Basmisanil, an α5-GABAAR negative allosteric modulator, produces rapid and sustained antidepressant-like responses in male mice.

There is a critical need for safer and better-tolerated alternatives to address the current limitations of antidepressant treatments for major depressive disorder. Recently, drugs targeting the GABA system via α5-containing GABAA receptors (α5-GABAAR) as negative allosteric modulators (α5-NAMs) have shown promise in alleviating stress-related behaviors in preclinical studies, suggesting that α5-NAMs may have translational relevance as novel antidepressant medications. Here, we evaluated the efficacy of Basmisanil, an α5-NAM that has been evaluated in Phase 2 clinical studies as a cognitive enhancer, in a battery of behavioral tests relevant to coping strategies, motivation, and aversion in male mice, along with plasma and brain pharmacokinetic measurements. Our findings reveal that Basmisanil induces dose-dependent rapid antidepressant-like responses in the forced swim test and sucrose splash test without promoting locomotor stimulating effects. Furthermore, Basmisanil elicits sustained behavioral responses in the female urine sniffing test and sucrose splash test, observed 24 h and 48 h post-treatment, respectively. Bioanalysis of plasma and brain samples confirms effective blood-brain barrier penetration by Basmisanil and extrapolation to previously published data suggest that effects were observed at doses (10 and 30 mg/kg i.p.) corresponding to relatively modest levels of α5-GABAAR occupancy (40-65 %). These results suggest that Basmisanil exhibits a combination of rapid and sustained antidepressant-like effects highlighting the potential of α5-NAMs as a novel therapeutic strategy for depression.

Hypersocial behavior and biological redundancy in mice with reduced expression of PSD95 or PSD93.

The postsynaptic density proteins 95 (PSD95) and 93 (PSD93) belong to a family of scaffolding proteins, the membrane-associated guanylate kinases (MAGUKs), which are highly enriched in synapses and responsible for organizing the numerous protein complexes required for synaptic development and plasticity. Genetic studies have associated MAGUKs with diseases like autism and schizophrenia, but knockout mice show severe, complex defects with difficult-to-interpret behavioral abnormalities due to major motor dysfunction which is atypical for psychiatric phenotypes. Therefore, rather than studying loss-of-function mutants, we comprehensively investigated the behavioral consequences of reduced PSD95 expression, using heterozygous PSD95 knockout mice (PSD95+/-). Specifically, we asked whether heterozygous PSD95 deficient mice would exhibit alterations in the processing of social stimuli and social behavior. Additionally, we investigated whether PSD95 and PSD93 would reveal any indication of functional or biological redundancy. Therefore, homozygous and heterozygous PSD93 deficient mice were examined in a similar behavioral battery as PSD95 mutants. We found robust hypersocial behavior in the dyadic interaction test in both PSD95+/- males and females. Additionally, male PSD95+/- mice exhibited higher levels of aggression and territoriality, while female PSD95+/- mice showed increased vocalization upon exposure to an anesthetized female mouse. Both male and female PSD95+/- mice revealed mild hypoactivity in the open field but no obvious motor deficit. Regarding PSD93 mutants, homozygous (but not heterozygous) knockout mice displayed prominent hypersocial behavior comparable to that observed in PSD95+/- mice, despite a more severe motor phenotype, which precluded several behavioral tests or their interpretation. Considering that PSD95 and PSD93 reduction provoke strikingly similar behavioral consequences, we explored a potential substitution effect and found increased PSD93 protein expression in hippocampal synaptic enrichment preparations of PSD95+/- mice. These data suggest that both PSD95 and PSD93 are involved in processing of social stimuli and control of social behavior. This important role may be partly assured by functional/behavioral and biological/biochemical redundancy.

The SocioBox: A Novel Paradigm to Assess Complex Social Recognition in Male Mice.

Impairments in social skills are central to mental disease, and developing tools for their assessment in mouse models is essential. Here we present the SocioBox, a new behavioral paradigm to measure social recognition. Using this paradigm, we show that male wildtype mice of different strains can readily identify an unfamiliar mouse among 5 newly acquainted animals. In contrast, female mice exhibit lower locomotor activity during social exploration in the SocioBox compared to males and do not seem to discriminate between acquainted and unfamiliar mice, likely reflecting inherent differences in gender-specific territorial tasks. In addition to a simple quantification of social interaction time of mice grounded on predefined spatial zones (zone-based method), we developed a set of unbiased, data-driven analysis tools based on heat map representations and characterized by greater sensitivity. First proof-of-principle that the SocioBox allows diagnosis of social recognition deficits is provided using male PSD-95 heterozygous knockout mice, a mouse model related to psychiatric pathophysiology.

Impairment in the aversive memory of mice in the inhibitory avoidance task but not in the elevated plus maze through intra-amygdala injections of histamine.

RATIONALE: Evidence indicates that histamine (HA) modulates learning and memory in different types of behavioral tasks; however, the exact nature of this modulation and its mechanisms are controversial. Furthermore, emotions are able to influence memory processing in a crucial way through the involvement of the amygdala. Our research aims to contribute to the neurobiological body of knowledge on acquisition and retrieval of emotional memory via the histaminergic amygdaloid system in mice. OBJECTIVES: The present study investigated whether exogenous HA infused into the amygdala differentially modulates the anxiety- and fear-related memory of mice assessed by unconditioned and conditioned tasks. METHODS: Over two consecutive days, animals received bilateral microinjections of either vehicle or HA (0.1, 0.5 and 1.0µg by 0.1µl/side volume) into the amygdala before behavioral tests were performed. Mice were examined under two paradigms: an exposure/re-exposure procedure in the elevated plus-maze (EPM) or in the inhibitory avoidance (IA) with electric foot shock trials 1 and 2 and retention test (without foot shock). RESULTS: Pre-test intra-amygdala microinjection of 0.5µg HA induced anxiolytic-like responses, but none of the three doses interfered in mnemonic processing examined in the EPM. Concerning the IA task, step-through retention latencies increased in all groups compared with their respective trials, except in the animals microinjected with 0.5 or 1.0µg HA before the retention test. Thus, HA caused statistically significant amnesia during the session repeated 24h after training without drugs. Retention latency was not modified by microinjections of HA both pre-trial and pre-test or by pre-trial infusion in mice subjected to IA. CONCLUSIONS: Our data indicate that the amygdaloid histaminergic system could modulate anxiety-related behaviors in the EPM and impair the retrieval process in fear conditioning with a strong aversive stimulus. These results contribute further evidence of the distinct histaminergic influence on different emotional pathways.