Publications by authors named "Julia Steffen"

18 Publications

  • Page 1 of 1

Hippocampal hyperactivity in a rat model of Alzheimer's disease.

J Neurochem 2021 Feb 14. Epub 2021 Feb 14.

Neuronal Networks Group, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.

Neuronal network dysfunction is a hallmark of Alzheimer's disease (AD). However, the underlying pathomechanisms remain unknown. We analyzed the hippocampal micronetwork in transgenic McGill-R-Thy1-APP rats (APPtg) at the beginning of extracellular amyloid beta (Aβ) deposition. We established two-photon Ca -imaging in vivo in the hippocampus of rats and found hyperactivity of CA1 neurons. Patch-clamp recordings in brain slices in vitro revealed increased neuronal input resistance and prolonged action potential width in CA1 pyramidal neurons. We did neither observe changes in synaptic inhibition, nor in excitation. Our data support the view that increased intrinsic excitability of CA1 neurons may precede inhibitory dysfunction at an early stage of Aβ-deposition and disease progression.
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http://dx.doi.org/10.1111/jnc.15323DOI Listing
February 2021

Selecting the Most Effective DBS Contact in Essential Tremor Patients Based on Individual Tractography.

Brain Sci 2020 Dec 20;10(12). Epub 2020 Dec 20.

Faculty of Medicine and University Hospital Cologne, Department of Neurology, University of Cologne, 50923 Köln, Germany.

Postoperative choice of the most effective deep brain stimulation (DBS) contact in patients with essential tremor (ET) so far relies on lengthy clinical testing. Previous studies showed that the postoperative effectiveness of DBS contacts depends on the distance to the dentatorubrothalamic tract (DRTT). Here, we investigated whether the most effective DBS contact could be determined from calculating stimulation overlap with the individual DRTT. Seven ET patients with bilateral thalamic deep brain stimulation were included retrospectively. Tremor control was assessed for each contact during test stimulation with 2mA. Individual DRTTs were identified from diffusion tensor imaging and contacts were ranked by their stimulation overlap with the respective DRTT in relation to their clinical effectiveness. A linear mixed-effects model was calculated to determine the influence of the DRTT overlap on tremor control. In 92.9% of investigated DBS leads, the contact with the best clinical effect was the contact with the highest or second-highest DRTT-overlap. At the group level, the DRTT-overlap explained 26.7% of the variance in the clinical outcomes ( < 0.001). Our data suggest that the overlap with the DRTT based on individual tractography may serve as a marker to determine the most effective DBS contact in ET patients and reduce burdensome clinical testing in the future.
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http://dx.doi.org/10.3390/brainsci10121015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766799PMC
December 2020

Thalamic Deep Brain Stimulation in Essential Tremor Plus Is as Effective as in Essential Tremor.

Brain Sci 2020 Dec 11;10(12). Epub 2020 Dec 11.

Department of Neurology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany.

The new essential tremor (ET) classification defined ET-plus (ET-p) as an ET subgroup with additional neurological signs besides action tremor. While deep brain stimulation (DBS) is effective in ET, there are no studies specifically addressing DBS effects in ET-p. 44 patients with medication-refractory ET and thalamic/subthalamic DBS implanted at our center were postoperatively classified into ET and ET-p according to preoperative documentation. Tremor suppression with DBS (stimulation ON vs. preoperative baseline and vs. stimulation OFF), measured via the Fahn-Tolosa-Marin tremor rating scale (TRS), stimulation parameters, and the location of active contacts were compared between patients classified as ET and ET-p. TRS scores at baseline were higher in ET-p. ET-p patients showed comparable tremor reduction as patients with ET, albeit higher stimulation parameters were needed in ET-p. Active electrode contacts were located more dorsally in ET-p of uncertain reason. Our data show that DBS is similarly effective in ET-p compared to ET. TRS scores were higher in ET-p preoperatively, and higher stimulation parameters were needed for tremor reduction compared to ET. The latter may be related to a more dorsal location of active electrode contacts in the ET-p group of this cohort. Prospective studies are warranted to investigate DBS in ET-p further.
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http://dx.doi.org/10.3390/brainsci10120970DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763605PMC
December 2020

Response to Letter to the Editor regarding: "Bipolar Directional Deep Brain Stimulation in Essential and Parkinsonian Tremor"-A Technology Underutilized.

Neuromodulation 2020 Dec 22;23(8):1229-1230. Epub 2020 Nov 22.

Department of Neurology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.

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http://dx.doi.org/10.1111/ner.13311DOI Listing
December 2020

Network Fingerprint of Stimulation-Induced Speech Impairment in Essential Tremor.

Ann Neurol 2021 02 26;89(2):315-326. Epub 2020 Nov 26.

Department of Neurology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.

Objective: This study was undertaken to gain insights into structural networks associated with stimulation-induced dysarthria (SID) and to predict stimulation-induced worsening of intelligibility in essential tremor patients with bilateral thalamic deep brain stimulation (DBS).

Methods: Monopolar reviews were conducted in 14 essential tremor patients. Testing included determination of SID thresholds, intelligibility ratings, and a fast syllable repetition task. Volumes of tissue activated (VTAs) were calculated to identify discriminative fibers for stimulation-induced worsening of intelligibility in a structural connectome. The resulting fiber-based atlas structure was then validated in a leave-one-out design.

Results: Fibers determined as discriminative for stimulation-induced worsening of intelligibility were mainly connected to the ipsilateral precentral gyrus as well as to both cerebellar hemispheres and the ipsilateral brain stem. In the thalamic area, they ran laterally to the thalamus and posteromedially to the subthalamic nucleus, in close proximity, mainly anterolaterally, to fibers beneficial for tremor control as published by Al-Fatly et al in 2019. The overlap of the respective clinical stimulation setting's VTAs with these fibers explained 62.4% (p < 0.001) of the variance of stimulation-induced change in intelligibility in a leave-one-out analysis.

Interpretation: This study demonstrates that SID in essential tremor patients is associated with both motor cortex and cerebellar connectivity. Furthermore, the identified fiber-based atlas structure might contribute to future postoperative programming strategies to achieve optimal tremor control without speech impairment in essential tremor patients with thalamic DBS. ANN NEUROL 2021;89:315-326.
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http://dx.doi.org/10.1002/ana.25958DOI Listing
February 2021

Memory trace interference impairs recall in a mouse model of Alzheimer's disease.

Nat Neurosci 2020 08 8;23(8):952-958. Epub 2020 Jun 8.

Neuroimmunology and Imaging Group, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.

In Alzheimer's disease (AD), hippocampus-dependent memories underlie an extensive decline. The neuronal ensemble encoding a memory, termed engram, is partially recapitulated during memory recall. Artificial activation of an engram can restore memory in a mouse model of early AD, but its fate and the factors that render the engram nonfunctional are yet to be revealed. Here, we used repeated two-photon in vivo imaging to analyze fosGFP transgenic mice (which express enhanced GFP under the Fos promoter) performing a hippocampus-dependent memory task. We found that partial reactivation of the CA1 engram during recall is preserved under AD-like conditions. However, we identified a novelty-like ensemble that interfered with the engram and thus compromised recall. Mimicking a novelty-like ensemble in healthy mice was sufficient to affect memory recall. In turn, reducing the novelty-like signal rescued the recall impairment under AD-like conditions. These findings suggest a novel mechanistic process that contributes to the deterioration of memories in AD.
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http://dx.doi.org/10.1038/s41593-020-0652-4DOI Listing
August 2020

PSA and VIM DBS efficiency in essential tremor depends on distance to the dentatorubrothalamic tract.

Neuroimage Clin 2020 4;26:102235. Epub 2020 Mar 4.

University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Neurology, Germany.

Objective: To investigate the relation between deep brain stimulation (DBS) of the posterior-subthalamic-area (PSA) and the ventral-intermediate-nucleus (VIM) and the distance to the dentatorubrothalamic tract (DRTT) in essential tremor (ET).

Methods: Tremor rating scale (TRS) hemi-scores were analyzed in 13 ET patients, stimulated in both the VIM and the PSA in a randomized, crossover trial. Distances of PSA and VIM contacts to population-based DRTTs were calculated. The relationships between distance to DRTT and stimulation amplitude, as well as DBS efficiency (TRS improvement per amplitude) were investigated.

Results: PSA contacts were closer to the DRTT (p = 0.019) and led to a greater improvement in TRS hemi-scores (p = 0.005) than VIM contacts. Proximity to the DRTT was related to lower amplitudes (p < 0.001) and higher DBS efficiency (p = 0.017).

Conclusions: Differences in tremor outcome and stimulation parameters between contacts in the PSA and the VIM can be explained by their different distance to the DRTT.
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http://dx.doi.org/10.1016/j.nicl.2020.102235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7076091PMC
February 2021

Bipolar Directional Deep Brain Stimulation in Essential and Parkinsonian Tremor.

Neuromodulation 2020 Jun 10;23(4):543-549. Epub 2020 Feb 10.

Faculty of Medicine and University Hospital Cologne, Department of Neurology, University of Cologne, Cologne, Germany.

Objective: To compare directional monopolar, bipolar, and directional bipolar thalamic deep brain stimulation (DBS) in tremor patients.

Methods: Fourteen tremor patients (7 Essential Tremor and 7 Parkinson's Disease) implanted with directional DBS electrodes in the ventral intermediate nucleus (VIM) were enrolled. Side-effect thresholds of monopolar directional stimulation (DIRECT) were compared to circular DBS as well as, in a randomized design, to those of two different bipolar stimulation settings (BIPOLAR = circular anode; BI-DIRECT = directional anode). Tremor suppression (Tremor Rating Scale, TRS) right below the side-effect threshold was also assessed.

Results: Directional DBS in the individually best direction showed higher side-effect thresholds than circular DBS (p = 0.0063). The thresholds were raised further using either one of the bipolar stimulation paradigms (BIPOLAR p = 0.0029, BI-DIRECT p = 0.0022). The side-effect thresholds did not differ between both bipolar settings, but side-effects were less frequent with BI-DIRECT. No difference in TRS scores with stimulation just below the side-effect threshold was found between all stimulation conditions.

Conclusions: Side-effect thresholds of monopolar directional and bipolar stimulation with both circular and directional anodes were higher compared to traditional monopolar circular stimulation in the VIM. Bipolar DBS with directional anodes evoked side-effect less frequently than bipolar and monopolar directional stimulation. All stimulation settings had comparable effects on tremor suppression just below their side-effect thresholds. Thus, directional and different bipolar settings should be explored in patients with bothersome side-effects of thalamic stimulation when monopolar stimulation settings are not satisfying. Further studies are needed to explore the efficiency of the different bipolar stimulation paradigms.
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http://dx.doi.org/10.1111/ner.13109DOI Listing
June 2020

Prominence marking in parkinsonian speech and its correlation with motor performance and cognitive abilities.

Neuropsychologia 2020 02 16;137:107306. Epub 2019 Dec 16.

University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Neurology, Kerpener Str. 62, 50937, Köln, Germany. Electronic address:

Objectives: Research suggests that people with Parkinson's disease (PwPD) do not only suffer from motor but also non-motor impairment. This interdisciplinary study investigated how prominence marking is influenced by problems on the motoric and cognitive level.

Materials And Methods: We collected speech production data from 38 native German speakers: 19 PwPD (under medication) with a mild to moderate motor impairment, 13 males and 6 females (mean 66.2 years old, SD = 7.7), and 19 healthy age- and gender-matched control participants (mean 65.4 years old, SD = 9.3). Target words were produced in an accented and unaccented condition within a speech production task. The data were analyzed for intensity, syllable duration, F0 and vowel production. Furthermore, we assessed motor impairment and cognitive functions, i.e. working memory, task-switching, attention control and speed of information processing.

Results: Both groups were able to mark prominence by increasing pitch, syllable duration and intensity and by adjusting their vowel production. Comparisons between PwPD and control participants revealed that the vowel space was smaller in PwPD even in mildly impaired speakers. Further, task-switching as an executive function, which was tested with the trail making test, was correlated with modulation of F0 and intensity in PwPD: the worse the task-switching performance, the stronger intensity and F0 were modulated (target overshoot). Moreover, motor impairment within the PwPD group was related to a decrease in the acoustic vowel space (target undershoot), which further resulted in a decrease in speech intelligibility and naturalness. This behaviour of target over- and undershoot indicates an inefficient way of prominence marking in PwPD with mildly affected speech.

Conclusion: PwPD with signs of mild dysarthria did not differ from the control speakers with respect to their strategies of prominence marking. However, only the PwPD overused F0 and intensity in prominent positions. Overmodulation of F0 and intensity was correlated with the patient's task-switching ability and reflected abnormalities in the regulatory mechanism for expressing prosodic prominence. This is the first study to report a link between cognitive skills and speech production at the phonetic level in PwPD.
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http://dx.doi.org/10.1016/j.neuropsychologia.2019.107306DOI Listing
February 2020

Evaluation of a German version of the Bain and Findley Tremor ADL scale.

Parkinsonism Relat Disord 2019 11 25;68:46-48. Epub 2019 Sep 25.

University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Neurology, Kerpener Str. 62, 50937, Cologne, Germany. Electronic address:

The Movement Disorder Society recommends the Bain and Findley Tremor ADL Scale to assess ADL in patients with ET. In 45 medically and 14 surgically (DBS) treated ET patients, a German version of the scale correlated well with tremor severity and quality of life and was sensitive to postoperative change.
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http://dx.doi.org/10.1016/j.parkreldis.2019.09.024DOI Listing
November 2019

DBS of the PSA and the VIM in essential tremor: A randomized, double-blind, crossover trial.

Neurology 2018 08 3;91(6):e543-e550. Epub 2018 Jul 3.

From the Department of Neurology (M.T.B., P.R., T.A.D., J.B., J.K.S., H.S.D., G.R.F., L.T.) and Department of Stereotaxy and Functional Neurosurgery (T.A.D., J.W., V.V.-V.), University Hospital of Cologne; Institute of Medical Statistics and Computational Biology (S.H., J.F.) and Clinical Trials Center Cologne (D.K.), University of Cologne; Neurological Rehabilitation Center Godeshöhe (N.A.), Bonn, Germany; National Parkinson Foundation International Centre of Excellence (H.S.D.), Kings College Hospital, London, UK; Department of Stereotactic Neurosurgery (J.V.), Otto-von-Guericke University Magdeburg and Leibniz Institute for Neurobiology; Cognitive Neuroscience (G.R.F.), Institute of Neuroscience and Medicine (INM-3), Research Centre Jülich; and Department of Neurology (L.T.), University Hospital Marburg, Germany.

Objective: To evaluate deep brain stimulation (DBS) of the posterior subthalamic area (PSA) in essential tremor (ET) and compare it to the ventral intermediate nucleus of the thalamus (VIM) in terms of stimulation efficacy, efficiency, and side effects.

Methods: DBS leads were implanted such that contacts were placed in the VIM, on the intercommissural line, and in the PSA. Thirteen patients with ET entered a randomized, double-blind crossover phase and completed a 1-year follow-up.

Results: PSA-DBS significantly reduced tremor severity and improved quality of life. There were no relevant differences in quality and frequency of stimulation side effects between VIM and PSA, with a tendency toward greater tremor improvement with PSA stimulation. Clinical benefit was achieved at significantly lower stimulation amplitudes in the PSA. The majority of patients remained with PSA-DBS after 1 year.

Conclusion: In accordance with previous retrospective investigations, our prospective data suggest that PSA-DBS is at least equally effective as but possibly more efficient than VIM-DBS.

Classification Of Evidence: This study provides Class I evidence that for patients with essential tremor, PSA-DBS is not significantly different from VIM-DBS in suppressing tremor, but clinical benefit from PSA-DBS is attained at lower stimulation amplitudes.
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http://dx.doi.org/10.1212/WNL.0000000000005956DOI Listing
August 2018

Nonmotor symptoms evolution during 24 months of bilateral subthalamic stimulation in Parkinson's disease.

Mov Disord 2018 03 21;33(3):421-430. Epub 2018 Feb 21.

Department of Neurology, University Hospital Cologne, Cologne, Germany.

Background: The objective of this study was to investigate 24-month of effects of bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) on nonmotor symptoms in Parkinson's disease (PD).

Methods: In this prospective, observational, multicenter, international study including 67 PD patients undergoing bilateral STN-DBS, we examined the Non-motor Symptom Scale, Non-Motor Symptoms Questionnaire, Parkinson's Disease Questionnaire-8, Scales for Outcomes in Parkinson's Disease-motor examination, -activities of daily living, and -complications, and levodopa-equivalent daily dose preoperatively and at 5 and 24-month of follow-up. After checking distribution normality, longitudinal outcome changes were investigated with Friedman tests or repeated-measures analysis of variance and Bonferroni correction for multiple comparisons using multiple tests. Post hoc, Wilcoxon signed rank t tests were computed to compare visits. The strength of clinical responses was analyzed using effect size. Explorative Spearman correlations of change scores from baseline to 24-month follow-up were calculated for all outcomes.

Results: The Non-motor Symptom Scale and all other outcome parameters significantly improved from baseline to the 5-month follow-up. From 5 to 24-month, partial decrements in these gains were found. Nonetheless, comparing baseline with 24-month follow-up, significant improvements were observed for the Non-motor Symptom Scale (small effect), Scales for Outcomes in PD-motor examination showed a moderate effect, and Scales for Outcomes in Parkinson's Disease-complications and levodopa-equivalent daily dose showed large effects. Non-motor Symptom Scale change scores from baseline to 24-month follow-up correlated significantly with Parkinson's Disease Questionnaire-8, Scales for Outcomes in Parkinson's Disease-activities of daily living, and -motor complications change scores.

Conclusions: This study provides evidence of beneficial effects of bilateral STN-DBS on nonmotor symptoms at 24-month follow-up. The extent of nonmotor symptom improvement was directly proportionate to improvements in quality of life, activities of daily living, and motor complications. This study underlines the importance of nonmotor symptoms for holistic assessments of DBS outcomes. © 2018 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27283DOI Listing
March 2018

Quality of life outcome after subthalamic stimulation in Parkinson's disease depends on age.

Mov Disord 2018 01 18;33(1):99-107. Epub 2017 Nov 18.

Department of Neurology, University Hospital Cologne, Cologne, Germany.

Objective: The purpose of this study was to investigate how quality of life outcome after bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) in Parkinson's disease (PD) depends on age.

Methods: In this prospective, open-label, multicenter study including 120 PD patients undergoing bilateral STN-DBS, we investigated the PDQuestionnaire-8 (PDQ-8), Unified PD Rating Scale-III, Scales for Outcomes in PD-motor examination, complications, activities of daily living, and levodopa equivalent daily dose preoperatively and at 5 months follow-up. Significant changes at follow-up were analyzed with Wilcoxon signed-rank test and Bonferroni correction for multiple comparisons. To explore the influence of age post hoc, the patients were classified into 3 age groups (≤59, 60-69, ≥70 years). Intragroup changes were analyzed with Wilcoxon signed-rank and intergroup differences with Kruskal-Wallis tests. The strength of clinical responses was evaluated using effect size.

Results: The PDQuestionnaire-8, Scales for Outcomes in PD-motor complications, activities of daily living, and levodopa equivalent daily dose significantly improved in the overall cohort and all age groups with no significant intergroup differences. However, PDQuestionnaire-8 effect sizes for age groups ≤59, 60 to 69, and ≥70 years, respectively, were strong, moderate, and small. Furthermore, PDQuestionnaire-8 domain analyses revealed that all domains except cognition and emotional well-being significantly improved in patients aged ≤59 years, whereas only communication, activities of daily living, and stigma improved in patients aged 60-69 years, and activities of daily living and stigma in patients aged ≥70 years.

Conclusions: Although quality of life, motor complications, and activities of daily living significantly improved in all age groups after bilateral STN-DBS, the beneficial effect on overall quality of life was more pronounced and affected a wider range of quality of life domains in younger patients. © 2017 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27222DOI Listing
January 2018

Dysfunction of Somatostatin-Positive Interneurons Associated with Memory Deficits in an Alzheimer's Disease Model.

Neuron 2016 Oct 15;92(1):114-125. Epub 2016 Sep 15.

Neuroimmunology and Imaging Group, German Center for Neurodegenerative Diseases, Ludwig-Erhard-Allee 2, 53175 Bonn, Germany. Electronic address:

Alzheimer's disease (AD) is characterized by cognitive decline and neuronal network dysfunction, but the underlying mechanisms remain unknown. In the hippocampus, microcircuit activity during learning and memory processes is tightly controlled by O-LM interneurons. Here, we investigated the effect of beta-amyloidosis on O-LM interneuron structural and functional connectivity, combining two-photon in vivo imaging of synaptic morphology, awake Ca imaging, and retrograde mono-transsynaptic rabies tracing. We find severely impaired synaptic rewiring that occurs on the O-LM interneuron input and output level in a mouse model of AD. Synaptic rewiring that occurs upon fear learning on O-LM interneuron input level is affected in mice with AD-like pathology. This process requires the release of acetylcholine from septo-hippocampal projections. We identify decreased cholinergic action on O-LM interneurons in APP/PS1 mice as a key pathomechanism that contributes to memory impairment in a mouse model, with potential relevance for human AD.
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http://dx.doi.org/10.1016/j.neuron.2016.08.034DOI Listing
October 2016

Reducing tau aggregates with anle138b delays disease progression in a mouse model of tauopathies.

Acta Neuropathol 2015 Nov 6;130(5):619-31. Epub 2015 Oct 6.

German Center for Neurodegenerative Diseases (DZNE), Ludwig-Erhard-Allee 2, 53175, Bonn, Germany.

Pathological tau aggregation leads to filamentous tau inclusions and characterizes neurodegenerative tauopathies such as Alzheimer's disease and frontotemporal dementia and parkinsonism linked to chromosome 17. Tau aggregation coincides with clinical symptoms and is thought to mediate neurodegeneration. Transgenic mice overexpressing mutant human P301S tau exhibit many neuropathological features of human tauopathies including behavioral deficits and increased mortality. Here, we show that the di-phenyl-pyrazole anle138b binds to aggregated tau and inhibits tau aggregation in vitro and in vivo. Furthermore, anle138b treatment effectively ameliorates disease symptoms, increases survival time and improves cognition of tau transgenic PS19 mice. In addition, we found decreased synapse and neuron loss accompanied by a decreased gliosis in the hippocampus. Our results suggest that reducing tau aggregates with anle138b may represent an effective and promising approach for the treatment of human tauopathies.
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http://dx.doi.org/10.1007/s00401-015-1483-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4612332PMC
November 2015

Longitudinal testing of hippocampal plasticity reveals the onset and maintenance of endogenous human Aß-induced synaptic dysfunction in individual freely behaving pre-plaque transgenic rats: rapid reversal by anti-Aß agents.

Acta Neuropathol Commun 2014 Dec 24;2:175. Epub 2014 Dec 24.

Long before synaptic loss occurs in Alzheimer's disease significant harbingers of disease may be detected at the functional level. Here we examined if synaptic long-term potentiation is selectively disrupted prior to extracellular deposition of Aß in a very complete model of Alzheimer's disease amyloidosis, the McGill-R-Thy1-APP transgenic rat. Longitudinal studies in freely behaving animals revealed an age-dependent, relatively rapid-onset and persistent inhibition of long-term potentiation without a change in baseline synaptic transmission in the CA1 area of the hippocampus. Thus the ability of a standard 200 Hz conditioning protocol to induce significant NMDA receptor-dependent short- and long-term potentiation was lost at about 3.5 months of age and this deficit persisted for at least another 2-3 months, when plaques start to appear. Consistent with in vitro evidence for a causal role of a selective reduction in NMDA receptor-mediated synaptic currents, the deficit in synaptic plasticity in vivo was associated with a reduction in the synaptic burst response to the conditioning stimulation and was overcome using stronger 400 Hz stimulation. Moreover, intracerebroventricular treatment for 3 days with an N-terminally directed monoclonal anti- human Aß antibody, McSA1, transiently reversed the impairment of synaptic plasticity. Similar brief treatment with the BACE1 inhibitor LY2886721 or the γ-secretase inhibitor MRK-560 was found to have a comparable short-lived ameliorative effect when tracked in individual rats. These findings provide strong evidence that endogenously generated human Aß selectively disrupts the induction of long-term potentiation in a manner that enables potential therapeutic options to be assessed longitudinally at the pre-plaque stage of Alzheimer's disease amyloidosis.
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http://dx.doi.org/10.1186/s40478-014-0175-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4293804PMC
December 2014

Long-term in vivo imaging of dendritic spines in the hippocampus reveals structural plasticity.

J Neurosci 2014 Oct;34(42):13948-53

German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany

Hippocampal function is important for learning and memory. During memory processing, hippocampal CA1 neurons play a crucial role by integrating excitatory synaptic input from CA3 and the entorhinal cortex. These neurons receive excitatory input almost exclusively on dendritic spines. The formation and elimination--structural plasticity--of dendritic spines reflect wiring changes within the hippocampal network. Despite the relevance of the hippocampus in learning and memory, most in vivo data on structural plasticity derive from cortical regions. We established a chronic hippocampal window approach using two-photon microscopy to visualize dendritic spines throughout all CA1 hippocampal layers and over a time course of weeks. Moreover, even granule cells in dentate gyrus could be reliably detected. We found that the spine density in stratum radiatum (∼1.1 per micrometer) remained stable over weeks. However, a small fraction (3.4%) of spines were formed and eliminated between imaging sessions, which demonstrated that spines of CA1 neurons exhibit structural plasticity in adult mice. In addition, we tested for possible inflammatory or behavioral side effects of hippocampal window implantation. Mice exhibited a transient increase in microgliosis and astrogliosis, which declined within a few weeks. We did not detect any difference in behavioral performance in an open-field and contextual fear-conditioning paradigm. In conclusion, hippocampal long-term two-photon imaging revealed structural plasticity of dendritic spines in CA1 pyramidal neurons. This approach may provide a powerful tool to analyze changes in neuronal network rewiring during hippocampal learning and memory processes in health and disease.
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http://dx.doi.org/10.1523/JNEUROSCI.1464-14.2014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6705298PMC
October 2014