# Necl-4/CADM4 regulates GABAergic synaptic strength on GABAergic inhibitory neurons via ErbB4 activation and prevents neuronal impairments

## TL;DR

Necl-4/CADM4 helps regulate GABAergic synapses on inhibitory neurons through ErbB4 activation, preventing neuronal damage and death.

## Contribution

Necl-4/CADM4's role in regulating GABAergic synaptic strength and preventing neuronal impairments is newly identified.

## Key findings

- Necl-4 is expressed in GABAergic inhibitory neurons and localizes at their synapses.
- Necl-4 genetic ablation increases GABAergic synapse density and synaptic molecules via ErbB4 activation.
- Necl-4 deficiency leads to excitotoxicity and neuronal death in hippocampal cultures.

## Abstract

Neural networks comprise excitatory and inhibitory neurons, linked through excitatory and inhibitory synapses. Synaptic excitation/inhibition balance is controlled for brain development and functions, and its dysregulations are implicated in aging-dependent neuronal impairments. Here, we found that Necl-4/CADM4, an immunoglobulin superfamily cell adhesion molecule, is expressed in γ-aminobutyric acidergic (GABAergic) inhibitory neurons and localizes at GABAergic synapses on inhibitory neurons in cultured hippocampal neurons and the mouse hippocampus. Necl-4 genetic ablation induced neuronal loss with synaptic degenerations in the hippocampus, and cultured Necl-4-knockout (KO) hippocampal neurons were more susceptible to death. Prior to the neuronal death, the Necl-4-KO hippocampal neurons showed an increase in GABAergic synapse density on inhibitory neurons and in synaptic molecules at GABAergic synapses on inhibitory neurons, which were regulated by ErbB4 activation. Furthermore, electrophysiological analysis revealed that Necl-4 genetic ablation enhanced GABAergic synaptic currents on inhibitory neurons and induced high-frequency firing in dissociated hippocampal cultures composed of glutamatergic excitatory neurons and inhibitory neurons, contributing to excitotoxicity-mediated neuronal death. Thus, Necl-4 regulates GABAergic synaptic strength on inhibitory neurons via ErbB4 activation and prevents neuronal impairments.

The online version contains supplementary material available at 10.1007/s12035-025-05230-8.