Targeting Peripheral Somatosensory Neurons to Improve Tactile-Related Phenotypes in ASD Models

Orefice, Lauren L.; Mosko, Jacqueline R.; Morency, Danielle T.; Wells, Michael F.; Tasnim, Aniqa; Mozeika, Shawn M.; Ye, Mengchen; Chirila, Anda M.; Emanuel, Alan J.; Rankin, Genelle; Fame, Ryann M.; Lehtinen, Maria K.; Feng, Guoping; Ginty, David D.

doi:10.1016/j.cell.2019.07.024

Cited by 185 publications

(297 citation statements)

References 90 publications

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“…Cortical PV cell activity modulates sensory responses (Cardin et al, 2009, Cao et al, 2018a, which are required for the development of normal social interaction behaviours (Orefice et al, 2016). Postmortem analysis of brains from ASD patients as well as animal models for ASD (such as Mecp2 and Shank3 mutants) revealed abnormalities in PV cell circuits in multiple brain regions, including primary sensory cortices (Mierau et al, 2016, Chao et al, 2010, Patrizi et al, 2019, Orefice et al, 2019, Selimbeyoglu et al, 2017, Zikopoulos and Barbas, 2013, Nelson and Valakh, 2015, Vogt et al, 2018, Tomassy et al, 2014, Hashemi et al, 2017, Fukuda et al, 2005, Filice et al, 2016. Targeting PV cell circuit impairments might thus be a rational approach to ameliorate social interaction problems, however the developmental and cellular processes that lead to PV cell dysfunction are likely dependent of the underlying aetiology.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of mTOR during a postnatal critical sensitive window rescues deficits in GABAergic PV cell connectivity and social behavior caused by loss ofTSC1

Choudhury

Amegandjin

Jadhav

et al. 2020

Preprint

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Mutations in regulators of the Mechanistic Target Of Rapamycin Complex 1 (mTORC1), such as Tsc1/2, lead to neurodevelopmental disorders associated with autism, intellectual disabilities and epilepsy. Whereas the effects of mTORC1 signaling dysfunction within diverse cell types are likely critical for the onset of the diverse neurological symptoms associated with mutations in mTORC1 regulators, they are not well understood. In particular, the effects of mTORC1 dys-regulation in specific types of inhibitory interneurons are unclear.Here, we showed that Tsc1 haploinsufficiency in parvalbumin (PV)-positive GABAergic interneurons either in cortical organotypic cultures or in vivo caused a premature increase in their perisomatic innervations, followed by a striking loss in adult mice. This effects were accompanied by alterations of AMPK-dependent autophagy in pre-adolescent but not adult mice. PV cell-restricted Tsc1 mutant mice showed deficits in social behavior. Treatment with the mTOR inhibitor Rapamycin restricted to the third postnatal week was sufficient to permanently rescue deficits in both PV cell innervation and social behavior in adult conditional haploinsufficient mice. All together, these findings identify a novel role of Tsc1-mTORC1 signaling in the regulation of the developmental time course and maintenance of cortical PV cell connectivity and provide a mechanistic basis for the targeted rescue of autism-related behaviors in disorders associated with deregulated mTORC1 signaling.

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Section: Discussionmentioning

confidence: 99%

Inhibition of mTOR during a postnatal critical sensitive window rescues deficits in GABAergic PV cell connectivity and social behavior caused by loss ofTSC1

Choudhury

Amegandjin

Jadhav

et al. 2020

Preprint

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“…In fact, reported pain hyposensitivity in Shank3 mice has been linked to the loss of Shank3 in neurons in the dorsal root ganglia and the direct effect of Shank3 absence on TRPV channel expression (Han et al, 2016). Likewise, autism-related behavioural dysfunctions have been linked to the disturbed sensory input generated by abnormal sensory neurons in dorsal root ganglia (Orefice et al, 2016;Orefice et al, 2019). Conversely, loss of function of the ASD-associated gene Caspr2 is associated with neuropathic pain (Dawes et al, 2018) through mechanisms involving increased sensitization of neurons in dorsal root ganglia.…”

Section: Discussionmentioning

confidence: 99%

Shank2 expression identifies a subpopulation of glycinergic interneurons involved in nociception and altered in an autism mouse model

Heuvel

Ouali-Alami

Wilhelm

et al. 2020

Preprint

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Patients suffering from Autism Spectrum Disorders (ASD) experience disturbed nociception in form of either hyposensitivity to pain or hypersensitivity and allodynia. We have determined that Shank2-KO mice, which recapitulate the genetic and behavioural disturbances of ASD, display increased sensitivity to formalin pain and thermal, but not mechanical allodynia. We demonstrate that high levels of Shank2 expression identifies a subpopulation of neurons in murine and human dorsal spinal cord, composed mainly by glycinergic interneurons and that loss of Shank2 causes the decrease in NMDAR in excitatory synapses on these inhibitory interneurons. In fact, in the subacute phase of the formalin test, glycinergic interneurons are strongly activated in WT mice but not in Shank2-KO mice. As consequence, nociception projection neurons in lamina I are activated in larger numbers in Shank2-KO mice. Our findings prove that Shank2 expression identifies a new subset of inhibitory interneurons involved in reducing the transmission of nociceptive stimuli and whose unchecked activation is associated with pain hypersensitivity. Thus, we provide evidence that dysfunction of spinal cord pain processing circuits may underlie the nociceptive phenotypes in ASD patients and mouse models.

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“…(PPI). PPI testing was performed essentially as a previously described (Orefice et al, 2016;Orefice et al, 2019) with some modifications. The tests were carried out on the same setup used for testing hairy skin sensitivity.…”

Section: Home Cage Video Recording (As Inmentioning

confidence: 99%

Presynaptic inhibition of cutaneous afferents prevents self-generated itch

Escalante

Klein

2019

Preprint

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Chronic itch represents an incapacitating burden on patients suffering a wide spectrum of diseases. Despite recent advances in our understanding of the cells and circuits implicated in the processing of itch information, chronic itch often presents itself without apparent cause. Here, we identify a spinal subpopulation of inhibitory neurons defined by the expression of Ptf1a involved in gating mechanosensory information self-generated during locomotion. These neurons receive tactile and motor input and establish presynaptic inhibitory contacts on mechanosensory afferents. Loss of these neurons leads to increased hairy skin sensitivity and chronic itch, at least partially mediated through the classic GRPR pathway. These findings shed new light on the mechanisms implicated in chronic itch and open novel targets for therapy developments. Methodology: A.E.; Validation: A.E. and R.K.; Formal Analysis: A.E.; Investigation: A.E.; Resources: A.E.; Data Curation: A.E.; Writing-Original Draft: A.E. and R.K.; Writing-Review and Editing: A.E. and R.K.; Visualization: A.E.; Supervision: R.K.; Funding Acquisition: R.K.

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Targeting Peripheral Somatosensory Neurons to Improve Tactile-Related Phenotypes in ASD Models

Cited by 185 publications

References 90 publications

Inhibition of mTOR during a postnatal critical sensitive window rescues deficits in GABAergic PV cell connectivity and social behavior caused by loss ofTSC1

Inhibition of mTOR during a postnatal critical sensitive window rescues deficits in GABAergic PV cell connectivity and social behavior caused by loss ofTSC1

Shank2 expression identifies a subpopulation of glycinergic interneurons involved in nociception and altered in an autism mouse model

Presynaptic inhibition of cutaneous afferents prevents self-generated itch

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