Abstract:
:Huntington's disease (HD) is a neurodegenerative disorder caused by a tandem repeat mutation encoding an expanded polyglutamine tract in the huntingtin protein, which leads to cognitive, psychiatric and motor dysfunction. Exposure to environmental enrichment (EE), which enhances levels of cognitive stimulation and physical activity, has therapeutic effects on cognitive, affective and motor function of transgenic HD mice. The present study investigated gene expression changes and behavioral pharmacology in male and female R6/1 transgenic HD mice at an early time-point in HD progression associated with onset of cognitive and affective abnormalities, following EE and exercise (wheel running) interventions. We have demonstrated changes in expression levels of the serotonin (5-HT) receptor Htr1a, Htr1b, Htr2a and Htr2c genes (encoding the 5-HT1A, 5-HT1B, 5-HT2A and 5-HT2C receptors, respectively) in HD brains at 8 weeks of age, using quantitative real-time PCR. In contrast, expression of the serotonin transporter (SerT, also known as 5-HTT or Slc6a4) was not altered in these brains. Furthermore, we identified region-specific, sex-specific and environmentally regulated (comparing EE, exercise and standard housing conditions) impacts on gene expression of particular 5-HT receptors, as well as SerT. For example, SerT gene expression was upregulated by exercise (wheel running from 6 to 8 weeks of age) in the hippocampus. Interestingly, when EE was introduced from 6 to 8 weeks of age, Htr2a gene expression was upregulated in the cortex, striatum and hippocampus of male mice. EE also rescued the functional activity of 5-HT2 receptors as observed in the head-twitch test, reflecting sexually dimorphic effects of environmental stimulation. These findings demonstrate that disruption of the serotonergic system occurs early in HD pathogenesis and, together with previous findings, show that the timing and duration of environmental interventions are critical in terms of their ability to modify gene expression. This study is the first to show that EE is able to selectively enhance both gene expression of a neurotransmitter receptor and the functional consequences on behavioral pharmacology, and links this molecular modulation to the therapeutic effects of environmental stimulation in this neurodegenerative disease.
journal_name
Front Mol Neuroscijournal_title
Frontiers in molecular neuroscienceauthors
Zajac MS,Renoir T,Perreau VM,Li S,Adams W,van den Buuse M,Hannan AJdoi
10.3389/fnmol.2018.00433subject
Has Abstractpub_date
2018-12-10 00:00:00pages
433issn
1662-5099journal_volume
11pub_type
杂志文章abstract::Emerging studies have demonstrated that interleukin (IL)-33 and its receptor ST2 act as key factors in inflammatory diseases. Moreover, accumulating evidence has suggested that cytokines, including tumor necrosis factor (TNF)-α and IL-1β, trigger an inflammatory cascade. SIRT1 has been shown to suppress the expression...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2020.00017
更新日期:2020-02-12 00:00:00
abstract::ADP-ribosylation of the P2X7k splice variant on mouse T cells by Ecto-ADP-ribosyltransferase ARTC2.2 in response to its substrate extracellular nicotinamide adenine dinucleotide (NAD+) triggers cell death. Since NAD+ is released as a danger signal during tissue damage, this NAD+-induced cell death (NICD) may impact th...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2019.00330
更新日期:2020-01-14 00:00:00
abstract::Some therapeutic side-effects result from simultaneous activation of homolog receptors by the same ligand. Tropomyosin receptor kinases (TrkA, TrkB and TrkC) play a major role in the development and biology of neurons through neurotrophin signaling. The wide range of cross-interactions between Trk receptors and neurot...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2017.00130
更新日期:2017-05-03 00:00:00
abstract::Status epilepticus (SE, a prolonged seizure activity) leads to reactive astrogliosis and astroglial apoptosis in the regional specific manners, independent of hemodynamics. Poly(ADP-ribose) polymerase-1 (PARP1) activity is relevant to these distinct astroglial responses. Since various regulatory signaling molecules be...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2019.00180
更新日期:2019-07-24 00:00:00
abstract::Microglial activation and the inflammatory response in the central nervous system (CNS) play important roles in secondary damage after traumatic brain injury (TBI). Transcriptional activation of genes that limit secondary damage to the CNS are mediated by a cis-acting element called the antioxidant responsive element ...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2018.00117
更新日期:2018-04-17 00:00:00
abstract::The brain is complex and heterogeneous. Even though numerous independent studies indicate cortical hyperexcitability as a potential contributor to amyotrophic lateral sclerosis (ALS) pathology, the mechanisms that are responsible for upper motor neuron (UMN) vulnerability remain elusive. To reveal the electrophysiolog...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2020.00073
更新日期:2020-05-19 00:00:00
abstract::The competitive ectodomain shedding of amyloid-β precursor protein (APP) by α-secretase and β-secretase, and the subsequent regulated intramembrane proteolysis by γ-secretase are the key processes in amyloid-β peptides (Aβ) generation. Previous studies indicate that secretases form binary complex and the interactions ...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2018.00431
更新日期:2018-11-27 00:00:00
abstract::The bioactive lipid sphingosine-1-phosphate (S1P) is an important regulator in the nervous system. Here, we explored the role of S1P and its receptors in vitro and in preclinical models of peripheral nerve regeneration. Adult sensory neurons and motor neuron-like cells were exposed to S1P in an in vitro assay, and vir...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2017.00317
更新日期:2017-10-10 00:00:00
abstract::Many genes controlling neuronal development also regulate adult neurogenesis. We investigated in vivo the effect of Sonic hedgehog (Shh) signaling activation on patterning and neurogenesis of the hippocampus and behavior of Patched1 (Ptch1) heterozygous mice (Ptch1+/- ). We demonstrated for the first time, that Ptch1+...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2018.00168
更新日期:2018-05-23 00:00:00
abstract::A fundamental characteristic of neurons is the relationship between the architecture of the polarized neuron and synaptic transmission between neurons. Intracellular membrane trafficking is paramount to establish and maintain neuronal structure; perturbation in trafficking results in defects in neurodevelopment and ne...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章,评审
doi:10.3389/fnmol.2020.597391
更新日期:2020-11-26 00:00:00
abstract::Epilepsy, one of the most prevalent neurological conditions, presents as a complex disorder of network homeostasis characterized by spontaneous non-provoked seizures and associated comorbidities. Currently used antiepileptic drugs have been designed to suppress neuronal hyperexcitability and thereby to suppress epilep...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章,评审
doi:10.3389/fnmol.2016.00026
更新日期:2016-04-13 00:00:00
abstract::There are many unanswered questions about the roles of the actin pointed end capping and actin nucleation by tropomodulins (Tmod) in regulating neural morphology. Previous studies indicate that Tmod1 and Tmod2 regulate morphology of the dendritic arbor and spines. Tmod3, which is expressed in the brain, had only a min...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2018.00357
更新日期:2018-10-09 00:00:00
abstract::Genetic studies have managed to explain many cases of familial amyotrophic lateral sclerosis (ALS) through mutations in several genes. However, the cause of a majority of sporadic cases remains unknown. Recently, epigenetics, especially miRNA studies, show some promising aspects. We aimed to evaluate the differential ...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2018.00106
更新日期:2018-04-04 00:00:00
abstract::Recoverin (Rcv) is a low molecular-weight, neuronal calcium sensor (NCS) primarily located in photoreceptor outer segments of the vertebrate retina. Calcium ions (Ca2+)-bound Rcv has been proposed to inhibit G-protein-coupled receptor kinase (GRKs) in darkness. During the light response, the Ca2+-free Rcv releases GRK...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章,评审
doi:10.3389/fnmol.2018.00473
更新日期:2018-12-20 00:00:00
abstract::Transient global cerebral ischemia (tGCI) causes excessive release of glutamate from neurons. Astrocytic glutamate transporter-1 (GLT-1) and glutamine synthetase (GS) together play a predominant role in maintaining glutamate at normal extracellular concentrations. Though our previous studies reported the alleviation o...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2018.00344
更新日期:2018-10-01 00:00:00
abstract::Collateral sprouting of surviving axons contributes to the synaptic reorganization after brain injury. To study this clinically relevant phenomenon, we used complex organotypic tissue cultures of mouse entorhinal cortex (EC) and hippocampus (H). Single EC-H cultures were generated to analyze associational sprouting, a...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2019.00270
更新日期:2019-11-12 00:00:00
abstract::[This corrects the article DOI: 10.3389/fnmol.2019.00099.]. ...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章,已发布勘误
doi:10.3389/fnmol.2019.00149
更新日期:2019-06-12 00:00:00
abstract::Ligand-binding of Cys-loop receptors results in rearrangements of extracellular loop structures which are further translated into the tilting of membrane spanning helices, and finally opening of the ion channels. The cryo-EM structure of the homopentameric α1 glycine receptor (GlyR) demonstrated an involvement of the ...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2017.00322
更新日期:2017-10-09 00:00:00
abstract::The constitutively active protein glycogen synthase kinase 3 (GSK3), a serine/threonine kinase, acts paradoxically as a tumor suppressor in some cancers while potentiates growth in others. Deciphering what governs its actions is vital for understanding many pathological conditions, including brain cancer. What are see...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2011.00047
更新日期:2011-11-25 00:00:00
abstract::GABA(A) receptors are located on the majority of neurons in the central and peripheral nervous system, where they mediate important actions of the neurotransmitter gamma-aminobutyric acid. Early in development the trophic properties of GABA allow a healthy development of the nervous system. Most neurons have a high in...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/neuro.02.007.2008
更新日期:2008-05-30 00:00:00
abstract::Ca2+ signaling plays a significant role in the development of the vertebrate nervous system where it regulates neurite growth as well as synapse and neurotransmitter specification. Elucidating the role of Ca2+ signaling in mammalian neuronal development has been largely restricted to either small animal models or prim...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2018.00178
更新日期:2018-06-11 00:00:00
abstract::Synaptic vesicle proteins 2 (SV2) were discovered in the early 80s, but the clear demonstration that SV2A is the target of efficacious anti-epileptic drugs from the racetam family stimulated efforts to improve understanding of its role in the brain. Many functions have been suggested for SV2 proteins including ions or...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章,评审
doi:10.3389/fnmol.2017.00148
更新日期:2017-05-22 00:00:00
abstract::The phosphoinositide 3-kinase (PI3K) complex plays important roles in virtually all cells of the body. The enzymatic activity of PI3K to phosphorylate phosphoinositides in the membrane is mediated by a group of catalytic and regulatory subunits. Among those, the class I catalytic subunits, p110α, p110β, p110γ, and p11...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章,评审
doi:10.3389/fnmol.2014.00012
更新日期:2014-02-13 00:00:00
abstract::In this review we provide an overview of key in vivo experiments undertaken in the cat spinal cord in the 1950s and 1960s, and point out their contributions to our present understanding of glycine receptor (GlyR) function. Importantly, some of these discoveries were made well before an inhibitory receptor, or its agon...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2010.00013
更新日期:2010-05-21 00:00:00
abstract::Parkinson's disease (PD) is a debilitating neurodegenerative disease characterized primarily by the selective death of dopaminergic (DA) neurons in the substantia nigra pars compacta of the midbrain. Although several genetic forms of PD have been identified, the precise molecular mechanisms underlying DA neuron loss i...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章,评审
doi:10.3389/fnmol.2013.00040
更新日期:2013-11-20 00:00:00
abstract::Mutations in Leucine-rich repeat kinase 2 (LRRK2) are associated with Parkinson's disease (PD) and, as such, LRRK2 is considered a promising therapeutic target for age-related neurodegeneration. Although the cellular functions of LRRK2 in health and disease are incompletely understood, robust evidence indicates that P...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2017.00417
更新日期:2017-12-14 00:00:00
abstract::Amyotrophic lateral sclerosis (ALS) and spinal and bulbar muscular atrophy (SBMA) are two motoneuron diseases (MNDs) characterized by aberrant protein behavior in affected cells. In familial ALS (fALS) and in SBMA specific gene mutations lead to the production of neurotoxic proteins or peptides prone to misfold, which...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章,评审
doi:10.3389/fnmol.2017.00176
更新日期:2017-06-21 00:00:00
abstract::[This corrects the article on p. 257 in vol. 10, PMID: 28855859.]. ...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章,已发布勘误
doi:10.3389/fnmol.2017.00392
更新日期:2017-11-20 00:00:00
abstract::Glycine receptors (GlyRs) containing the α2 subunit are highly expressed in the developing brain, where they regulate neuronal migration and maturation, promote spontaneous network activity and subsequent development of synaptic connections. Mutations in GLRA2 are associated with autism spectrum disorder, but the unde...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2018.00380
更新日期:2018-10-15 00:00:00
abstract::Among all organs of an adult animal, the central nervous system stands out because of its vast complexity and morphological diversity. During early development, the entire central nervous system develops from an apparently homogenous group of progenitors that differentiate into all neural cell types. Therefore, unders...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章,评审
doi:10.3389/fnmol.2019.00140
更新日期:2019-05-31 00:00:00