Dysfunction of the corticostriatal pathway in autism spectrum disorders

Li, Wei; Pozzo-Miller, Lucas

doi:10.1002/jnr.24560

Cited by 73 publications

(64 citation statements)

References 242 publications

(326 reference statements)

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“…Striatal SPNs are receiving excitatory synaptic inputs mainly from the cortex and thalamus [45]. It is well known that the corticostriatal projection plays an important role in the regulation of repetitive behavior, as previously found in the studies using animal models of obsessive-compulsive disorder [70] and ASD [47,71]. Given that the expression levels of Dlg2 mRNA are abundant not only in the striatum but also the cortex during early development ( Fig.…”

Section: Discussionmentioning

confidence: 76%

“…It is well known that repetitive self-grooming behavior in rodents is strongly associated with dysfunction of the striatum [38,40]. Aberrant connectivity related to the striatum is also thought to be a major culprit in the repetitive behavior of humans with ASD [45][46][47]. It should be noted that Dlg2 knockout induced a significant increase in selfgrooming behavior during home-cage activity monitoring, even in "light-on" periods ( Fig.…”

Section: Discussionmentioning

confidence: 95%

“…Aberrant striatal circuits have been implicated in neurodevelopmental disorders, including schizophrenia [42,43], obsessive-compulsive disorder [38,44], and autism spectrum disorders [45][46][47]. Interestingly, emerging evidence supports the involvement of DLG2 in striatal development in the human brain.…”

Section: Discussionmentioning

confidence: 99%

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A DLG2 deficiency in mice leads to reduced sociability and increased repetitive behavior accompanied by aberrant synaptic transmission in the dorsal striatum

et al. 2020

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Background: DLG2, also known as postsynaptic density protein-93 (PSD-93) or chapsyn-110, is an excitatory postsynaptic scaffolding protein that interacts with synaptic surface receptors and signaling molecules. A recent study has demonstrated that mutations in the DLG2 promoter region are significantly associated with autism spectrum disorder (ASD). Although DLG2 is well known as a schizophrenia-susceptibility gene, the mechanisms that link DLG2 gene disruption with ASD-like behaviors remain unclear. Methods: Mice lacking exon 14 of the Dlg2 gene (Dlg2-/mice) were used to investigate whether Dlg2 deletion leads to ASD-like behavioral abnormalities. To this end, we performed a battery of behavioral tests assessing locomotion, anxiety, sociability, and repetitive behaviors. In situ hybridization was performed to determine expression levels of Dlg2 mRNA in different mouse brain regions during embryonic and postnatal brain development. We also measured excitatory and inhibitory synaptic currents to determine the impacts of Dlg2 deletion on synaptic transmission in the dorsolateral striatum. Results: Dlg2-/mice showed hypoactivity in a novel environment. They also exhibited decreased social approach, but normal social novelty recognition, compared with wild-type animals. In addition, Dlg2-/mice displayed strong self-grooming, both in home cages and novel environments. Dlg2 mRNA levels in the striatum were heightened until postnatal day 7 in mice, implying potential roles of DLG2 in the development of striatal connectivity. In addition, the frequency of excitatory, but not inhibitory, spontaneous postsynaptic currents in the Dlg2-/dorsolateral striatum was significantly reduced. Conclusion: These results suggest that homozygous Dlg2 deletion in mice leads to ASD-like behavioral phenotypes, including social deficits and increased repetitive behaviors, as well as reductions in excitatory synaptic input onto dorsolateral spiny projection neurons, implying that the dorsal striatum is one of the brain regions vulnerable to the developmental dysregulation of DLG2.

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Section: Discussionmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 95%

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A DLG2 deficiency in mice leads to reduced sociability and increased repetitive behavior accompanied by aberrant synaptic transmission in the dorsal striatum

et al. 2020

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“…Mouse studies support the link between striatal alterations and ASD-related behaviors (Fuccillo, 2016;Li and Pozzo-Miller, 2019;Rothwell, 2016), showing that mutations in ASD-risk genes can endow the striatum with an enhanced ability to acquire fixed motor routines (Kwon et al, 2006;Nakatani et al, 2009;Penagarikano et al, 2011;Platt et al, 2017;Rothwell et al, 2014). Changes in striatal synaptic properties have been reported in multiple mouse models with mutations in ASD-risk genes (Fuccillo, 2016;Li and Pozzo-Miller, 2019;Peca et al, 2011;Peixoto et al, 2016).…”

Section: Introductionmentioning

confidence: 82%

Loss of Tsc1 from striatal direct pathway neurons impairs endocannabinoid-LTD and enhances motor routine learning

Benthall

Cording

Chen

et al. 2019

Preprint

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Tuberous Sclerosis Complex (TSC) is a neurodevelopmental disorder in which individualsfrequently present with autism spectrum disorder (ASD). A core diagnostic criterion for ASD is the presence of restricted, repetitive behaviors (RRBs), which may result from abnormal activity in striatal circuits that mediate motor learning, action selection and habit formation. Striatal control over motor behavior relies on the coordinated activity of two subtypes of principle neurons, direct pathway and indirect pathway spiny projection neurons (dSPNs or iSPNs, respectively), which provide the main output of the striatum. To test if altered striatal activity is sufficient to cause repetitive behaviors in the context of TSC, we conditionally deleted Tsc1 from dSPNs or iSPNs in mice and measured the consequences on synaptic function and motor behavior. We find that mice with loss of Tsc1 from dSPNs, but not iSPNs, have enhanced motor routine learning in the accelerating rotarod task. This increased motor learning is associated with an impairment in endocannabinoid-mediated long-term depression (eCB-LTD) at cortico-dSPN synapses in the dorsal striatum. Consistent with a loss of eCB-LTD, disruption of Tsc1 in dSPNs, but not iSPNs, results in a strong enhancement of corticostriatal synaptic drive. Together these findings demonstrate that within the striatum dSPNs show selective sensitivity to Tsc1 loss and indicate that enhanced activation of the striatal direct pathway is a potential contributor to RRBs in TSC.

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“…Another highly conserved transcription factor is the Forkhead box protein P2 (FoxP2), known to affect speech in human and song learning in songbirds (Lai et al 2001;Haesler et al 2004Haesler et al , 2007Teramitsu et al 2004;MacDermot et al 2005;Feuk et al 2006;Vernes et al 2011). FoxP2 has been associated with autism through interactions with known ASD-related genes, including contactin-associated protein-like 2 (CNTNAP2) (Larsen et al 2016;Adam et al 2017;Li and Pozzo-Miller 2019). In mice, cortical Foxp2 was suggested to be vital for social behavior, causing aberrations in autism-related gene expression and ultrasonic vocalization production (Medvedeva et al 2019).…”

Section: Introductionmentioning

confidence: 99%

Sex-and Region-Dependent Expression of the Autism-Linked ADNP Correlates with Social- and Speech-Related Genes in the Canary Brain

et al. 2020

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The activity-dependent neuroprotective protein (ADNP) syndrome is an autistic-like disorder, instigated by mutations in ADNP. This syndrome is characterized by developmental delays, impairments in speech, motor function, abnormal hearing, and intellectual disabilities. In the Adnp-haploinsufficient mouse model, many of these impediments are evident, appearing in a sex-dependent manner. In zebra finch songbird (ZF; Taeniopygia guttata), an animal model used for song/language studies, ADNP mRNA most robust expression is observed in the cerebrum of young males, potentially corroborating with male ZF exclusive singing behavior and developed cerebral song system. Herein, we report a similar sex-dependent ADNP expression profile, with the highest expression in the cerebrum (qRT-PCR) in the brain of another songbird, the domesticated canary (Serinus canaria domestica). Additional analyses for the mRNA transcripts of the ADNP regulator, vasoactive intestinal peptide (VIP), sister gene ADNP2, and speech-related Forkhead box protein P2 (FoxP2) revealed multiple sex and brain region-dependent positive correlations between the genes (including ADNP). Parallel transcript expression patterns for FoxP2 and VIP were observed alongside specific FoxP2 increase in males compared with females as well as VIP/ADNP2 correlations. In spatial view, a sexually independent extensive form of expression was found for ADNP in the canary cerebrum (RNA in situ hybridization). The songbird cerebral mesopallium area stood out as a potentially high-expressing ADNP tissue, further strengthening the association of ADNP with sense integration and auditory memory formation, previously implicated in mouse and human.

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Dysfunction of the corticostriatal pathway in autism spectrum disorders

Abstract: The majority of cortical areas, including sensory, motor, and limbic cortices, send monosynaptic excitatory projections to the striatum (Hintiryan et al., 2016), which contribute to diverse sen

Cited by 73 publications

References 242 publications

A DLG2 deficiency in mice leads to reduced sociability and increased repetitive behavior accompanied by aberrant synaptic transmission in the dorsal striatum

A DLG2 deficiency in mice leads to reduced sociability and increased repetitive behavior accompanied by aberrant synaptic transmission in the dorsal striatum

Loss of Tsc1 from striatal direct pathway neurons impairs endocannabinoid-LTD and enhances motor routine learning

Sex-and Region-Dependent Expression of the Autism-Linked ADNP Correlates with Social- and Speech-Related Genes in the Canary Brain

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