No abstract

Neuronal dendrites dynamically protrude many fine filopodia in the early stages of neuronal development and gradually establish complex structures. The importance of the dendritic filopodia in the formation of axo-dendritic connections is established, but their role in dendrite morphogenesis remains unknown. Using time-lapse imaging of cultured rat hippocampal neurons, we revealed here that many filopodia dynamically protruded from dendrites and transiently interacted with each other to form dendritic filopodia-filopodia contacts in the early stages of neuronal development. The MAGUK family member, Zonula Occludens-1 (ZO-1), which is known to be associated with the nectin and cadherin cell adhesion systems, was concentrated at these dendritic filopodia-filopodia contact sites and also at the tips of free dendritic filopodia. Overexpression of ZO-1 increased the formation of dendritic filopodia and their interactions, and induced abnormal dendrite morphology. Conversely, knockdown of ZO-1 decreased the formation of dendritic filopodia and their interactions, and induced abnormal dendrite morphology which was different from that induced by the overexpression of ZO-1. The components of the nectin and cadherin systems were co-localized with ZO-1 at the dendritic filopodia-filopodia contact sites, but not at the tips of free dendritic filopodia. Overexpression of ZO-1 increased the accumulation of these cell adhesive components at the dendritic filopodia-filopodia contact sites and stabilized their interactions, whereas knockdown of ZO-1 reduced their accumulation at the dendritic filopodia-filopodia contact sites. These results indicate that ZO-1 regulates dendritic filopodial dynamics, which is implicated in dendrite morphogenesis cooperatively with the nectin and cadherin systems in cultured neurons.

Hiccups (singultus) are one of the most challenging symptoms to diagnose a cause. Causes range from the gastrointestinal and cardiovascular systems to the neurological system. 1 It is essential to remember that area postrema syndrome (APS), particularly in cases caused by neuromyelitis optica spectrum disorders (NMOSD), is an important differential diagnosis. 2 Persistent and intractable hiccups are a representative symptom in patients with NMOSD and associated with damage to areas abundant with the aquaporin protein. [3][4][5] However, intractable hiccups caused by APS with NMOSD rarely are associated with sick sinus syndrome (SSS). 6,7 | C A S EA 77-year-old man presented with an acute onset of hiccups and reported vomiting 8 days prior to admission. Hiccups occurred about 10 times per minute and persisted over 48 hours. An electrocardiogram (ECG) did not show any abnormal findings. A gastrointestinal endoscope revealed an esophageal hiatal hernia and atrophic gastritis, but there was no clear cause of the hiccups. Intravenous administration of metoclopramide, haloperidol, diazepam, and chlorpromazine did not relieve the hiccups. At this point, he was transferred to our hospital, where he lost consciousness because of sinus arrests lasting 13 seconds. He was diagnosed with SSS (Figure 1A

Ramified, polarized protoplasmic astrocytes interact with synapses via perisynaptic astrocyte processes (PAPs) to form tripartite synapses. These astrocyte-synapse interactions mutually regulate their structures and functions. However, molecular mechanisms for tripartite synapse formation remain elusive. We developed an in vitro co-culture system for mouse astrocytes and neurons that induced astrocyte ramifications and PAP formation. Co-cultured neurons were required for astrocyte ramifications in a neuronal activity-dependent manner and synaptically released glutamate and activation of astrocytic mGluR5 metabotropic glutamate receptor were likely involved in astrocyte ramifications. Astrocytic Necl-2/CADM1 trans-interacted with axonal Necl-3/CADM2, inducing astrocyte-synapse interactions and astrocyte functional polarization by recruiting EAAT1/2 glutamate transporters and Kir4.1 K+ channel to the PAPs, without affecting astrocyte ramifications. This Necl-2/3 trans-interaction increased functional synapse number. Thus, astrocytic Necl-2, synaptically released glutamate, and axonal Necl-3 cooperatively formed tripartite glutamatergic synapses in vitro. Studies on hippocampal mossy fiber synapses in Necl-3 knockout and Necl-2/3 double knockout mice confirmed these novel mechanisms for astrocyte-synapse interactions and astrocyte functional polarization in vivo.