Abstract
Disturbances of the excitation/inhibition (E/I) balance in the brain were recently suggested as potential factors underlying disorders like autism and schizophrenia resulting in associated behavioral alterations including changes in social and emotional behavior as well as abnormal aggression. Neuronal cell adhesion molecules (nCAMs) and mutations in these genes were found to be strongly implicated in the pathophysiology of these disorders. Neuroligin2 (nlgn2) is a postsynaptic cell adhesion molecule, which is predominantly expressed at inhibitory synapses and required for synapse specification and stabilization. Changes in the expression of nlgn2 were shown to result in alterations of social behavior as well as altered inhibitory synaptic transmission, hence modifying the E/I balance. In our study, we focused on the role of nlgn2 in the dorsal hippocampus in the regulation of emotional and social behaviors. To this purpose, we injected an AAV construct overexpressing nlgn2 in the hippocampus of rats and investigated the effects on behavior and on markers for the E/I ratio. We could show an increase in GAD65, a GABA-synthesizing protein in neuronal terminals, and furthermore, reduced exploration of novel stimuli and less offensive behavior. Our data suggest nlgn2 in the hippocampus to be strongly implicated in maintaining the E/I balance in the brain and thereby modulating social and emotional behavior.
Highlights
Cell adhesion molecules are crucially involved in synapse development and stabilization [1,2,3]
We evaluated the impact of overexpressing nlgn2 in the dorsal hippocampus of adult rats using an adeno-associated virus
In the open field test (OF) test, rats overexpressing nlgn2 revealed normal locomotor activity and anxiety-related behavior, but in the novel object trial they spent significantly less time exploring the novel stimuli compared to control animals and showed thigmotaxis as demonstrated by the higher percentage of time spent in the wall zone
Summary
Cell adhesion molecules are crucially involved in synapse development and stabilization [1,2,3]. Neuroligins are postsynaptic neuronal cell adhesion molecules, which link the presynapse to the postsynaptic density by binding to their presynaptic partners neurexins in an alternative splice-dependent manner [4] They were initially thought to be required for synapse formation, but recent studies indicated a crucial involvement rather in synapse maturation and specification [5]. Consistent with this, knockout of nlgn was shown to impair NMDA-receptor mediated signaling, whereas nlgn2-KO was reported to result in deficits in inhibitory synaptic transmission [9,2] Due to their differential expression in different types of synapses, neuroligins were implicated in the control of excitatory versus inhibitory synapse specification and the regulation of the excitation/inhibition (E/I) balance in the hippocampus [10]
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