Somatosensory cortex hyperconnectivity and impaired whisker-dependent responses in Cntnap2−/− mice

Balasco, Luigi; Pagani, Marco; Pangrazzi, Luca; Chelini, Gabriele; Viscido, Francesca; Chama, Alessandra Georgette Ciancone; Galbusera, Alberto; Provenzano, Giovanni; Gozzi, Alessandro; Bozzi, Yuri

doi:10.1016/j.nbd.2022.105742

Cited by 20 publications

(14 citation statements)

References 51 publications

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“…For example, compared with the WT mice, Fmr1 KO mice displayed hyperactivity and anxiety phenotype [ 32 ], however, the basal expression level of c-fos is decreased in OFC and mPFC of Fmr1 KO mice [ 33 ]. In addition, Cntnap2 −/− mice showed impaired texture discrimination through whiskers and showed an increase in c-fos expression following stimulated by whisker [ 34 ]. In our model, the upregulation of c-fos indicated higher excitation in general neuronal cells, but not in behaviors which might be regulated by multiple brain regions and more complex mechanisms.…”

Section: Discussionmentioning

confidence: 99%

SARM1 deletion in parvalbumin neurons is associated with autism-like behaviors in mice

et al. 2022

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Autism spectrum disorder (ASD), a group of neurodevelopmental disorder diseases, is characterized by social deficits, communication difficulties, and repetitive behaviors. Sterile alpha and TIR motif-containing 1 protein (SARM1) is known as an autism-associated protein and is enriched in brain tissue. Moreover, SARM1 knockdown mice exhibit autism-like behaviors. However, its specific mechanism in ASD pathogenesis remains unclear. Here we generated parvalbumin-positive interneurons (PVI)-specific conditional SARM1 knockout (SARM1PV-CKO) mice. SARM1PV-CKO male mice showed autism-like behaviors, such as mild social interaction deficits and repetitive behaviors. Moreover, we found that the expression level of parvalbumin was reduced in SARM1PV-CKO male mice, together with upregulated apoptosis-related proteins and more cleaved-caspase-3-positive PVIs, suggesting that knocking out SARM1 may cause a reduction in the number of PVIs due to apoptosis. Furthermore, the expression of c-fos was shown to increase in SARM1PV-CKO male mice, in combination with upregulation of excitatory postsynaptic proteins such as PSD-95 or neuroligin-1, indicating enhanced excitatory synaptic input in mutant mice. This notion was further supported by the partial rescue of autism-like behavior deficits by the administration of GABA receptor agonists in SARM1PV-CKO male mice. In conclusion, our findings suggest that SARM1 deficiency in PVIs may be involved in the pathogenesis of ASD.

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Section: Discussionmentioning

confidence: 99%

SARM1 deletion in parvalbumin neurons is associated with autism-like behaviors in mice

et al. 2022

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“…Moreover, recent work on cortical networks (Haroush & Marom, 2019) suggests that inhibition may reduce discrimination between stimuli. Thus, upregulation of Gad1 in the TG of juvenile Shank3b -/and Cntnap2 -/mice may lead to an increase in inhibition from sensory neurons upstream to higher-level sensory cortex leading to altered texture discrimination, as observed in these mice (Balasco et al, 2021(Balasco et al, , 2022.…”

Section: Discussionmentioning

confidence: 99%

“…It should be noted that a similar upregulation in mRNA expression has been shown in the cerebellum and parietal cortex of individuals with ASD (Fatemi et al, 2014). Upregulation found in GABAergic markers in the trigeminal ganglia can be consequently interpreted as underlining increased inhibition and thus giving way to hyporeactive/hyposensitive behaviors in adult Shank3b -/- and Cntnap2 -/- mice (Balasco et al, 2020; Balasco et al, 2021). In juvenile mice, on the other hand, an upregulation was found among Shank3b -/- TG for Gabrd, a gene whose dysfunction promotes psychomotor delay and epilepsy (Windpassinger et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

“…Given the fundamental role of early-life tactile experiences in shaping the acquisition of normal social behavior and communication skills in humans as well as in rodents, we hypothesized that peripheral tactile processing defects might contribute to ASD symptomatology. We recently reported aberrant somatosensory processing in the central nervous system of adult Shank3b and Cntnap2 mutant mice following whisker stimulation (Balasco et al, 2020; Balasco et al, 2021). Nonetheless, to infer a possible peripheral contribution to such defects, here we performed a gene expression profiling of TG in Cntnap2 -/- and Shank3b -/- mice, in both adult and juvenile stages.…”

Section: Introductionmentioning

confidence: 99%

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Gene expression profiling in trigeminal ganglia from Cntnap2^-/-and Shank3b^-/-mouse models of autism spectrum disorder

Ciancone-Chama

Bozzi

Balasco

2022

Preprint

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Sensory difficulties represent a crucial issue in the life of autistic individuals. The diagnostic and statistical manual of mental disorders describes both hyper- and hypo-responsiveness to sensory stimulation as a criterion for the diagnosis autism spectrum disorders (ASD). Among the sensory domain affected in ASD, altered responses to tactile stimulation represent the most commonly reported sensory deficits. Although tactile abnormalities have been reported in monogenic cohorts of patients and genetic mouse models of ASD, the underlying mechanisms are still unknown. Traditionally, autism research has focused on the central nervous system as the target to infer the neurobiological bases of such tactile abnormalities. Nonetheless, the peripheral nervous system represents the initial site of processing of sensory information and a potential site of dysfunction in the sensory cascade. Here we investigated the gene expression deregulation in the trigeminal ganglion (which directly receives tactile information from whiskers) in two genetic models of syndromic autism (Shank3b and Cntnap2 mutant mice) at both adult and juvenile ages. We found several neuronal and non-neuronal markers involved in inhibitory, excitatory, neuroinflammatory and sensory neurotransmission to be differentially regulated within the trigeminal ganglia of both adult and juvenile Shank3b and Cntnap2 mutant mice. These results may help in entangling the multifaced complexity of sensory abnormalities in autism and open avenues for the development of peripherally targeted treatments for tactile sensory deficits exhibited in ASD.

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“…A total of 48 age-matched adult wild-type littermates of both sexes (weight 25–35 g) were used for the study. All mice were generated from our CNTNAP2 colony (C57BL/6 background) 11 . Thirty-six mice were assigned to the whisker stimulation test, while 12 did not receive any stimulation and served as controls.…”

Section: Methodsmentioning

confidence: 99%

Automated decoding the mouse body postures in a whisker nuisance test

Chelini

Fortunato-Asquini

Ollari

et al. 2022

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Abnormal response to sensory stimuli characterizes multiple neuropsychiatric conditions. However, not many tools are currently available to assess somatosensory abnormalities in rodent models of brain disorders, limiting the possibilities to study cellular and molecular correlates of this phenotypic trait. To this goal, previous studies relied on the whisker nuisance test (WNt), in which freely moving mice are constantly stimulated on their whiskers using a wood stick for a set time. The whisker-guided response is then deconstructed in behavioral categories indicative of either anxiety or curiosity. Thus far, WNt was shown to be a valuable tool to investigate sensory-driven abnormalities in mouse models of autism spectrum disorders (ASD), demonstrating a solid translational validity. Nevertheless, assessment of behavioral response in the WNt is currently limited by the lack of an objective quantification method. To overcome this limitation, we developed WNt3R (Whisker Nuisance Test in 3D for Rodents), a MATLAB toolbox that uses the output of the open-source software DeepLabCut to determine discrete body postures associated with multiple ethologically-relevant behaviors. Our results show that behavioral modules identified using WNt3R reliably decode mouse body postures, outperforming the manual user, thus offering a novel and unbiased approach to study altered somatosensory function in rodents.

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Somatosensory cortex hyperconnectivity and impaired whisker-dependent responses in Cntnap2−/− mice

Cited by 20 publications

References 51 publications

SARM1 deletion in parvalbumin neurons is associated with autism-like behaviors in mice

SARM1 deletion in parvalbumin neurons is associated with autism-like behaviors in mice

Gene expression profiling in trigeminal ganglia from Cntnap2^-/-and Shank3b^-/-mouse models of autism spectrum disorder

Automated decoding the mouse body postures in a whisker nuisance test

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Somatosensory cortex hyperconnectivity and impaired whisker-dependent responses in Cntnap2−/− mice

Cited by 20 publications

References 51 publications

SARM1 deletion in parvalbumin neurons is associated with autism-like behaviors in mice

SARM1 deletion in parvalbumin neurons is associated with autism-like behaviors in mice

Gene expression profiling in trigeminal ganglia from Cntnap2-/-and Shank3b-/-mouse models of autism spectrum disorder

Automated decoding the mouse body postures in a whisker nuisance test

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Gene expression profiling in trigeminal ganglia from Cntnap2^-/-and Shank3b^-/-mouse models of autism spectrum disorder