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BMC Medicine Jul 2023Schizophrenia and bipolar disorder (BD) are believed to share clinical symptoms, genetic risk, etiological factors, and pathogenic mechanisms. We previously reported...
BACKGROUND
Schizophrenia and bipolar disorder (BD) are believed to share clinical symptoms, genetic risk, etiological factors, and pathogenic mechanisms. We previously reported that single nucleotide polymorphisms spanning chromosome 3p21.1 showed significant associations with both schizophrenia and BD, and a risk SNP rs2251219 was in linkage disequilibrium with a human specific Alu polymorphism rs71052682, which showed enhancer effects on transcriptional activities using luciferase reporter assays in U251 and U87MG cells.
METHODS
CRISPR/Cas9-directed genome editing, real-time quantitative PCR, and public Hi-C data were utilized to investigate the correlation between the Alu polymorphism rs71052682 and NISCH. Primary neuronal culture, immunofluorescence staining, co-immunoprecipitation, lentiviral vector production, intracranial stereotaxic injection, behavioral assessment, and drug treatment were used to examine the physiological impacts of Nischarin (encoded by NISCH).
RESULTS
Deleting the Alu sequence in U251 and U87MG cells reduced mRNA expression of NISCH, the gene locates 180 kb from rs71052682, and Hi-C data in brain tissues confirmed the extensive chromatin contacts. These data suggested that the genetic risk of schizophrenia and BD predicted elevated NISCH expression, which was also consistent with the observed higher NISCH mRNA levels in the brain tissues from psychiatric patients compared with controls. We then found that overexpression of NISCH resulted in a significantly decreased density of mushroom dendritic spines with a simultaneously increased density of thin dendritic spines in primary cultured neurons. Intriguingly, elevated expression of this gene in mice also led to impaired spatial working memory in the Y-maze. Given that Nischarin is the target of anti-hypertensive agents clonidine and tizanidine, which have shown therapeutic effects in patients with schizophrenia and patients with BD in preliminary clinical trials, we demonstrated that treatment with those antihypertensive drugs could reduce NISCH mRNA expression and rescue the impaired working memory in mice.
CONCLUSIONS
We identify a psychiatric risk gene NISCH at 3p21.1 GWAS locus influencing dendritic spine morphogenesis and cognitive function, and Nischarin may have potentials for future therapeutic development.
Topics: Humans; Mice; Animals; Dendritic Spines; Genome-Wide Association Study; Cognition; Polymorphism, Single Nucleotide; Morphogenesis; RNA, Messenger
PubMed: 37443018
DOI: 10.1186/s12916-023-02931-6 -
Psychiatry and Clinical Neurosciences Sep 2019Dendritic spines are tiny postsynaptic protrusions from a dendrite that receive most of the excitatory synaptic input in the brain. Functional and structural changes in... (Review)
Review
Dendritic spines are tiny postsynaptic protrusions from a dendrite that receive most of the excitatory synaptic input in the brain. Functional and structural changes in dendritic spines are critical for synaptic plasticity, a cellular model of learning and memory. Conversely, altered spine morphology and plasticity are common hallmarks of human neurodevelopmental disorders, such as intellectual disability and autism. The advances in molecular and optical techniques have allowed for exploration of dynamic changes in structure and signal transduction at single-spine resolution, providing significant insights into the molecular regulation underlying spine structural plasticity. Here, I review recent findings on: how synaptic stimulation leads to diverse forms of spine structural plasticity; how the associated biochemical signals are initiated and transmitted into neuronal compartments; and how disruption of single genes associated with neurodevelopmental disorders can lead to abnormal spine structure in human and mouse brains. In particular, I discuss the functions of the Ras superfamily of small GTPases in spatiotemporal regulation of the actin cytoskeleton and protein synthesis in dendritic spines. Multiple lines of evidence implicate disrupted Ras signaling pathways in the spine structural abnormalities observed in neurodevelopmental disorders. Both deficient and excessive Ras activities lead to disrupted spine structure and deficits in learning and memory. Dysregulation of spine Ras signaling, therefore, may play a key role in the pathogenesis of multiple neurodevelopmental disorders with distinct etiologies.
Topics: Actin Cytoskeleton; Angelman Syndrome; Animals; Autism Spectrum Disorder; Dendritic Spines; Fragile X Syndrome; Humans; Intellectual Disability; Neurodevelopmental Disorders; Neuronal Plasticity; Neurons; Protein Biosynthesis; Signal Transduction; Synapses; Tuberous Sclerosis; ras Proteins
PubMed: 31215705
DOI: 10.1111/pcn.12899 -
PloS One 2023Proteins from the NANOS family are conserved translational repressors with a well-known role in gonad development in both vertebrates and invertebrates. In addition,...
Proteins from the NANOS family are conserved translational repressors with a well-known role in gonad development in both vertebrates and invertebrates. In addition, Drosophila Nanos controls neuron maturation and function, and rodent Nanos1 affects cortical neuron differentiation. Here we show that rat Nanos1 is expressed in hippocampal neurons and that the siRNA-mediated knockdown of Nanos1 impairs synaptogenesis. We found that both dendritic spine size and number were affected by Nanos1 KD. Dendritic spines were smaller and more numerous. Moreover, whereas in control neurons most dendritic PSD95 clusters contact pre-synaptic structures, a larger proportion of PSD95 clusters lacked a synapsin counterpart upon Nanos1 loss-of-function. Finally, Nanos1 KD impaired the induction of ARC typically triggered by neuron depolarization. These results expand our knowledge on the role of NANOS1 in CNS development and suggest that RNA regulation by NANOS1 governs hippocampal synaptogenesis.
Topics: Animals; Rats; RNA; Hippocampus; RNA-Binding Proteins; Dendritic Spines
PubMed: 37058523
DOI: 10.1371/journal.pone.0284589 -
Journal of Neural Engineering Aug 2022: Techniques to identify monosynaptic connections between neurons have been vital for neuroscience research, facilitating important advancements concerning network...
: Techniques to identify monosynaptic connections between neurons have been vital for neuroscience research, facilitating important advancements concerning network topology, synaptic plasticity, and synaptic integration, among others.: Here, we introduce a novel approach to identify and monitor monosynaptic connections using high-resolution dendritic spine Caimaging combined with simultaneous large-scale recording of extracellular electrical activity by means of high-density microelectrode arrays.: We introduce an easily adoptable analysis pipeline that associates the imaged spine with its presynaptic unit and test it onrecordings. The method is further validated and optimized by simulating synaptically-evoked spine Catransients based on measured spike trains in order to obtain simulated ground-truth connections.: The proposed approach offers unique advantages as (a) it can be used to identify monosynaptic connections with an accurate localization of the synapse within the dendritic tree, (b) it provides precise information of presynaptic spiking, and (c) postsynaptic spine Casignals and, finally, (d) the non-invasive nature of the proposed method allows for long-term measurements. The analysis toolkit together with the rich data sets that were acquired are made publicly available for further exploration by the research community.
Topics: Dendritic Spines; Neuronal Plasticity; Neurons; Synapses
PubMed: 35931040
DOI: 10.1088/1741-2552/ac8765 -
Science Advances Aug 2023The insulin superfamily of peptides is essential for homeostasis as well as neuronal plasticity, learning, and memory. Here, we show that insulin-like growth factors 1...
The insulin superfamily of peptides is essential for homeostasis as well as neuronal plasticity, learning, and memory. Here, we show that insulin-like growth factors 1 and 2 (IGF1 and IGF2) are differentially expressed in hippocampal neurons and released in an activity-dependent manner. Using a new fluorescence resonance energy transfer sensor for IGF1 receptor (IGF1R) with two-photon fluorescence lifetime imaging, we find that the release of IGF1 triggers rapid local autocrine IGF1R activation on the same spine and more than several micrometers along the stimulated dendrite, regulating the plasticity of the activated spine in CA1 pyramidal neurons. In CA3 neurons, IGF2, instead of IGF1, is responsible for IGF1R autocrine activation and synaptic plasticity. Thus, our study demonstrates the cell type-specific roles of IGF1 and IGF2 in hippocampal plasticity and a plasticity mechanism mediated by the synthesis and autocrine signaling of IGF peptides in pyramidal neurons.
Topics: Autocrine Communication; Dendritic Spines; Hippocampus; Neuronal Plasticity; Pyramidal Cells
PubMed: 37531435
DOI: 10.1126/sciadv.adg0666 -
Developmental Neurobiology May 2020Angelman syndrome (AS) is a rare neurodevelopmental disorder characterized by severe mental retardation, microcephaly, speech impairment, frequent epilepsy, EEG... (Review)
Review
Angelman syndrome (AS) is a rare neurodevelopmental disorder characterized by severe mental retardation, microcephaly, speech impairment, frequent epilepsy, EEG abnormalities, ataxic movements, tongue protrusion, bursts of laughter, sleep abruptions, and hyperactivity. AS results from loss of function of the imprinted UBE3A (ubiquitin-protein ligase E3A) gene on chromosome 15q11-q13, including a mutation on the maternal allele of Ube3a, a large deletion of the maternally inherited chromosomal region 15q11-13, paternal uniparental disomy of chromosome 15q11-13, or an imprinting defect. The Ube3a maternal deleted mouse model recaptured the major phenotypes of AS patients include seizure, learning and memory impairments, sleep disturbance, and motor problems. Owing to the activity-dependent structural and functional plasticity, dendritic spines are believed as the basic subcellular compartment for learning and memory and the sites where LTP and LTD are induced. Defects of spine formation and dynamics are common among several neurodevelopmental disorders and neuropsychiatric disorders including AS and reflect the underlying synaptopathology, which drives clinically relevant behavioral deficits. This review will summarize the impaired spine density, morphology, and synaptic plasticity in AS and propose that future explorations on spine dynamics and synaptic plasticity may help develop novel interventions and therapy for neurodevelopmental disorders like AS.
Topics: Angelman Syndrome; Animals; Dendritic Spines; Humans; Neuronal Plasticity
PubMed: 32378784
DOI: 10.1002/dneu.22757 -
Behavioural Brain Research May 2021In this study, apical dendritic spine density of neurons in hippocampal, amygdalar and prefrontal cortical areas was compared in rats that were repeatedly winning or...
In this study, apical dendritic spine density of neurons in hippocampal, amygdalar and prefrontal cortical areas was compared in rats that were repeatedly winning or losing social conflicts. Territorial male wild-type Groningen (WTG) rats were allowed multiple daily attacks (>20 times) on intruder males in the resident-intruder paradigm. Frequent winning experiences are known to facilitate uncontrolled aggressive behavior reflected in aggressive attacks on anesthetized males which was also observed in the winners in this study. Both winners and losers were socially housed during the experiments; winners with females to stimulate territorial behavior, and losers with two other losing male rats. Twenty-four hours after the last social encounter, brains from experienced residential winners and repeatedly defeated intruder rats were collected and neuronal morphology in selected brain regions was studied via Golgi-Cox staining. Results indicate that spine density in the apical dendrites of the hippocampal CA1 reduced similarly in both winners and losers. In addition, winners showed increased spine densities at the proximal segments (20-30 μm) of the basolateral amygdala neurons and losers tended to show a decreased spine density at the more proximal segments of the infralimbic region of prefrontal cortex neurons. No effect of winning and losing was observed in the medial amygdala. The atrophic effect of repeated defeats in hippocampal and prefrontal regions was anticipated despite the fact that social housing of the repeatedly losing intruder males may have played a protective role. The reduction of hippocampal spine density in the winners seems surprising but supports previous findings in hierarchical dominant males in rat colonies. The dominants showed even greater shrinkage of the apical dendritic arbors of hippocampal CA3 pyramidal neurons compared to the stressed subordinates.
Topics: Animals; Basolateral Nuclear Complex; Behavior, Animal; CA1 Region, Hippocampal; Competitive Behavior; Dendritic Spines; Male; Neuronal Plasticity; Prefrontal Cortex; Pyramidal Cells; Rats; Social Dominance
PubMed: 33727049
DOI: 10.1016/j.bbr.2021.113243 -
The Journal of Comparative Neurology Apr 2021Lafora disease (LD) is a genetic and fatal form of neurodegenerative disorder characterized by myoclonic epilepsy and cognitive deficits. LD is caused by...
Lafora disease (LD) is a genetic and fatal form of neurodegenerative disorder characterized by myoclonic epilepsy and cognitive deficits. LD is caused by loss-of-function mutations in the EPM2A or the NHLRC1 gene. A major hallmark of LD is the presence of abnormal glycogen aggregates in neurons and other tissues. Functional studies on the genes have, therefore, mostly focused on glycogen metabolism. The physiological basis of cognitive deficits in LD is thus largely unexplored. Alterations in dendritic spine morphology are known in neurodevelopmental and neuropsychiatric disorders. We, therefore, analyzed the dendritic spine morphologies in pyramidal neurons of the hippocampal and Cortical layer V of the Epm2a or Nhlrc1 knockout mice brain. We found a significant increase in the density, length, and reduction in the width of the dendritic spines in Postnatal day 21 to 12-month-old LD animals. Similar observations were made in the primary cultures of neurons derived from the hippocampi of the embryonic brain, suggesting that the aberrant spine phenotype could be a developmental defect in LD. We also looked at the cognitive and behavioral deficits as a possible readout of the spine abnormalities. The LD animals exhibited hyperactivity, reduced anxiety-like behavior, and deficits in the spatial and nonspatial memory. Such abnormalities were seen in the younger (1-2 months) as well as the older (7-8 months) age groups. Taken together, our results suggest that the dendritic spine abnormalities are primary developmental defects in the LD model and these defects might underlie some of the symptoms, including cognitive deficits, in LD.
Topics: Animals; Cells, Cultured; Cerebral Cortex; Cognitive Dysfunction; Dendritic Spines; Female; Hippocampus; Lafora Disease; Male; Memory; Mice; Mice, Knockout; Pregnancy; Protein Tyrosine Phosphatases, Non-Receptor; Ubiquitin-Protein Ligases
PubMed: 32785985
DOI: 10.1002/cne.25006 -
Neuroscience Oct 2019We recently found that non-stressed female rats have higher basal prepro-orexin expression and activation of orexinergic neurons compared to non-stressed males, which...
We recently found that non-stressed female rats have higher basal prepro-orexin expression and activation of orexinergic neurons compared to non-stressed males, which lead to impaired habituation to repeated restraint stress at the behavioral, neural, and endocrine level. Here, we extended our study of sex differences in the orexin system by examining spine densities and dendritic morphology in putative orexin neurons in adult male and female rats that were exposed to 5 consecutive days of 30-min restraint. Analysis of spine distribution and density indicated that putative orexinergic neurons in control non-stressed females had significantly more dendritic spines than those in control males, and the majority of these were mushroom spines. This morphological finding may suggest more excitatory input onto orexin neurons in female rats. As orexin neurons are known to promote the hypothalamic-pituitary-adrenal response, this morphological change in orexin neurons could underlie the impaired habituation to repeated stress in female rats. Dendritic complexity did not differ between non-stressed males and females, however repeated restraint stress decreased total dendritic length, nodes, and branching primarily in males. Thus, reduced dendritic complexity of putative orexinergic neurons is observed in males but not in females after 5days of repeated restraint stress. This morphological change might be reflective of decreased orexin system function, which may allow males to habituate more fully to repeated restraint than females. These results extend our understanding of the role of orexin neurons in regulating habituation and demonstrate changes in putative orexin cell morphology and spines that may underlie sex differences in habituation.
Topics: Animals; Dendritic Spines; Female; Male; Orexin Receptors; Orexins; Pituitary-Adrenal System; Restraint, Physical; Sex Characteristics; Stress, Psychological
PubMed: 31442567
DOI: 10.1016/j.neuroscience.2019.08.026 -
Cells Dec 2021Dendritic spines are small, thin, hair-like protrusions found on the dendritic processes of neurons. They serve as independent compartments providing large amplitudes of... (Review)
Review
Dendritic spines are small, thin, hair-like protrusions found on the dendritic processes of neurons. They serve as independent compartments providing large amplitudes of Ca signals to achieve synaptic plasticity, provide sites for newer synapses, facilitate learning and memory. One of the common and severe complication of neurodegenerative disease is cognitive impairment, which is said to be closely associated with spine pathologies viz., decreased in spine density, spine length, spine volume, spine size etc. Many treatments targeting neurological diseases have shown to improve the spine structure and distribution. However, concise data on the various modulators of dendritic spines are imperative and a need of the hour. Hence, in this review we made an attempt to consolidate the effects of various pharmacological (cholinergic, glutamatergic, GABAergic, serotonergic, adrenergic, and dopaminergic agents) and non-pharmacological modulators (dietary interventions, enriched environment, yoga and meditation) on dendritic spines structure and functions. These data suggest that both the pharmacological and non-pharmacological modulators produced significant improvement in dendritic spine structure and functions and in turn reversing the pathologies underlying neurodegeneration. Intriguingly, the non-pharmacological approaches have shown to improve intellectual performances both in preclinical and clinical platforms, but still more technology-based evidence needs to be studied. Thus, we conclude that a combination of pharmacological and non-pharmacological intervention may restore cognitive performance synergistically via improving dendritic spine number and functions in various neurological disorders.
Topics: Cholinergic Agents; Cognitive Dysfunction; Dendritic Spines; Diet; Excitatory Amino Acid Agents; GABA Agents; Humans; Meditation; Neurodegenerative Diseases; Neurons; Synapses; Yoga
PubMed: 34943913
DOI: 10.3390/cells10123405