Hippocampal dysfunction defines disease onset in Huntington's disease

Begeti, Faye; Schwab, Laetitia; Mason, Sarah; Barker, Roger A.

doi:10.1136/jnnp-2015-312413

Cited by 53 publications

(51 citation statements)

References 47 publications

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“…Additionally, similar symptoms are observed in HD mouse models [61]. While HD patients show hippocampal memory and learning deficits, changes in excitatory synaptic plasticity and spatial cognition in the hippocampus have been reported in HD mouse models [62][63][64].…”

Section: Huntington Diseasesupporting

confidence: 58%

The Role of the SLC Transporters Protein in the Neurodegenerative Disorders

Ayka¹,

Şehirli²

2020

Clin Psychopharmacol Neurosci

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The solute carrier (SLC) superfamily is one of the major subgroups of membrane proteins in mammalian cells. The solute carrier proteins include more than 400 different membrane-spanning solute carriers organized with 65 families in the human. In solute carrier family neurons, neurotransmitter is considered to be a pharmacological target of neuropsychiatric drugs because of their important role in the recovery of neurotransmitters such as GABA, glutamate, serotonin, dopamine and noradrenaline and regulation of their concentration in synaptic regions. Therefore, solute carrier transporters play vital and different roles in neurodegenerative disorders. In this article, the role of solute carrier transporters in neurodegenerative disorders such as Alzheimer disease, amyotrophic lateral sclerosis, Huntington disease, Parkinson's diseases, depression, post-traumatic stress disorder, dementia, schizophrenia, and Epilepsy reviewed and discussed to see how defects or absences in SLC transporter cause neurodegenerative disorders. In this review, we try to summarize what is known about solute carriers with respect to brain distribution and expression. The review summarizes current knowledge on the roles of solute carrier transporters in neurodegenerative disorders.

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Section: Huntington Diseasesupporting

confidence: 58%

The Role of the SLC Transporters Protein in the Neurodegenerative Disorders

Ayka¹,

Şehirli²

2020

Clin Psychopharmacol Neurosci

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“…An example case is a recent report on Huntington's disease (HD) [85,86], a monogenic, autosomal-dominant trinucleotide CAG-repeat expansion within exon 1 of the HTT gene, resulting in an abnormally long polyglutamine (polyQ) tract of the mutant Huntingtin (mHTT) protein [87,88]. Although midlife onset of the classical HD disease symptoms are manifested as a movement disorder, psychiatric problems and cognitive impairments could precede the motor symptoms [89][90][91]. HTT is a scaffolding protein with many cellular partners [92].…”

Section: Rebalancing the Chloride-nkcc1 Versus Kcc2 Targetingmentioning

confidence: 99%

The Expanding Therapeutic Potential of Neuronal KCC2

Tang

2020

Cells

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Dysfunctions in GABAergic inhibitory neural transmission occur in neuronal injuries and neurological disorders. The potassium–chloride cotransporter 2 (KCC2, SLC12A5) is a key modulator of inhibitory GABAergic inputs in healthy adult neurons, as its chloride (Cl−) extruding activity underlies the hyperpolarizing reversal potential for GABAA receptor Cl− currents (EGABA). Manipulation of KCC2 levels or activity improve symptoms associated with epilepsy and neuropathy. Recent works have now indicated that pharmacological enhancement of KCC2 function could reactivate dormant relay circuits in an injured mouse’s spinal cord, leading to functional recovery and the attenuation of neuronal abnormality and disease phenotype associated with a mouse model of Rett syndrome (RTT). KCC2 interacts with Huntingtin and is downregulated in Huntington’s disease (HD), which contributed to GABAergic excitation and memory deficits in the R6/2 mouse HD model. Here, these recent advances are highlighted, which attest to KCC2’s growing potential as a therapeutic target for neuropathological conditions resulting from dysfunctional inhibitory input.

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“…Moreover, some cognitive tasks analyzed in human studies such as the evaluation of spatial working memory, spatial recognition memory, object recognition memory, episodic memories and some forms of associative learning, can involve the participation of the hippocampus and temporal lobe structures (38,54,75,109,138,196). Patients are unable to learn the location of the platform in the virtual Morris water maze and performance correlates to the estimated years to disease onset (12). A recent study using tests analogous to those employed in HD mouse models describes hippocampal-dependent impairments in patients in early HD stage, ahead of motor symptoms.…”

Section: Hippocampal Dysfunctionmentioning

confidence: 99%

“…A recent study using tests analogous to those employed in HD mouse models describes hippocampal-dependent impairments in patients in early HD stage, ahead of motor symptoms. Patients are unable to learn the location of the platform in the virtual Morris water maze and performance correlates to the estimated years to disease onset (12). In early-mild symptomatic HD patients, alterations in associative learning, spatial short-term memory, spatial working memory and recognition memory have been described (150,197).…”

Section: Hippocampal Dysfunctionmentioning

confidence: 99%

Cognitive dysfunction in Huntington's disease: mechanisms and therapeutic strategies beyond BDNF

2016

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One of the main focuses in Huntington's disease (HD) research, as well as in most neurodegenerative diseases, is the development of new therapeutic strategies, as currently there is no treatment to delay or prevent the progression of the disease. Neuronal dysfunction and neuronal death in HD are caused by a combination of interrelated pathogenic processes that lead to motor, cognitive and psychiatric symptoms. Understanding how mutant huntingtin impacts on a plethora of cellular functions could help to identify new molecular targets. Although HD has been classically classified as a neurodegenerative disease affecting voluntary movement, lately cognitive dysfunction is receiving increased attention as it is very invalidating for patients. Thus, an ambitious goal in HD research is to find altered molecular mechanisms that contribute to cognitive decline. In this review, we have focused on those findings related to corticostriatal and hippocampal cognitive dysfunction in HD, as well as on the underlying molecular mechanisms, which constitute potential therapeutic targets. These include alterations in synaptic plasticity, transcriptional machinery and neurotrophic and neurotransmitter signaling.

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Hippocampal dysfunction defines disease onset in Huntington's disease

Cited by 53 publications

References 47 publications

The Role of the SLC Transporters Protein in the Neurodegenerative Disorders

The Role of the SLC Transporters Protein in the Neurodegenerative Disorders

The Expanding Therapeutic Potential of Neuronal KCC2

Cognitive dysfunction in Huntington's disease: mechanisms and therapeutic strategies beyond BDNF

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