Inhibition of Trpv4 rescues circuit and social deficits unmasked by acute inflammatory response in a Shank3 mouse model of Autism

Tzanoulinou, Stamatina; Musardo, Stefano; Contestabile, Alessandro; Bariselli, Sebastiano; Casarotto, Giulia; Magrinelli, Elia; Jiang, Yong‐Hui; Jabaudon, Denis; Bellone, Camilla

doi:10.1038/s41380-021-01427-0

Cited by 21 publications

(29 citation statements)

References 98 publications

(86 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Mutations in the SHANK3 gene have been recognized as a genetic risk factor for ASD ( 2 ). Notably, heterozygous SHANK3 mutations are typically associated with idiopathic ASD in patients, but heterozygous deletion of Shank3 gene in mice does not commonly induce ASD-related behavioral deficit ( 7 , 8 ). Using △e4-22 Shank3 full knockout strategy, Shank3 haploinsufficiency was sufficient to cause marked deficits in TRPV1-medicated heat pain.…”

Section: Discussionmentioning

confidence: 99%

“…Autism spectrum disorder (ASD) is defined by persistent deficits in the ability to initiate and to sustain reciprocal social interaction and social communication and characterized by a range of restricted, repetitive, and inflexible patterns of behavior, as well as various sensory abnormalities (1)(2)(3)(4)(5). SHANK3 is a scaffolding protein located at excitatory synapses, and mutations of SHANK3 (haploinsufficiency) may account for 1-2% of all ASD cases including Phelan-McDermid syndrome (PMS) (2,6,7). The disrupted striatum centered brain structures and synaptic transmission in this brain region are associated with ASD children with SHANK3 mutations and animal models of Shank3 deficiency (2,4,8,9).…”

Section: Introductionmentioning

confidence: 99%

“…Subacute neuropsychiatric syndrome in girls with SHANK3 mutations responds to immunomodulation ( 19 ). Preclinical study shows that acute inflammatory challenge induced by lipopolysaccharide (LPS) can unmask behavioral deficits of Shank3 +/− mice ( 7 ). However, the mechanisms of excessive immune reaction in ASD are not fully understood.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

SHANK3 in vagal sensory neurons regulates body temperature, systemic inflammation, and sepsis

Zhang

Bang²,

He³

et al. 2023

Front. Immunol.

Self Cite

View full text Add to dashboard Cite

Excessive inflammation has been implicated in autism spectrum disorder (ASD), but the underlying mechanisms have not been fully studied. SHANK3 is a synaptic scaffolding protein and mutations of SHANK3 are involved in ASD. Shank3 expression in dorsal root ganglion sensory neurons also regulates heat pain and touch. However, the role of Shank3 in the vagus system remains unknown. We induced systemic inflammation by lipopolysaccharide (LPS) and measured body temperature and serum IL-6 levels in mice. We found that homozygous and heterozygous Shank3 deficiency, but not Shank2 and Trpv1 deficiency, aggravates hypothermia, systemic inflammation (serum IL-6 levels), and sepsis mortality in mice, induced by lipopolysaccharide (LPS). Furthermore, these deficits can be recapitulated by specific deletion of Shank3 in Nav1.8-expressing sensory neurons in conditional knockout (CKO) mice or by selective knockdown of Shank3 or Trpm2 in vagal sensory neurons in nodose ganglion (NG). Mice with Shank3 deficiency have normal basal core temperature but fail to adjust body temperature after perturbations with lower or higher body temperatures or auricular vagus nerve stimulation. In situ hybridization with RNAscope revealed that Shank3 is broadly expressed by vagal sensory neurons and this expression was largely lost in Shank3 cKO mice. Mechanistically, Shank3 regulates the expression of Trpm2 in NG, as Trpm2 but not Trpv1 mRNA levels in NG were significantly reduced in Shank3 KO mice. Our findings demonstrated a novel molecular mechanism by which Shank3 in vagal sensory neurons regulates body temperature, inflammation, and sepsis. We also provided new insights into inflammation dysregulation in ASD.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

SHANK3 in vagal sensory neurons regulates body temperature, systemic inflammation, and sepsis

Zhang

Bang²,

He³

et al. 2023

Front. Immunol.

Self Cite

View full text Add to dashboard Cite

show abstract

“…One of such studies has shown that acute inflammation from a lipopolysaccharide challenge can acutely unmask behavioural deficits in Shank3 haploinsufficient mice. The loss of social preference can be reversed by Trpv4 inhibition in the Nucleus Accumbens (NA) [ 29 ]. Early postnatal downregulation of NA Shank3 creates a similar behavioural deficit by shifting the membrane properties of dopamine type 1-expressing medium spiny neurons.…”

Section: Possible Gene-environment Interactions In Phelan–mcdermid Sy...mentioning

confidence: 99%

Phenotypic Variability in Phelan–McDermid Syndrome and Its Putative Link to Environmental Factors

Boccuto

Mitz

Abenavoli

et al. 2022

Genes

View full text Add to dashboard Cite

Phelan–McDermid syndrome (PMS) is a multi-systemic disorder characterized by both genetic and phenotypic variability. Genetic abnormalities causing PMS span from pathogenic variants of the SHANK3 gene to chromosomal rearrangements affecting the 22q13 region and leading to the loss of up to over nine megabases. The clinical presentation of individuals with PMS includes intellectual disability, neonatal hypotonia, delayed or absent speech, developmental delay, and minor dysmorphic facial features. Several other features may present with differences in age of onset and/or severity: seizures, autism, regression, sleep disorders, gastrointestinal problems, renal disorders, dysplastic toenails, and disrupted thermoregulation. Among the causes of this phenotypic variability, the size of the 22q13 deletion has effects that may be influenced by environmental factors interacting with haploinsufficiency or hemizygous variants of certain genes. Another mechanism linking environmental factors and phenotypic variability in PMS involves the loss of one copy of genes like BRD1 or CYP2D6, located at 22q13 and involved in the regulation of genomic methylation or pharmacokinetics, which are also influenced by external agents, such as diet and drugs. Overall, several non-mutually exclusive genetic and epigenetic mechanisms interact with environmental factors and may contribute to the clinical variability observed in individuals with PMS. Characterization of such factors will help to better manage this disorder.

show abstract

“…Among available DREADD systems, those based on the metabotropic acetylcholine receptors, the hM3Dq and hM4Di receptors, might be the most widely used . The hM3Dq and hM4Di receptors (together with their selective agonists, clozapine N-oxide (CNO) and clozapine (CZP)) have been widely used to enhance and suppress neuronal activities, respectively. ,, This application has especially contributed substantially to the identification of behavior-associated neuronal circuitries, including those in the striatum (e.g., refs − ).…”

Section: Introductionmentioning

confidence: 99%

Evidence that GIRK Channels Mediate the DREADD-hM4Di Receptor Activation-Induced Reduction in Membrane Excitability of Striatal Medium Spiny Neurons

Shan

Fang

Tian

2022

ACS Chem. Neurosci.

View full text Add to dashboard Cite

The hM4Di receptor-based chemogenetic DREADD system has been widely used to suppress neuronal activities, which has contributed substantially to the identification of behavior-associated neuronal circuitries including those in the striatum. One major mechanism by which hM4Di receptor activation suppresses neuronal activity is that the activation reduces membrane excitability, which is thought to be mediated by the opening of GIRK channels. However, previous studies have suggested that GIRK channels are barely expressed in the striatum, which naturally raises the question whether the hM4Di receptor activation-induced reduction in membrane excitability found in striatal medium spiny neurons (MSNs, which constitute 95–98% of the striatal neuronal population) is truly mediated by the endogenous GIRK channels in such scarcity. This study aims to answer this question by applying a GIRK channel-selective blocker, tertiapin-Q (TPNQ), to striatal MSNs. This study first verified that application of clozapine (CZP), an hM4Di receptor agonist, to MSNs expressing the hM4Di receptors hyperpolarized the cell membrane, and reduced membrane excitability and input resistance. This study next revealed that TPNQ post-treatment completely canceled the above CZP-induced electrophysiological effects and that TPNQ pretreatment mostly prevented further expression of the above CZP-induced electrophysiological effects. In addition, confocal microscopy imaging also revealed significant above-background GIRK1 immunofluorescence signals in striatal MSNs. These data suggest that the TPNQ-sensitive GIRK channels, despite being expressed at low levels, are likely the major mediator downstream of hM4Di receptor activation to reduce membrane excitability in striatal MSNs. These results imply that the notion held by scientists in the field that GIRK channels are absent in the striatum or their expression level is not significant enough to exert any function might be oversimplified or incorrect.

show abstract

Inhibition of Trpv4 rescues circuit and social deficits unmasked by acute inflammatory response in a Shank3 mouse model of Autism

Cited by 21 publications

References 98 publications

SHANK3 in vagal sensory neurons regulates body temperature, systemic inflammation, and sepsis

SHANK3 in vagal sensory neurons regulates body temperature, systemic inflammation, and sepsis

Phenotypic Variability in Phelan–McDermid Syndrome and Its Putative Link to Environmental Factors

Evidence that GIRK Channels Mediate the DREADD-hM4Di Receptor Activation-Induced Reduction in Membrane Excitability of Striatal Medium Spiny Neurons

Contact Info

Product

Resources

About