Pituitary adenylate cyclase-activating polypeptide deficient mice show length abnormalities of the axon initial segment.

We previously found that pituitary adenylate cyclase-activating polypeptide (PACAP)-deficient (PACAP-/-) mice exhibit dendritic spine morphology impairment and neurodevelopmental disorder (NDD)-like behaviors such as hyperactivity, increased novelty-seeking behavior, and deficient pre-pulse inhibition. Recent studies have indicated that rodent models of NDDs (e.g., attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder) show abnormalities in the axon initial segment (AIS). Here, we revealed that PACAP-/- mice exhibited a longer AIS length in layer 2/3 pyramidal neurons of the primary somatosensory barrel field compared with wild-type control mice. Further, we previously showed that a single injection of atomoxetine, an ADHD drug, improved hyperactivity in PACAP-/- mice. In this study, we found that repeated treatments of atomoxetine significantly improved AIS abnormality along with hyperactivity in PACAP-/- mice. These results suggest that AIS abnormalities are associated with NDDs-like behaviors in PACAP-/- mice. Thus, improvement in AIS abnormalities will be a novel drug therapy for NDDs.

Fezf2-positive fork cell-like neurons in the mouse insular cortex.

The fork cell and von Economo neuron, which are found in the insular cortex and/or the anterior cingulate cortex, are defined by their unique morphologies. Their shapes are not pyramidal; the fork cell has two primary apical dendrites and the von Economo neurons are spindle-shaped (bipolar). Presence of such neurons are reported only in the higher animals, especially in human and great ape, indicating that they are specific for most evolved species. Although it is likely that these neurons are involved in higher brain function, lack of results with experimental animals makes further investigation difficult. We here ask whether equivalent neurons exist in the mouse insular cortex. In human, Fezf2 has been reported to be highly expressed in these morphologically distinctive neurons and thus, we examined the detailed morphology of Fezf2-positive neurons in the mouse brain. Although von Economo-like neurons were not identified, Fezf2-positive fork cell-like neurons with two characteristic apical dendrites, were discovered. Examination with electron microscope indicated that these neurons did not embrace capillaries, rather they held another cell. We here term such neurons as holding neurons. We further observed several molecules, including neuromedin B (NMB) and gastrin releasing peptide (GRP) that are known to be localized in the fork cells and/or von Economo cells in human, were localized in the mouse insular cortex. Based on these observations, it is likely that an equivalent of the fork cell is present in the mouse.