Molecular insights into cortico-striatal miscommunications in Huntington's disease

Veldman, Matthew B.; Yang, Xiangdong

doi:10.1016/j.conb.2017.10.019

Cited by 52 publications

(47 citation statements)

References 72 publications

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“…Next generation RNA-sequencing studies performed in HD mouse models and human HD patient induced pluripotent stem cell (iPSC)-derived or directly converted neural cultures have all highlighted dysregulation of synaptic genes. In particular, there was a downregulation of transcripts involved in the postsynaptic scaffold, neurotransmitter signaling, Ca 2+ signaling, long-term synaptic plasticity, as well as reduced transcription of neuronal activity-regulated genes (Langfelder et al, 2016;HD iPSC Consortium, 2017;Veldman and Yang, 2018;Victor et al, 2018). Importantly, these changes also hold true at the proteomic level (Langfelder et al, 2016;Hosp et al, 2017;Skotte et al, 2018).…”

Section: Insights From Systems Biology Studiesmentioning

confidence: 95%

Cortical and Striatal Circuits in Huntington’s Disease

Blumenstock

Dudanova

2020

Front. Neurosci.

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Huntington's disease (HD) is a hereditary neurodegenerative disorder that typically manifests in midlife with motor, cognitive, and/or psychiatric symptoms. The disease is caused by a CAG triplet expansion in exon 1 of the huntingtin gene and leads to a severe neurodegeneration in the striatum and cortex. Classical electrophysiological studies in genetic HD mouse models provided important insights into the disbalance of excitatory, inhibitory and neuromodulatory inputs, as well as progressive disconnection between the cortex and striatum. However, the involvement of local cortical and striatal microcircuits still remains largely unexplored. Here we review the progress in understanding HD-related impairments in the cortical and basal ganglia circuits, and outline new opportunities that have opened with the development of modern circuit analysis methods. In particular, in vivo imaging studies in mouse HD models have demonstrated early structural and functional disturbances within the cortical network, and optogenetic manipulations of striatal cell types have started uncovering the causal roles of certain neuronal populations in disease pathogenesis. In addition, the important contribution of astrocytes to HD-related circuit defects has recently been recognized. In parallel, unbiased systems biology studies are providing insights into the possible molecular underpinnings of these functional defects at the level of synaptic signaling and neurotransmitter metabolism. With these approaches, we can now reach a deeper understanding of circuit-based HD mechanisms, which will be crucial for the development of effective and targeted therapeutic strategies.

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Section: Insights From Systems Biology Studiesmentioning

confidence: 95%

Cortical and Striatal Circuits in Huntington’s Disease

Blumenstock

Dudanova

2020

Front. Neurosci.

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“…In HD mouse models, several evidences point to a progressive disconnection between cortex and striatum (Cepeda et al, 2007;Veldman and Yang, 2018). Cortico-striatal dysfunction in HD is strongly supported by the impaired cortico-striatal-dependent motor functions (Hong et al, 2012;Puigdellívol et al, 2015), altered paired-pulse facilitation at cortico-striatal synapses (Milnerwood and Raymond, 2007), reduction of striatal excitatory postsynaptic currents with loss of cortico-striatal synapses (Cepeda et al, 2003;Deng et al, 2013); and altered glutamate release in striatum of transgenic R6/1 mice (NicNiocaill et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

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

Fernández-García

Conde-Berriozabal

García-García

et al. 2020

Preprint

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Huntington'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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“…According to the information available from extracellular recordings or imaging of neuronal activity in intact HD mice, motor symptoms may evolve as a consequence of disinhibition and abnormal synchronicity in the corticostriatal pathway (Miller et al, 2012;Burgold et al, 2019). Most studies point to functional uncoupling rather than enhanced glutamatergic input to the striatum (Plotkin and Surmeier, 2015;Reiner and Deng, 2018;Veldman and Yang, 2018). Moreover, there is a tendency for a down-regulation of vGlut1 immunofluorescence (Rothe et al, 2015), a decrease in the number of vGluT1+ terminals (Deng et al, 2013) and a reduction of synaptic glutamate release from individual corticostriatal terminals in mice with symptomatic HD (Dvorzhak et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Expression of a modified astrocytic glutamate transporter alleviates Huntington’s hypokinesia, promotes synaptic glutamate clearance and counteracts potentially adverse EAAT2 interactions

Hirschberg

Dvorzhak

Rasooli-Nejad

et al. 2020

Preprint

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SUMMARYDeficiency of the astrocytic excitatory amino acid transporter type 2 (EAAT2) and, consequently, inefficient glutamate clearance at corticostriatal synapses may contribute to the depression of self-initiated movements in Huntington’s disease (HD). Here we report that the removal of the last 68 amino-acids in the C-terminal of EAAT2 increases the levels of native EAAT2 in striatal lysates and counteracts some of the HD-related changes in the interactor spectrum of mYFP-tagged EAAT2. Using the Q175 mouse model of HD, we explored the functional consequences of C-terminal modifications. It was found that astrocytic expression of EAAT2-S506X or -4KR alleviates the HD-related decrease in the incidence and velocity of exploratory movements. It also stimulates astrocytic glutamate uptake, increases the level of synaptic EAAT2 and improves glutamate clearance at single corticostriatal synapse. The experiments illuminate a link between the intracellular regulation of astrocytic glutamate transport in the striatum and symptoms of hypokinesia in HD mice.

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Molecular insights into cortico-striatal miscommunications in Huntington's disease

Cited by 52 publications

References 72 publications

Cortical and Striatal Circuits in Huntington’s Disease

Cortical and Striatal Circuits in Huntington’s Disease

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

Expression of a modified astrocytic glutamate transporter alleviates Huntington’s hypokinesia, promotes synaptic glutamate clearance and counteracts potentially adverse EAAT2 interactions

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