Altered theta / beta frequency synchrony links abnormal anxiety-related behavior to synaptic inhibition in Neuroligin-2 knockout mice

Abstract

Inhibitory synaptic transmission plays a key role in the circuits underlying anxiety behaviors, but the network mechanisms by which disruptions in synaptic inhibition contribute to pathological anxiety processing remain largely unknown. Here we addressed this question in mice lacking the inhibitory synapse-specific adhesion protein Neuroligin-2 (Nlgn2), which display widespread reduction in inhibitory synaptic transmission as well as a pronounced anxiety phenotype. To investigate how the lack of synaptic inhibition alters the communication between key brain regions in anxiety processing, we recorded local field potentials (LFPs) simultaneously from a network of brain regions involved in anxiety processing, including the basolateral amygdala (BLA), centromedial amygdala, bed nucleus of the stria terminalis, prefrontal cortex and ventral hippocampus (vHPC). We found that LFP power in the vHPC was profoundly increased while vHPC-directed theta frequency synchrony was disrupted in Nlgn2 KO mice under anxiogenic conditions. Instead, deletion of Nlgn2 increased beta frequency synchrony across the anxiety network, and the theta / beta synchrony ratio strongly predicted anxiety behaviors in an open field paradigm. Local deletion of Nlgn2 in the vHPC and BLA revealed that they encode distinct aspects of the anxiety phenotype of the Nlgn2 KO mice, with vHPC linked to anxiety induced freezing and BLA linked to reduction in exploratory activity.Together, our data demonstrate that alterations in long-range functional connectivity link synaptic inhibition to abnormal anxiety behaviors, and that Nlgn2 KO mice represent an interesting model to study the role of inhibitory synaptic transmission in the circuits underlying anxiety disorders.

Neuroligin-2 as a central organizer of inhibitory synapses in health and disease

“…In particular, constitutive deletion of NLGN2 resulted in an exag gerated activation of the BLA and its projections to the CeA under aversive conditions, consistent with the notion that the reduced synaptic inhibition results in neuronal overactivation in key regions mediating affective behaviors (45,46). Accordingly, local Cremediated deletion of NLGN2 from the BLA recapitulated some (but not all) aspects of the anxiety phenotype of the constitutive Nlgn2 KO mouse (80). Similarly, loss of NLGN2 from the ventral hippocampus (vHPC), another key region in the anxiety circuitry, resulted in an increase in freezing behaviors under specific anxiogenic conditions (80).…”

“…Accordingly, local Cremediated deletion of NLGN2 from the BLA recapitulated some (but not all) aspects of the anxiety phenotype of the constitutive Nlgn2 KO mouse (80). Similarly, loss of NLGN2 from the ventral hippocampus (vHPC), another key region in the anxiety circuitry, resulted in an increase in freezing behaviors under specific anxiogenic conditions (80). In contrast, local deletion of Nlgn2 from the mPFC (48) or the LS (49) led to a pronounced reduction in anxietylike behaviors, likely re flecting a loss of inhibition onto anxiolytic projections from the mPFC to subcortical structures (48) or from the LS to the lateral hypothalamus (49).…”

“…Using approach avoidance paradigms, such as the open field test (OF), the elevated plus maze (EPM), and the lightdark box (LDB), it was shown that constitutive global deletion of Nlgn2 in mice results in a pronounced increase in avoid ance behaviors (Fig. 2A) that may, in their detail, depend on the strain background (45)(46)(47)(79)(80)(81). Interestingly, moderate over expression of NLGN2 resulted in an anxietylike phenotype that very much resembled that of the constitutive KO, indicating that shifting the E/I balance at NLGN2containing synapses in either direction may exacerbate these behaviors (41).…”

“…In contrast, local deletion of Nlgn2 from the mPFC (48) or the LS (49) led to a pronounced reduction in anxietylike behaviors, likely re flecting a loss of inhibition onto anxiolytic projections from the mPFC to subcortical structures (48) or from the LS to the lateral hypothalamus (49). Intriguingly, multisite local field potential (LFP) recordings from constitutive Nlgn2 KO mice during exploration of an OF arena indicated that alterations in the LFP coherence in the vHPCmPFC BLA circuit more strongly predict defensive behaviors than alterations in LFP power within a given brain region, indicat ing that a key role of NLGN2mediated synaptic inhibition within the anxiety network is to regulate longrange connectivity between brain regions (80).…”

Anxiety-like behavior induced by salicylate depends on age and can be prevented by a single dose of 5-MeO-DMT

“…In rodents, changes in slow hippocampal gamma rhythms are generally associated, among other things, with slower running speed or increase in synchronization between CA3 and the cingulate cortex during immobility (Ahmed and Mehta, 2012;Buzsáki, 1986;Buzsáki and Wang, 2012;Zheng et al, 2015). Other studies showed that alteration gamma with anxiety behaviors (Batashvili et al, 2019;Cruces-Solis et al, 2019;Zhou et al, 2018). Nevertheless, to our knowledge, there is no study showing a systematic effect of aging on magnitude of gamma power, except when degeneration is present (Etter et al, 2019;Goutagny et al, 2013).…”