Emerging Synaptic Molecules as Candidates in the Etiology of Neurological Disorders

Torres, Viviana; Vallejo, Daniela; Inestrosa, Nibaldo C.

doi:10.1155/2017/8081758

Cited by 67 publications

(60 citation statements)

References 289 publications

(323 reference statements)

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“…Decreased expression of hippocampal nr4a2 in crows with reduced NOE is also consistent with its suggested role in the novel object recognition and memory in mice (McNulty et al., ). At the same time, the lack of dLAN‐induced effect on expression of genes involved in neuronal plasticity ( egr1 , creb , syngap , syn2 , grin2a , and grin2b ) and neuronal death ( caspase2 , caspase3 , foxo3 ) do not support the changes in neuronal plasticity and apoptosis as possible factors for negative behavioural responses in Indian house crows under dLAN (Duclot & Kabbaj, ; Lee et al., ; Torres, Vallejo, & Inestrosa, ). We would not rule out though the other possibilities, e.g., (a) the involvement of other genes that we have not investigated, and (b) dLAN‐induced alteration of post‐transcriptional events and post‐translational modification of the protein target.…”

Section: Discussionmentioning

confidence: 99%

Illuminated night alters hippocampal gene expressions and induces depressive‐like responses in diurnal corvids

Taufique

Prabhat

Kumar

2018

Eur J of Neuroscience

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Artificial light at night induces circadian disruptions and causes cognitive impairment and mood disorders; yet very little is known about the neural and molecular correlates of these effects in diurnal animals. We manipulated the night environment and examined cellular and molecular changes in hippocampus, the brain region involved in cognition and mood, of Indian house crows (Corvus splendens) exposed to 12 hr light (150 lux): 12 hr darkness (0 lux). Diurnal corvids are an ideal model species with cognitive abilities at par with mammals. Dim light (6 lux) at night (dLAN) altered daily activity:rest pattern, reduced sleep, and induced depressive-like responses (decreased eating and self-grooming, self-mutilation, and reduced novel object exploration); return to an absolute dark night reversed these negative effects. dLAN suppressed nocturnal melatonin levels; however, diurnal corticosterone levels were unaffected. Concomitant reduction of immunoreactivity for DCX and BDNF suggested dLAN-induced suppression of hippocampal neurogenesis and compromised neuronal health. dLAN also negatively influenced hippocampal expression of genes associated with depressive-like responses (bdnf, il-1β, tnfr1, nr4a2), but not of those associated with neuronal plasticity (egr1, creb, syngap, syn2, grin2a, grin2b), cellular oxidative stress (gst, sod3, cat1) and neuronal death (caspase2, caspase3, foxo3). Furthermore, we envisaged the role of BDNF and showed epigenetic modification of bdnf gene by decreased histone H3 acetylation and increased hdac4 expression under dLAN. These results demonstrate transcriptional and epigenetic bases of dLAN-induced negative effects in diurnal crows, and provide insights into the risks of exposure to illuminated nights to animals including humans in an urban setting.

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Section: Discussionmentioning

confidence: 99%

Illuminated night alters hippocampal gene expressions and induces depressive‐like responses in diurnal corvids

Taufique

Prabhat

Kumar

2018

Eur J of Neuroscience

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“…They participate in synaptogenesis by helping to stabilize synapses early in development during the formation of neural circuits and simultaneously contribute to the specification of the diverse properties of synapses (1)(2)(3). Because of their central role in synaptic function, mutations in synaptic cell adhesion proteins contribute to a wide range of neuropsychiatric disorders (2,(4)(5)(6)(7)(8).…”

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confidence: 99%

Deletion of LRRTM1 and LRRTM2 in adult mice impairs basal AMPA receptor transmission and LTP in hippocampal CA1 pyramidal neurons

Bhouri

Morishita

Temkin

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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Leucine-rich repeat transmembrane (LRRTM) proteins are synaptic cell adhesion molecules that influence synapse formation and function. They are genetically associated with neuropsychiatric disorders, and via their synaptic actions likely regulate the establishment and function of neural circuits in the mammalian brain. Here, we take advantage of the generation of a and double conditional knockout mouse ( cKO) to examine the role of LRRTM1,2 at mature excitatory synapses in hippocampal CA1 pyramidal neurons. Genetic deletion of in vivo in CA1 neurons using Cre recombinase-expressing lentiviruses dramatically impaired long-term potentiation (LTP), an impairment that was rescued by simultaneous expression of LRRTM2, but not LRRTM4. Mutation or deletion of the intracellular tail of LRRTM2 did not affect its ability to rescue LTP, while point mutations designed to impair its binding to presynaptic neurexins prevented rescue of LTP. In contrast to previous work using shRNA-mediated knockdown of LRRTM1,2, KO of these proteins at mature synapses also caused a decrease in AMPA receptor-mediated, but not NMDA receptor-mediated, synaptic transmission and had no detectable effect on presynaptic function. Imaging of recombinant photoactivatable AMPA receptor subunit GluA1 in the dendritic spines of cultured neurons revealed that it was less stable in the absence of LRRTM1,2. These results illustrate the advantages of conditional genetic deletion experiments for elucidating the function of endogenous synaptic proteins and suggest that LRRTM1,2 proteins help stabilize synaptic AMPA receptors at mature spines during basal synaptic transmission and LTP.

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“…The indispensable role of SNAREs in NT release accords with the rarity of mutations in any of these proteins 7 . However, mutations in the direct regulators of SNARE proteins exhibit a range of clinical presentations, including autism spectrum disorder (ASD), schizophrenia, and an array of other neurological disorders 8 . Although the genetic variation underlying the clinical phenotype can be directly identified, there is no straightforward approach linking the observed mutation effect with the protein stability, interactions, and dynamics of the cellular processes involved in synaptic function.…”

Section: Main Textmentioning

confidence: 99%

Structural analysis ofde novoSTXBP1 mutation in complex with syntaxin 1A reveals a major alteration in the interaction interface in a child with developmental delay and spasticity

Banne

Falik‐Zaccai

Brielle

et al. 2019

Preprint

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STXBP1, also known as Munc-18, is a master regulator of neurotransmitter release and synaptic function in the human brain through its direct interaction with syntaxin 1A. STXBP1 related disorders are well characterized and cover a diverse range of neurological and neurodevelopmental conditions. Through exome sequencing of a child with developmental delay, hypotonia and spasticity, we found a novel de novo insertion mutation of three nucleotides in the STXBP1 coding region, resulting in an additional arginine after position 39 (R39dup).Inconclusive results from state-of-the-art variant prediction tools mandated a structure-based approach using molecular dynamics (MD) simulations of the STXBP1-syntaxin 1A complex.Comparison of the interaction interfaces of the wild type and the R39dup complexes revealed a reduced interaction surface area in the mutant, leading to destabilization of the interaction. We applied the same MD methodology to 7 additional previously reported STXBP1 mutations. We find that the stability of the STXBP1-syntaxin 1A interface correlates with the reported clinical phenotypes. We illustrate a direct link between a patient's genetic variations and the observed clinical phenotype through protein structure, dynamics, and function.

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Emerging Synaptic Molecules as Candidates in the Etiology of Neurological Disorders

Cited by 67 publications

References 289 publications

Illuminated night alters hippocampal gene expressions and induces depressive‐like responses in diurnal corvids

Illuminated night alters hippocampal gene expressions and induces depressive‐like responses in diurnal corvids

Deletion of LRRTM1 and LRRTM2 in adult mice impairs basal AMPA receptor transmission and LTP in hippocampal CA1 pyramidal neurons

Structural analysis ofde novoSTXBP1 mutation in complex with syntaxin 1A reveals a major alteration in the interaction interface in a child with developmental delay and spasticity

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