Age-Dependent Biphasic Changes in Ischemic Sensitivity in the Striatum of Huntington's Disease R6/2 Transgenic Mice

2005 ◽  
Vol 93 (2) ◽  
pp. 758-765 ◽  
Author(s):  
Gloria J. Klapstein ◽  
Michael S. Levine
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Glutamate Release ◽  
Age Groups ◽  
Brain Slices ◽  
Glucose Deprivation ◽  
Behavioral Phenotype ◽  
Crossover Point ◽  
Glutamate Receptor Antagonist ◽  
Age Dependent

We used the oxygen/glucose deprivation (OGD) model of ischemia in corticostriatal brain slices to test the hypothesis that metabolic deficiencies in R6/2 transgenic Huntington's disease (HD) mice will impair their recovery from an ischemic challenge. Corticostriatal extracellular field excitatory postsynaptic potentials (fEPSPs) were evoked in transgenic and wild-type (WT) mice in three age groups: 3–4 wk, before the overt behavioral phenotype develops; 5–9 wk, as overt behavioral symptoms begin; and 10–15 wk when symptoms were most severe. OGD for 8 min completely and reversibly inhibited fEPSPs. Although responses of 3–4 wk WTs showed a tolerance to ischemia and recovered rapidly, ischemic sensitivity developed progressively; at 5–9 and 10–15 wk, responses recovered more slowly from OGD. In contrast, although 3–4 wk R6/2 transgenic fEPSPs showed significantly more ischemic sensitivity than their WT counterparts, the R6/2 fEPSPs maintained a relative tolerance to ischemia at 5–9 and 10–15 wk. As a result, a “crossover” point occurred, roughly coinciding with the development of the overt behavioral phenotype (5–9 wk), after which time R6/2 fEPSPs were significantly more resistant to ischemia than WT responses. The increased ischemic sensitivity in 3–4 wk R6/2 responses was not due to excessive glutamate release during OGD as it persisted in the presence of the glutamate receptor antagonist kynurenic acid (1 mM). Although the mechanism for development of ischemic resistance in R6/2 transgenics remains unknown, it correlates with metabolic and biochemical changes described in this model and in HD patients.

scholarly journals Age-Dependent Degradation of Locomotion Encoding in Huntington’s Disease R6/2 Model Mice

2021 ◽  
Vol 10 (3) ◽  
pp. 391-404
Author(s):  
Hagar G. Yamin ◽  
Noa Menkes-Caspi ◽  
Edward A. Stern ◽  
Dana Cohen
Keyword(s):  
Huntington's Disease ◽  
Firing Rate ◽  
Huntington’S Disease ◽  
Disease Progression ◽  
Age Groups ◽  
Dorsal Striatum ◽  
Projection Neurons ◽  
Novel Environment ◽  
Age Dependent ◽  
Exploratory Locomotion

Background: Huntington’s disease (HD) is an inherited fatal neurodegenerative disease, leading to neocortical and striatal atrophy. The commonly studied R6/2 HD transgenic mouse model displays progressive motor and cognitive deficits in parallel to major pathological changes in corticostriatal circuitry. Objective: To study how disease progression influences striatal encoding of movement. Methods: We chronically recorded neuronal activity in the dorsal striatum of R6/2 transgenic (Tg) mice and their age-matched nontransgenic littermate controls (WTs) during novel environment exposure, a paradigm which engages locomotion to explore the novel environment. Results: Exploratory locomotion degraded with age in Tg mice as compared to WTs. We encountered fewer putative medium spiny neurons (MSNs)—striatal projection neurons, and more inhibitory interneurons—putative fast spiking interneurons (FSIs) in Tg mice as compared to WTs. MSNs from Tg mice fired less spikes in bursts without changing their firing rate, while FSIs from these mice had a lower firing rate and more of them were task-responsive as compared to WTs. Additionally, MSNs from Tg mice displayed a reduced ability to encode locomotion across age groups, likely associated with their low prevalence in Tg mice, whereas the encoding of locomotion by FSIs from Tg mice was substantially reduced solely in old Tg mice as compared to WTs. Conclusion: Our findings reveal an age-dependent decay in striatal information processing in transgenic mice. We propose that the ability of FSIs to compensate for the loss of MSNs by processes of recruitment and enhanced task-responsiveness diminishes with disease progression, possibly manifested in the displayed age-dependent degradation of exploratory locomotion.

Electrophysiological and Morphological Changes in Striatal Spiny Neurons in R6/2 Huntington's Disease Transgenic Mice

2001 ◽  
Vol 86 (6) ◽  
pp. 2667-2677 ◽  
Author(s):  
Gloria J. Klapstein ◽  
Robin S. Fisher ◽  
Hadi Zanjani ◽  
Carlos Cepeda ◽  
Eve S. Jokel ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Action Potentials ◽  
Morphological Changes ◽  
Brain Slices ◽  
Cag Repeats ◽  
Membrane Properties ◽  
Striatal Neurons ◽  
Spiny Neurons ◽  
Active Membrane

We examined passive and active membrane properties and synaptic responses of medium-sized spiny striatal neurons in brain slices from presymptomatic (∼40 days of age) and symptomatic (∼90 days of age) R6/2 transgenics, a mouse model of Huntington's disease (HD) and their age-matched wild-type (WT) controls. This transgenic expresses exon 1 of the human HD gene with ∼150 CAG repeats and displays a progressive behavioral phenotype associated with numerous neuronal alterations. Intracellular recordings were obtained using standard techniques from R6/2 and age-matched WT mice. Few electrophysiological changes occurred in striatal neurons from presymptomatic R6/2 mice. The changes in this age group were increased neuronal input resistance and lower stimulus intensity to evoke action potentials (rheobase). Symptomatic R6/2 mice exhibited numerous electrophysiological alterations, including depolarized resting membrane potentials, increased input resistances, decreased membrane time constants, and alterations in action potentials. Increased stimulus intensities were required to evoke excitatory postsynaptic potentials (EPSPs) in neurons from symptomatic R6/2 transgenics. These EPSPs had slower rise times and did not decay back to baseline by 45 ms, suggesting a more prominent component mediated by activation of N-methyl-d-aspartate receptors. Neurons from both pre- and symptomatic R6/2 mice exhibited reduced paired-pulse facilitation. Data from biocytin-filled or Golgi-impregnated neurons demonstrated decreased dendritic spine densities, smaller diameters of dendritic shafts, and smaller dendritic fields in symptomatic R6/2 mice. Taken together, these findings indicate that passive and active membrane and synaptic properties of medium-sized spiny neurons are altered in the R6/2 transgenic. These physiological and morphological alterations will affect communication in the basal ganglia circuitry. Furthermore, they suggest areas to target for pharmacotherapies to alleviate and reduce the symptoms of HD.

scholarly journals Direct assessment of presynaptic modulation of cortico-striatal glutamate release in a Huntington’s disease mouse model

2018 ◽  
Vol 120 (6) ◽  
pp. 3077-3084 ◽  
Author(s):  
Ellen T. Koch ◽  
Cameron L. Woodard ◽  
Lynn A. Raymond
Keyword(s):  
Mouse Model ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
High Frequency ◽  
Glutamate Release ◽  
Presynaptic Receptors ◽  
High Frequency Stimulation ◽  
Presynaptic Modulation ◽  
Frequency Stimulation

Glutamate is the main excitatory neurotransmitter in the brain, and impairments in its signaling are associated with many neurological disorders, including Huntington’s disease (HD). Previous studies in HD mouse models demonstrate altered glutamate receptor distribution and signaling at cortico-striatal synapses, and some studies suggest that glutamate release is altered; however, traditional methods to study synaptic glutamate release are indirect or have poor temporal resolution. Here we utilize iGluSnFR, a modified green fluorescent protein reporter for real-time imaging of glutamate transmission, to study presynaptic modulation of cortical glutamate release in the striatum of the YAC128 HD mouse model. We determined that iGluSnFR can be used to accurately measure short- and long-term changes in glutamate release caused by modulation of extracellular Ca2+ levels, activation of presynaptic receptors, and high-frequency stimulation (HFS) protocols. We also confirmed a difference in the expression of HFS-induced long-term depression in YAC128. Together, this research demonstrates the utility of iGluSnFR in studying presynaptic modulation of glutamate release in healthy mice and disease models that display impairments in glutamate signaling. NEW & NOTEWORTHY We use iGluSnFR to directly assess presynaptic modulation of cortico-striatal glutamate release in brain slice and compare changes in glutamate release between wild type and a Huntington’s disease mouse model, YAC128. We observed reductions in glutamate release after low extracellular Ca2+ and activation of various presynaptic receptors. We also demonstrate a presynaptic mechanism of reduced glutamate release in high-frequency stimulation-induced long-term depression and show this to be altered in YAC128.

scholarly journals Neuroprotective strategies for NMDAR-mediated excitotoxicity in Huntington’s Disease

2016 ◽  
Author(s):  
KD Girling ◽  
YT Wang
Keyword(s):  
Cell Death ◽  
Huntington's Disease ◽  
Cell Survival ◽  
Huntington’S Disease ◽  
Glutamate Release ◽  
Clinical Approach ◽  
Wide Range ◽  
Pubmed Search ◽  
Nmdar Activation ◽  
Cell Death Signaling

AbstractBACKGROUNDHuntington’s Disease (HD) is an autosomal dominant neurodegenerative disease causing severe neurodegeneration of the striatum as well as marked cognitive and motor disabilities. Excitotoxicity, caused by overstimulation of NMDA receptors (NMDARs) has been shown to have a key role in the neuropathogenesis of HD, suggesting that targeting NMDAR-dependent signaling may be an effective clinical approach for HD. However, broad NMDAR antagonists are generally poor therapeutics in clinical practice. It has been suggested that GluN2A-containing, synaptically located NMDARs activate cell survival signaling pathways, while GluN2B-containing, primarily extrasynaptic NMDARs trigger cell death signaling. A better approach to development of effective therapeutics for HD may be to target, specifically, the cell-death specific pathways associated with extrasynaptic GluN2B NMDAR activation, while maintaining or potentiating the cell-survival activity of GluN2A-NMDARs.OBJECTIVEThis review outlines the role of NMDAR-mediated excitotoxicity in HD and overviews current efforts to develop better therapeutics for HD where NMDAR excitotoxicity is the target.METHODSA systematic review process was conducted using the PubMed search engine focusing on research conducted in the past 5-10 years. 250 articles were consulted for the review, with key search terms including “Huntington’s Disease”, “excitotoxicity”, “NMDAR” and “therapeutics”.RESULTSA wide range of NMDAR excitotoxicity-based targets for HD were identified and reviewed, including targeting NMDARs directly by blocking GluN2B, extrasynaptic NMDARs and/or potentiating GluN2A, synaptic NMDARs, targeting glutamate release or uptake, or targeting specific downstream cell-death signaling of NMDARs.CONCLUSIONThe current review identifies NMDAR-mediated excitotoxicity as a key player in HD pathogenesis and points to various excitotoxicity-focused targets as potential future preventative therapeutics for HD.

Donor age dependent graft development and recovery in a rat model of Huntington's disease: Histological and behavioral analysis

2013 ◽  
Vol 256 ◽  
pp. 56-63 ◽  
Author(s):  
Stefanie Schackel ◽  
Marie-Christin Pauly ◽  
Tobias Piroth ◽  
Guido Nikkhah ◽  
Máté D. Döbrössy
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Rat Model ◽  
Behavioral Analysis ◽  
Donor Age ◽  
Age Dependent

Age-dependent gene expression profile and protein expression in a transgenic rat model of Huntington's disease

2008 ◽  
Vol 2 (12) ◽  
pp. 1638-1650 ◽  
Author(s):  
Huu Phuc Nguyen ◽  
Silke Metzger ◽  
Carsten Holzmann ◽  
Dirk Koczan ◽  
Hans-Jürgen Thiesen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein Expression ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Gene Expression Profile ◽  
Expression Profile ◽  
Rat Model ◽  
Transgenic Rat ◽  
Age Dependent ◽  
Transgenic Rat Model

scholarly journals Enhanced GABAergic Inhibition of Cholinergic Interneurons in the zQ175+/− Mouse Model of Huntington's Disease

2021 ◽  
Vol 14 ◽  
Author(s):  
Sean Austin O. Lim ◽  
D. James Surmeier
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
Ex Vivo ◽  
Brain Slices ◽  
Projection Neurons ◽  
Gabaergic Inhibition ◽  
Indirect Pathway ◽  
Cholinergic Interneurons ◽  
Specific Alteration

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder that initially manifests itself in the striatum. How intrastriatal circuitry is altered by the disease is poorly understood. To help fill this gap, the circuitry linking spiny projection neurons (SPNs) to cholinergic interneurons (ChIs) was examined using electrophysiological and optogenetic approaches in ex vivo brain slices from wildtype mice and zQ175+/− models of HD. These studies revealed a severalfold enhancement of GABAergic inhibition of ChIs mediated by collaterals of indirect pathway SPNs (iSPNs), but not direct pathway SPNs (dSPNs). This cell-specific alteration in synaptic transmission appeared in parallel with the emergence of motor symptoms in the zQ175+/− model. The adaptation had a presynaptic locus, as it was accompanied by a reduction in paired-pulse ratio but not in the postsynaptic response to GABA. The alterations in striatal GABAergic signaling disrupted spontaneous ChI activity, potentially contributing to the network dysfunction underlying the hyperkinetic phase of HD.

scholarly journals M2 Cortex-Dorsolateral striatum stimulation reverses motor symptoms and synaptic deficits in Huntington’s Disease

2020 ◽  
Author(s):  
Sara Fernández-García ◽  
Sara Conde-Berriozabal ◽  
Esther García-García ◽  
Clara Gort-Paniello ◽  
David Bernal-Casas ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Motor Behavior ◽  
Glutamate Release ◽  
Motor Symptoms ◽  
Striatal Neurons ◽  
Dorsolateral Striatum ◽  
Electrophysiological Responses

AbstractHuntington’s disease (HD) is a neurological disorder characterized by motor disturbances. HD pathology is most prominent in the striatum, the central hub of basal ganglia. The cortex is the main striatal afference and progressive cortico-striatal disconnection characterizes HD. We mapped cortico-striatal dysfunction in HD mice to ultimately modulate the activity of selected cortico-striatal circuits to ameliorate motor symptoms and recover synaptic plasticity. Multimodal MRI in vivo suggested prominent functional network deficits in fronto-striatal compared to motor-striatal pathways, which were accompanied by reduced glutamate levels in the striatum of HD mice. Moreover, optogenetically-stimulated glutamate release from fronto-striatal terminals was reduced in HD mice and electrophysiological responses in striatal neurons were blunted. Remarkably, repeated M2 Cortex-dorsolateral striatum optogenetic stimulation normalized motor behavior in HD mice and evoked a sustained increase of synaptic plasticity. Overall, these results reveal that the selective stimulation of fronto-striatal pathways can become an effective therapeutic strategy in HD.

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