In violation of Dale's principle several neuronal subtypes utilize more than one classical neurotransmitter. Molecular identification of vesicular glutamate transporter 3 and cholecystokinin expressing cortical interneurons (CCK+VGluT3+INTs) has prompted speculation of GABA/glutamate corelease from these cells for almost two decades despite a lack of direct evidence. We unequivocally demonstrate CCK+VGluT3+INT mediated GABA/glutamate cotransmission onto principal cells in adult mice using paired recording and optogenetic approaches. Although under normal conditions, GABAergic inhibition dominates CCK+VGluT3+INT signaling, glutamatergic signaling becomes predominant when glutamate decarboxylase (GAD) function is compromised. CCK+VGluT3+INTs exhibit surprising anatomical diversity comprising subsets of all known dendrite targeting CCK+ interneurons in addition to the expected basket cells, and their extensive circuit innervation profoundly dampens circuit excitability under normal conditions. However, in contexts where the glutamatergic phenotype of CCK+VGluT3+INTs is amplified, they promote paradoxical network hyperexcitability which may be relevant to disorders involving GAD dysfunction such as schizophrenia or vitamin B6 deficiency.
All data analyzed in this study are included in the manuscript/supporting files.
- Chris J McBain
- Gordon Fishell
- Gordon Fishell
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: All experiments were conducted in accordance with animal protocols approved by the National Institutes of Health (ASP# 17-045).
- Marlene Bartos, University of Freiburg, Germany
This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
The amyloid beta (Aβ) plaques found in Alzheimer’s disease (AD) patients’ brains contain collagens and are embedded extracellularly. Several collagens have been proposed to influence Aβ aggregate formation, yet their role in clearance is unknown. To investigate the potential role of collagens in forming and clearance of extracellular aggregates in vivo, we created a transgenic Caenorhabditis elegans strain that expresses and secretes human Aβ1-42. This secreted Aβ forms aggregates in two distinct places within the extracellular matrix. In a screen for extracellular human Aβ aggregation regulators, we identified different collagens to ameliorate or potentiate Aβ aggregation. We show that a disintegrin and metalloprotease a disintegrin and metalloprotease 2 (ADM-2), an ortholog of ADAM9, reduces the load of extracellular Aβ aggregates. ADM-2 is required and sufficient to remove the extracellular Aβ aggregates. Thus, we provide in vivo evidence of collagens essential for aggregate formation and metalloprotease participating in extracellular Aβ aggregate removal.
The cerebellar granule cell layer has inspired numerous theoretical models of neural representations that support learned behaviors, beginning with the work of Marr and Albus. In these models, granule cells form a sparse, combinatorial encoding of diverse sensorimotor inputs. Such sparse representations are optimal for learning to discriminate random stimuli. However, recent observations of dense, low-dimensional activity across granule cells have called into question the role of sparse coding in these neurons. Here, we generalize theories of cerebellar learning to determine the optimal granule cell representation for tasks beyond random stimulus discrimination, including continuous input-output transformations as required for smooth motor control. We show that for such tasks, the optimal granule cell representation is substantially denser than predicted by classical theories. Our results provide a general theory of learning in cerebellum-like systems and suggest that optimal cerebellar representations are task-dependent.