Nectin‐2α is localized at cholinergic neuron dendrites and regulates synapse formation in the medial habenula

Abstract

The medial habenula (MHb) receives afferents from the triangular septum and the medial septal complex, projects efferents to the interpeduncular nucleus (IPN) in the midbrain to regulate dopamine and serotonin levels, and is implicated in stress, depression, memory, and nicotine withdrawal syndrome. We previously showed that the cell adhesion molecule nectin-2α is localized at the boundary between adjacent somata of clustered cholinergic neurons and regulates the voltage-gated A-type K + channel Kv4.2 localization at membrane specializations in the MHb. This adhesion apparatus, named nectin-2α spots, is not associated with the nectin-binding protein afadin or any classic cadherins and their binding proteins p120-catenin and β-catenin. We showed here that nectin-2α was additionally localized at cholinergic neuron dendrites in synaptic regions of the MHb. The genetic ablation of nectin-2 reduced the number of synapses in the MHb without affecting their morphology. Nectin-2α was associated with afadin, cadherin-8, p120-catenin, β-catenin, and αN-catenin, forming puncta adherentia junctions (PAJs). Nectin-2α was observed in the IPN, but not in the triangular septum or the medial septal complex. The genetic ablation of nectin-2 did not affect synapse formation in the IPN. These results indicate that nectin-2α forms two types of adhesion apparatus in the MHb, namely nectin-2α spots at neighboring somata and PAJs at neighboring dendrites, and that dendritic PAJs regulate synapse formation in the MHb.

Necl2/3-mediated mechanism for tripartite synapse formation

“…Rabbit antiserum against Necl1 [1:300 for IF microscopy and 1:1000 for western blotting (WB)] and Necl3 (1:300 for IF microscopy and 1:1000 for WB) was prepared as described previously (Kakunaga et al, 2005;Shiotani et al, 2021). A rat anti-Necl2 monoclonal antibody (1C4-2) (1:300 for IF microscopy and 1:1000 for WB) was prepared as described (Shingai et al, 2003).…”

Synapse formation and plasticity by cell adhesion molecules cadherin and nectin

“…Thus, it is believed that optimal nectin-1 and 3 contacts between axon and dendrite is required for specific cadherin adhesion between axon and dendrite, which is important for subsequent synapse formation. A recent finding shows that the number of synapses in the medial habenula was decreased by genetically eliminating nectin-2 without changing their shape [19]. Among the neighboring somata of a set of cholinergic neurons, nectin-2, a molecule that facilitates cell adhesion, controls membrane specializations in the medial habenula's voltage-gated K + channel [19].…”

“…A recent finding shows that the number of synapses in the medial habenula was decreased by genetically eliminating nectin-2 without changing their shape [19]. Among the neighboring somata of a set of cholinergic neurons, nectin-2, a molecule that facilitates cell adhesion, controls membrane specializations in the medial habenula's voltage-gated K + channel [19]. Nectin-2 generated PAJs along with cadherin-8, p120-catenin, β-catenin, and N-catenin [19].…”

“…Among the neighboring somata of a set of cholinergic neurons, nectin-2, a molecule that facilitates cell adhesion, controls membrane specializations in the medial habenula's voltage-gated K + channel [19]. Nectin-2 generated PAJs along with cadherin-8, p120-catenin, β-catenin, and N-catenin [19]. The conclusion is that there are two different types of adhesion systems are created by nectin-2 in the medial habenula, including PAJs at nearby dendrites and nectin-2 spots at nearby somata, and dendritic PAJs also govern synapse formation in the medial habenula [19].…”

“…Nectin-2 generated PAJs along with cadherin-8, p120-catenin, β-catenin, and N-catenin [19]. The conclusion is that there are two different types of adhesion systems are created by nectin-2 in the medial habenula, including PAJs at nearby dendrites and nectin-2 spots at nearby somata, and dendritic PAJs also govern synapse formation in the medial habenula [19]. Also, the most prevalent type of dementia is Alzheimer's disease.…”