Synaptic Imbalance, Stereotypies, and Impaired Social Interactions in Mice with Altered Neuroligin 2 Expression

Abstract

The level of excitation in the brain is kept under control through inhibitory signals mainly exerted by GABA neurons. However, the molecular machinery that regulates the balance between excitation and inhibition (E/I) remains unclear. Candidate molecules implicated in this process are neuroligin (NL) adhesion molecules, which are differentially enriched at either excitatory or inhibitory contacts. In this study, we use transgenic mouse models expressing NL1 or NL2 to examine whether enhanced expression of specific NLs results in synaptic imbalance and altered neuronal excitability and animal behavior. Our analysis reveals several abnormalities selectively manifested in transgenic mice with enhanced expression of NL2 but not NL1. A small change in NL2 expression results in enlarged synaptic contact size and vesicle reserve pool in frontal cortex synapses and an overall reduction in the E/I ratio. The frequency of miniature inhibitory synaptic currents was also found to be increased in the frontal cortex of transgenic NL2 mice. These animals also manifested stereotyped jumping behavior, anxiety, impaired social interactions, and enhanced incidence of spike-wave discharges, as depicted by EEG analysis in freely moving animals. These findings may provide the neural basis for E/I imbalance and altered behavior associated with neurodevelopmental disorders.

Disrupting the clustering of GABAAreceptor α2 subunits in the frontal cortex leads to reduced γ-power and cognitive deficits

“…17, reciprocal social interaction paradigm was based on that used in ref. 22, and spontaneous alternation was based on ref. 46.…”

“…In a separate cohort of matched AAV-expressing mice we also assessed behaviors possibly relevant to negative symptoms including nest building (17-21) and reciprocal social interaction (22,23). AAV-expressing mice did not differ in either nest score (3.58 ± 0.42 vs. 3.42 ± 0.43; P = 0.811) or weight of unused nestlet (1.01 ± 0.29 g vs. 1.13 ± 0.31 g; P = 0.837; SI Appendix, Fig.…”

“…We also measured social interaction of AAVexpressing mice in a reciprocal social interaction paradigm. AAV-expressing test mice are simultaneously placed into a neutral home cage with a novel, age-matched target male (Friend Virus B (FVB) strain) and allowed to interact freely for 5 min (22). AAV-DN1-expressing mice did not differ in either the total time spent interacting (119.88 ± 3.13 s vs. 123.38 ± 3.42 s; P = 0.463) or average length of interaction (7.13 ± 1.20 s vs. 6.63 ± 1.15 s; P = 0.768) with the target mouse (SI Appendix, Fig.…”

Molecular architecture of glycinergic synapses

“…Strikingly, both neurexins and neuroligins have been genetically linked to cases of autism (Geschwind and Levitt 2007), and neuroligin 4 knockout mice display social interactions reminiscent of autistic behavior (Jamain et al 2008). Moreover, both transgenic mice overexpressing neuroligin 2 and transgenic mice expressing a mutated neuroligin 3, which mimics a neuroligin 3 point mutation genetically linked to autism show increased inhibitory transmission and a reduced E/I ratio as well as behavioral abnormalities reminiscent of autism (Hines et al 2008;Tabuchi et al 2007). A major challenge for the future will be to determine how GABA receptor activity and the neurexin-neuroligin system contribute to GABAergic, respectively glycinergic synapse organization, network activity and potentially behavior.…”

Toward an Efficient and Integrative Analysis of Limited-Choice Behavioral Experiments: Figure 1.

“…Statistical analysis is critical in the interpretation of such experiments. Traditionally, the outcome of such limitedchoice tests is presented as the arithmetic mean and its standard error (SE) and probed using classical parametric tests, such as Student's t test or ANOVA for means (Nadler et al, 2004;Moy et al, 2007;Saverino and Gerlai, 2008;Hines et al, 2008;Mery et al, 2009;Blundell et al, 2010;Peça et al, 2011). …”