Pathological gamma oscillations, impaired dopamine release, synapse loss and reduced dynamic range of unitary glutamatergic synaptic transmission in the striatum of hypokinetic Q175 Huntington mice

Rothe, Thomás; Deliano, Matthias; Wójtowicz, Anna; Dvorzhak, Anton; Harnack, Daniel; Paul, Steffanie; Vagner, Tatyana; Melnick, Igor V.; Stark, Holger; Grantyn, Rosemarie

doi:10.1016/j.neuroscience.2015.10.039

Cited by 39 publications

(57 citation statements)

References 71 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In pre-symptomatic R6/2 mice, for example, striatal D 1 receptor signaling is increased [113]; the same effect has been reported for pre-symptomatic Q175 mice [58]. In symptomatic R6/2 and YAC72 mice, D 1 receptor expression is decreased [188, 190], but both cAMP and the level of phosphorylation of DARPP-32 are increased [113, 188].…”

Section: Dopamine Modulationmentioning

confidence: 85%

“…In heterozygous Q175s, for example, hypokinesia is not accompanied by decreased DA content; in fact, the alteration in DA did not occur until the mice reached 12 months of age, and no changes in DA fibers were found [35]. In contrast, homozygous Q175s show decreased DA release in striatum accompanied by reduced TH immunoreactivity and VMAT-2 expression along with hypokinetic symptoms [58]. Furthermore, evidence of decreased DA content in the heterozygous nucleus accumbens is believed to contribute to cognitive neurological signs [164].…”

Section: Dopamine Modulationmentioning

confidence: 99%

“…Moreover, although D 1 receptor expression may decrease, receptor signaling is increased as shown by enhanced cAMP and DARPP-32 phosphorylation [58, 113, 182, 183, 188], suggesting augmented PKA activation, which in turn will increase NMDA receptor phosphorylation [222, 227, 228, 247]. Increased NMDA receptor activity and the synergistic action of D 1 receptors on intracellular calcium could activate apoptosis [214, 234, 235].…”

Section: Dopamine Modulationmentioning

confidence: 99%

“…For example, in hypokinetic Q175 homozygous mice, a loss of DA in the corticostriatal circuit impaired glutamate transmission and low gamma oscillations in striatal LFPs [58]. The change in gamma is interesting because in normal conditions an interaction between low and high gamma oscillations plays a role in motor states.…”

Section: Dopamine Modulationmentioning

confidence: 99%

“…The Q140 mouse shows many of the same neurological abnormalities in striatum and cortex as the R6/2 model [56, 57]. In addition, reduced synaptic transmission in the striatum has been correlated with hypokinetic symptoms in homozygous Q175 mice [58]. Although Q175s display slow disease progression and relatively subtle behavioral changes, this animal model contains the human mHTT allele with the expanded CAG repeat within the native mouse HTT gene.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Dysregulation of Corticostriatal Connectivity in Huntington’s Disease: A Role for Dopamine Modulation

Rangel‐Barajas

Rebec

2016

JHD

View full text Add to dashboard Cite

Aberrant communication between striatum, the main information processing unit of the basal ganglia, and cerebral cortex plays a critical role in the emergence of Huntington’s disease (HD), a fatal monogenetic condition that typically strikes in the prime of life. Although both striatum and cortex undergo substantial cell loss over the course of HD, corticostriatal circuits become dysfunctional long before neurons die. Understanding the dysfunction is key to developing effective strategies for treating a progressively worsening triad of motor, cognitive, and psychiatric symptoms. Cortical output neurons drive striatal activity through the release of glutamate, an excitatory amino acid. Striatal outputs, in turn, release γ-amino butyric acid (GABA) and exert inhibitory control over downstream basal ganglia targets. Ample evidence from transgenic rodent models points to dysregulation of corticostriatal glutamate transmission along with corresponding changes in striatal GABA release as underlying factors in the HD behavioral phenotype. Another contributor is dysregulation of dopamine (DA), a modulator of both glutamate and GABA transmission. In fact, pharmacological manipulation of DA is the only currently available treatment for HD symptoms. Here, we review data from animal models and human patients to evaluate the role of DA in HD, including DA interactions with glutamate and GABA within the context of dysfunctional corticostriatal circuitry.

show abstract

Section: Dopamine Modulationmentioning

confidence: 85%

Section: Dopamine Modulationmentioning

confidence: 99%

Section: Dopamine Modulationmentioning

confidence: 99%

Section: Dopamine Modulationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Dysregulation of Corticostriatal Connectivity in Huntington’s Disease: A Role for Dopamine Modulation

Rangel‐Barajas

Rebec

2016

JHD

View full text Add to dashboard Cite

show abstract

Progression of basal ganglia pathology in heterozygous Q175 knock‐in Huntington's disease mice

Deng

Wang

Joni

et al. 2020

J of Comparative Neurology

View full text Add to dashboard Cite

We used behavioral testing and morphological methods to detail the progression of basal ganglia neuron type-specific pathology and the deficits stemming from them in male heterozygous Q175 mice, compared to age-matched WT males. A rotarod deficit was not present in Q175 mice until 18 months, but increased open field turn rate (reflecting hyperkinesia) and open field anxiety were evident at 6 months. No loss of striatal neurons was seen out to 18 months, but ENK+ and DARPP32+ striatal perikarya were fewer by 6 months, due to diminished expression, with further decline by 18 months. No reduction in SP+ striatal perikarya or striatal interneurons was seen in Q175 mice at 18 months, but cholinergic interneurons showed dendrite attenuation by 6 months. Despite reduced ENK expression in indirect pathway striatal perikarya, ENK-immunostained terminals in globus pallidus externus (GPe) were more abundant at 6 months and remained so out to 18 months. Similarly, SP-immunostained terminals from striatal direct pathway neurons were more abundant in globus pallidus internus and substantia nigra at 6 months and remained so at 18 months. FoxP2+ arkypallidal GPe neurons and subthalamic nucleus neurons were lost by 18 months but not prototypical PARV+ GPe neurons or dopaminergic nigral neurons. Our results show that striatal projection neuron abnormalities and behavioral abnormalities reflecting them develop between 2 and 6 months of age in Q175 male heterozygotes, indicating early effects of the HD mutation. The striatal pathologies resemble those in human HD, but are less severe at 18 months than even in premanifest HD.

show abstract

Dysfunctional striatal dopamine signaling in Huntington's disease

Koch

Raymond

2019

J of Neuroscience Research

View full text Add to dashboard Cite

Dopamine signaling in the striatum is critical for a variety of behaviors including movement, behavioral flexibility, response to reward and many forms of learning. Alterations to dopamine transmission contribute to pathological features of many neurological diseases, including Huntington's disease (HD). HD is an autosomal dominant genetic disorder caused by a CAG repeat expansion in the Huntingtin gene. The striatum is preferentially degenerated in HD, and this region receives dopaminergic input from the substantia nigra. Studies of HD patients and genetic rodent models have shown changes to levels of dopamine and its receptors in the striatum, and alterations in dopamine receptor signaling and modulation of other neurotransmitters, notably glutamate. Throughout his career, Dr. Michael Levine's research has furthered our understanding of dopamine signaling in the striatum of healthy rodents and HD mouse models. This review will focus on the work of his group and others in elucidating alterations to striatal dopamine signaling that contribute to pathophysiology in HD mouse models, and how these findings relate to human HD studies. We will also discuss current and potential therapeutic interventions for HD that target the dopamine system, and future research directions for this field.

show abstract

Pathological gamma oscillations, impaired dopamine release, synapse loss and reduced dynamic range of unitary glutamatergic synaptic transmission in the striatum of hypokinetic Q175 Huntington mice

Cited by 39 publications

References 71 publications

Dysregulation of Corticostriatal Connectivity in Huntington’s Disease: A Role for Dopamine Modulation

Dysregulation of Corticostriatal Connectivity in Huntington’s Disease: A Role for Dopamine Modulation

Progression of basal ganglia pathology in heterozygous Q175 knock‐in Huntington's disease mice

Dysfunctional striatal dopamine signaling in Huntington's disease

Contact Info

Product

Resources

About