Cntnap2 loss drives striatal neuron hyperexcitability and behavioral inflexibility.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by two major diagnostic criteria - persistent deficits in social communication and interaction, and the presence of restricted, repetitive patterns of behavior (RRBs). Evidence from both human and animal model studies of ASD suggest that alteration of striatal circuits, which mediate motor learning, action selection, and habit formation, may contribute to the manifestation of RRBs. CNTNAP2 is a syndromic ASD risk gene, and loss of function of Cntnap2 in mice is associated with RRBs. How loss of Cntnap2 impacts striatal neuron function is largely unknown. In this study, we utilized Cntnap2-/- mice to test whether altered striatal neuron activity contributes to aberrant motor behaviors relevant to ASD. We find that Cntnap2-/- mice exhibit increased cortical drive of striatal projection neurons (SPNs), with the most pronounced effects in direct pathway SPNs. This enhanced drive is likely due to increased intrinsic excitability of SPNs, which make them more responsive to cortical inputs. We also find that Cntnap2-/- mice exhibit spontaneous repetitive behaviors, increased motor routine learning, and cognitive inflexibility. Increased corticostriatal drive, in particular of the direct pathway, may contribute to the acquisition of repetitive, inflexible behaviors in Cntnap2 mice.

Synchronous supratentorial and infratentorial oligodendrogliomas with incongruous IDH1 mutations, a case report.

Infratentorial oligodendrogliomas, a rare pathological entity, are generally considered metastatic lesions from supratentorial primary tumors. Here, we report the case of a 23-year-old man presenting with a histopathologically confirmed right precentral gyrus grade 2 oligodendroglioma and a concurrent pontine grade 3 oligodendroglioma. The pontine lesion was biopsied approximately a year after the biopsy of the precentral lesion due to disease progression despite 4 cycles of procarbazine-CCNU-vincristine (PCV) chemotherapy and stable supratentorial disease. Histology and genetic analysis of the pontine biopsy were consistent with grade 3 oligodendroglioma, and comparison of the two lesions demonstrated common 1p/19q co-deletions and TERT promoter mutations but distinct IDH1 mutations, with a non-canonical IDH1 R132G mutation identified in the infratentorial lesion and a R132H mutation identified in the cortical lesion. Initiation of Temozolomide led to complete response of the supratentorial lesion and durable disease control, while Temozolomide with subsequent radiation therapy of 54 Gy in 30 fractions resulted in partial response of the pontine lesion. This case report supports possible distinct molecular pathogenesis in supratentorial and infratentorial oligodendrogliomas and raises questions about the role of different IDH1 mutant isoforms in explaining treatment resistance to different chemotherapy regimens. Importantly, this case suggests that biopsies of all radiographic lesions, when feasible and safe, should be considered in order to adequately guide management in multicentric oligodendrogliomas.

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

Tuberous sclerosis complex (TSC) is a neurodevelopmental disorder that often presents with psychiatric conditions, including autism spectrum disorder (ASD). ASD is characterized by restricted, repetitive, and inflexible behaviors, which may result from abnormal activity in striatal circuits that mediate motor learning and action selection. To test whether altered striatal activity contributes to aberrant motor behaviors in the context of TSC, we conditionally deleted Tsc1 from direct or indirect pathway striatal projection neurons (dSPNs or iSPNs, respectively). We find that dSPN-specific loss of Tsc1 impairs endocannabinoid-mediated long-term depression (eCB-LTD) at cortico-dSPN synapses and strongly enhances corticostriatal synaptic drive, which is not observed in iSPNs. dSPN-Tsc1 KO, but not iSPN-Tsc1 KO, mice show enhanced motor learning, a phenotype observed in several mouse models of ASD. These findings demonstrate that dSPNs are particularly sensitive to Tsc1 loss and suggest that enhanced corticostriatal activation may contribute to altered motor behaviors in TSC.

Tsc1-mTORC1 signaling controls striatal dopamine release and cognitive flexibility.

Tuberous Sclerosis Complex (TSC) is a neurodevelopmental disorder caused by mutations in TSC1 or TSC2, which encode proteins that negatively regulate mTOR complex 1 (mTORC1). TSC is associated with significant cognitive, psychiatric, and behavioral problems, collectively termed TSC-Associated Neuropsychiatric Disorders (TAND), and the cell types responsible for these manifestations are largely unknown. Here we use cell type-specific Tsc1 deletion to test whether dopamine neurons, which modulate cognitive, motivational, and affective behaviors, are involved in TAND. We show that loss of Tsc1 and constitutive activation of mTORC1 in dopamine neurons causes somatodendritic hypertrophy, reduces intrinsic excitability, alters axon terminal structure, and impairs striatal dopamine release. These perturbations lead to a selective deficit in cognitive flexibility, preventable by genetic reduction of the mTOR-binding protein Raptor. Our results establish a critical role for Tsc1-mTORC1 signaling in setting the functional properties of dopamine neurons, and indicate that dopaminergic dysfunction may contribute to cognitive inflexibility in TSC.