDA receptor antagonist MK-801, a ligand with similar mechanisms to ketamine, has been found to increase gamma in the cortex by targeting pyramidal neurons and PV-interneurons (Hudson et al, 2020). Ketamine's therapeutic effects also extend to alleviating amblyopia via inhibitory cortical PV-neurons (Grieco et al, 2020). Prior work has shown that the long-term anti-dyskinetic effect of ketamine correlates with changes in dendritic spine density, specifically a reduction of multi-synaptic mushroom spines, in the striatum, yet changes in dendritic spines in the M1 had not been investigated in that study.…”

Section: Ketamine Exposure Is Associated With a Days-long Increase Inmentioning

confidence: 99%

Spectral Signatures of L-DOPA-Induced Dyskinesia Depend on L-DOPA Dose and are Suppressed by Ketamine

Bartlett

Sherman

et al. 2020

Preprint

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L-DOPA-induced dyskinesias (LID) are debilitating motor symptoms of dopamine-replacement therapy for Parkinson′s disease (PD) that emerge after years of L-DOPA treatment. While there is an abundance of research into the cellular and synaptic origins of LID, less is known about how LID impacts systems-level circuits and neural synchrony, how synchrony is affected by the dose and duration of L-DOPA exposure, or how potential novel treatments for LID, such as sub- anesthetic ketamine, alter this activity. Sub-anesthetic ketamine treatments have recently been shown to reduce LID, and ketamine is known to affect neural synchrony. To investigate these questions, we measured locomotor and local-field potential (LFP) activity from the motor cortex (M1) and the striatum of preclinical rodent models of PD and LID. In the first experiment, we investigated the effect of the LID priming procedures and L-DOPA dose on neural signatures of LID. Two common priming procedures were compared: a high-dose procedure that exposed unilateral 6-hydroxydopamine-lesioned rats to 12 mg/kg L-DOPA for 7 days, and a low-dose procedure that exposed rats to 7 mg/kg L-DOPA for 21 days. Consistent with reports from other groups, high-dose priming triggered LID and 80-Hz oscillations; however, these 80-Hz oscillations were not observed under the low-dose procedure despite clear evidence of LID, indicating that 80- Hz oscillations are not an exclusive signature of LID. Instead, the low-dose procedure resulted in the weeks-long gradual emergence of non-oscillatory broadband gamma activity (> 30 Hz) in the striatum and theta-to-high-gamma cross-frequency coupling (CFC) in M1. In a second set of experiments, we investigated how ketamine exposure affects spectral signatures of low-dose L- DOPA priming. During each neural recording session, ketamine was delivered through 5 injections (20 mg/kg, i.p.) administered every 2 hours. We found that ketamine exposure suppressed striatal broadband gamma associated with LID, but enhanced M1 broadband activity. We also found that M1 theta-to-high-gamma CFC associated with the LID on-state was suppressed by ketamine. These results suggest that ketamine′s therapeutic effects are region specific. Our findings also have clinical implications as we are the first to report novel oscillatory signatures associated with the common low-dose LID priming procedure that more closely models dopamine replacement therapy in individuals with PD, and as we identify neural correlates of the anti-dyskinetic activity of sub-anesthetic ketamine treatment.

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Subanesthetic Ketamine Reactivates Adult Cortical Plasticity to Restore Vision from Amblyopia

Cited by 43 publications

References 81 publications

Spatial coding defects of hippocampal neural ensemble calcium activities in the 3xTg-AD Alzheimer’s disease mouse model

Spatial coding defects of hippocampal neural ensemble calcium activities in the 3xTg-AD Alzheimer’s disease mouse model

Overexpression of neuregulin 1 in GABAergic interneurons results in reversible cortical disinhibition

Spectral Signatures of L-DOPA-Induced Dyskinesia Depend on L-DOPA Dose and are Suppressed by Ketamine

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