Person:

Silva, Michael

Summary Maternally inherited 15q11-13 chromosomal triplications cause a frequent and highly penetrant autism linked to increased gene dosages of UBE3A, which both possesses ubiquitin-ligase and transcriptional co-regulatory functions. Here, using in vivo mouse genetics, we show that increasing UBE3A in the nucleus down-regulates glutamatergic synapse organizer cerebellin-1 (Cbln1) that is needed for sociability in mice. Epileptic seizures also repress Cbln1 and are found to expose sociability impairments in mice with asymptomatic increases of UBE3A. This Ube3a-seizure synergy maps to glutamate neurons of the midbrain ventral tegmental area (VTA) where Cbln1 deletions impair sociability and weaken glutamatergic transmission. We provide preclinical evidence that viral-vector-based chemogenetic activations of, or Cbln1 restorations in VTA glutamatergic neurons rescues sociability deficits induced by Ube3a and/or seizures. Our results suggest a gene × seizure interaction in VTA glutamatergic neurons that impairs sociability by downregulating Cbln1, a key node in the expanding protein interaction network of autism genes.

Functional magnetic resonance imaging (fMRI) is increasingly used for preoperative counseling and planning, and intraoperative guidance for tumor resection in the eloquent cortex. Although there have been improvements in image resolution and artifact correction, there are still limitations of this modality. In this review, we discuss clinical fMRI's applications, limitations and potential solutions. These limitations depend on the following parameters: foundations of fMRI, physiologic effects of the disease, distinctions between clinical and research fMRI, and the design of the fMRI study. We also compare fMRI to other brain mapping modalities which should be considered as alternatives or adjuncts when appropriate, and discuss intraoperative use and validation of fMRI. These concepts direct the clinical application of fMRI in neurosurgical patients.