Abstract:Some autistic individuals exhibit abnormal development of the caudate nucleus and associative cortical areas, suggesting potential dysfunction of cortico-basal ganglia (BG) circuits. Using optogenetic and electrophysiological approaches in mice we identified a narrow postnatal period characterized by extensive glutamatergic synaptogenesis in striatal spiny projection neurons (SPNs) and a concomitant increase in corticostriatal circuit activity. SPNs during early development have high intrinsic excitability and… Show more
“…The evoked EPSCs (Figure 7C) and mEPSCs (Figure 7—figure supplement 1D–E) observed in animals with 1, 2, and 4 shn-1 copies were not significantly different, indicating that synaptic transmission is not sensitive to shn-1 copy number. Similar results were recently reported in mice where glutamatergic transmission in the striatum was enhanced in Shank3B -/- homozygotes but this effect was not observed in Shank3B +/- heterozygotes (Peixoto et al, 2016). 10.7554/eLife.18931.011Figure 7.Synaptic transmission at the NMJ is not sensitive to shn-1 gene dosage.Stimulus-evoked EPSCs were recorded from adult body wall muscles.…”
Shank is a post-synaptic scaffolding protein that has many binding partners. Shank mutations and copy number variations (CNVs) are linked to several psychiatric disorders, and to synaptic and behavioral defects in mice. It is not known which Shank binding partners are responsible for these defects. Here we show that the C. elegans SHN-1/Shank binds L-type calcium channels and that increased and decreased shn-1 gene dosage alter L-channel current and activity-induced expression of a CRH-1/CREB transcriptional target (gem-4 Copine), which parallels the effects of human Shank copy number variations (CNVs) on Autism spectrum disorders and schizophrenia. These results suggest that an important function of Shank proteins is to regulate L-channel current and activity induced gene expression.DOI:
http://dx.doi.org/10.7554/eLife.18931.001
“…The evoked EPSCs (Figure 7C) and mEPSCs (Figure 7—figure supplement 1D–E) observed in animals with 1, 2, and 4 shn-1 copies were not significantly different, indicating that synaptic transmission is not sensitive to shn-1 copy number. Similar results were recently reported in mice where glutamatergic transmission in the striatum was enhanced in Shank3B -/- homozygotes but this effect was not observed in Shank3B +/- heterozygotes (Peixoto et al, 2016). 10.7554/eLife.18931.011Figure 7.Synaptic transmission at the NMJ is not sensitive to shn-1 gene dosage.Stimulus-evoked EPSCs were recorded from adult body wall muscles.…”
Shank is a post-synaptic scaffolding protein that has many binding partners. Shank mutations and copy number variations (CNVs) are linked to several psychiatric disorders, and to synaptic and behavioral defects in mice. It is not known which Shank binding partners are responsible for these defects. Here we show that the C. elegans SHN-1/Shank binds L-type calcium channels and that increased and decreased shn-1 gene dosage alter L-channel current and activity-induced expression of a CRH-1/CREB transcriptional target (gem-4 Copine), which parallels the effects of human Shank copy number variations (CNVs) on Autism spectrum disorders and schizophrenia. These results suggest that an important function of Shank proteins is to regulate L-channel current and activity induced gene expression.DOI:
http://dx.doi.org/10.7554/eLife.18931.001
“…Interestingly, although an increase in SPN AP firing from elevated mGluR5 signaling is opposite to the prediction that would be derived based on the known effects of mGluR5 for weakening corticostriatal excitatory synaptic strength (12,13), our observation is concordant with recent findings in early striatal development, whereby increased evoked SPN firing rates and weaker corticostriatal synaptic strength coexist (58). In Sapap3 KO mice, mGluR5-mediated increases in SPN activity could arise through a number of local circuit mechanisms, including, but not limited to, increased SPN intrinsic excitability (31) and endocannabinoid-mediated suppression of inhibitory synaptic tone (30,59).…”
BACKGROUND
Development of treatments for obsessive-compulsive disorder (OCD) is hampered by a lack of mechanistic understanding about this prevalent neuropsychiatric condition. Although circuit changes such as elevated frontostriatal activity are linked to OCD, the underlying molecular signaling that drives OCD-related behaviors remains largely unknown. Here, we examine the significance of type 5 metabotropic glutamate receptors (mGluR5s) for behavioral and circuit abnormalities relevant to OCD.
METHODS
Sapap3 knockout (KO) mice treated acutely with an mGluR5 antagonist were evaluated for OCD-relevant phenotypes of self-grooming, anxiety-like behaviors, and increased striatal activity. The role of mGluR5 in the striatal circuit abnormalities of Sapap3 KO mice was further explored using two-photon calcium imaging to monitor striatal output from the direct and indirect pathways. A contribution of constitutive signaling to increased striatal mGluR5 activity in Sapap3 KO mice was investigated using pharmacologic and biochemical approaches. Finally, sufficiency of mGluR5 to drive OCD-like behavior in wild-type mice was tested by potentiating mGluR5 with a positive allosteric modulator.
RESULTS
Excessive mGluR5 signaling underlies OCD-like behaviors and striatal circuit abnormalities in Sapap3 KO mice. Accordingly, enhancing mGluR5 activity acutely recapitulates these behavioral phenotypes in wild-type mice. In Sapap3 KO mice, elevated mGluR5 signaling is associated with constitutively active receptors and increased and imbalanced striatal output that is acutely corrected by antagonizing striatal mGluR5.
CONCLUSIONS
These findings demonstrate a causal role for increased mGluR5 signaling in driving striatal output abnormalities and behaviors with relevance to OCD and show the tractability of acute mGluR5 inhibition to remedy circuit and behavioral abnormalities.
“…It is well established that eCB-LTD can be developmentally regulated. Considering the very recent work that demonstrated an early hyperactivity of corticostriatal circuits in Shank3B-KO mice (94), it is possible that a type of abnormal eCB signaling has formed during development. It thus will be interesting for our future studies to explore the potential abnormal eCB signaling in development in Shank3B-KO mice.…”
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