Ketamine exerts its sustained antidepressant effects via cell-type-specific regulation of Kcnq2

Mental disorders are a significant cause of disability worldwide. They profoundly affect individuals’ well-being and impose a substantial financial burden on societies and governments. However, despite decades of extensive research, the effectiveness of current therapeutics for mental disorders is often not satisfactory or well tolerated by the patient. Moreover, most novel therapeutic candidates fail in clinical testing during the most expensive phases (II and III), which results in the withdrawal of pharma companies from investing in the field. It also brings into question the effectiveness of using animal models in preclinical studies to discover new therapeutic agents and predict their potential for treating mental illnesses in humans. Here, we focus on rodents as animal models and propose that they are essential for preclinical investigations of candidate therapeutic agents’ mechanisms of action and for testing their safety and efficiency. Nevertheless, we argue that there is a need for a paradigm shift in the methodologies used to measure animal behavior in laboratory settings. Specifically, behavioral readouts obtained from short, highly controlled tests in impoverished environments and social contexts as proxies for complex human behavioral disorders might be of limited face validity. Conversely, animal models that are monitored in more naturalistic environments over long periods display complex and ethologically relevant behaviors that reflect evolutionarily conserved endophenotypes of translational value. We present how semi-natural setups in which groups of mice are individually tagged, and video recorded continuously can be attainable and affordable. Moreover, novel open-source machine-learning techniques for pose estimation enable continuous and automatic tracking of individual body parts in groups of rodents over long periods. The trajectories of each individual animal can further be subjected to supervised machine learning algorithms for automatic detection of specific behaviors (e.g., chasing, biting, or fleeing) or unsupervised automatic detection of behavioral motifs (e.g., stereotypical movements that might be harder to name or label manually). Compared to studies of animals in the wild, semi-natural environments are more compatible with neural and genetic manipulation techniques. As such, they can be used to study the neurobiological mechanisms underlying naturalistic behavior. Hence, we suggest that such a paradigm possesses the best out of classical ethology and the reductive behaviorist approach and may provide a breakthrough in discovering new efficient therapies for mental illnesses.

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“…In a recent study, Lopez et al demonstrated long-duration antidepressant effects in mice group behavior in the SB. [107].…”

Section: Semi-natural Setups-automatic Detection Of Groupsmentioning

confidence: 99%

A paradigm shift in translational psychiatry through rodent neuroethology

Shemesh

Chen

2023

Mol Psychiatry

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“…Thus, alterations of KCNQ2 have been associated with seizures, autism as well as cognitive and developmental disabilities [69]. In a recent study, Kcnq2 was presented as an important downstream regulator of ketamine in hippocampal glutamatergic neurons [70]. Also, we noted a downregulation of the G-protein coupled receptor Glp1r (glucagon-like peptide-1 receptor).…”

Section: Discussionmentioning

confidence: 71%

Neural extracellular matrix regulates visual sensory motor integration

Reinhard

Mueller-Buehl

Wiemann

et al. 2023

Preprint

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Visual processing depends on sensitive and balanced synaptic neurotransmission. Extracellular matrix proteins in the environment of cells are key modulators in synaptogenesis and synaptic plasticity. In the present study, we provide evidence that the combined loss of the four extracellular matrix components brevican, neurocan, tenascin-C and tenascin-R in quadruple knockout mice leads to severe retinal dysfunction and diminished visual motion processing in vivo. Remarkably, impaired visual motion processing was accompanied by a developmental loss of cholinergic direction-selective starburst amacrine cells. Additionally, we noted imbalance of inhibitory and excitatory synaptic signaling in the quadruple knockout retina. Collectively, the study offers novel insights into the functional importance of four key extracellular matrix proteins for retinal function, visual motion processing and synaptic integrity.

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“…The condition and day were set as fixed effects, and the individual mice nested within groups were set as random effects. As mentioned above, only the first 2 days were considered in the analysis, as during this time period major differences across conditions have been shown to arise ( 35 , 75 , 77 , 78 ). This is likely due to the novelty and anxiety generated by the new environment, which exacerbated differences in exploration and prosocial and antagonistic interactions between the groups, which tend to normalize after this time point due to habituation to the environment.…”

Section: Methodsmentioning

confidence: 99%

Early life adversity shapes social subordination and cell type–specific transcriptomic patterning in the ventral hippocampus

Kos,

Lopez,

Bordes

et al. 2023

Sci. Adv.

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Adverse events in early life can modulate the response to additional stressors later in life and increase the risk of developing psychiatric disorders. The underlying molecular mechanisms responsible for these effects remain unclear. Here, we uncover that early life adversity (ELA) in mice leads to social subordination. Using single-cell RNA sequencing (scRNA-seq), we identified cell type–specific changes in the transcriptional state of glutamatergic and GABAergic neurons in the ventral hippocampus of ELA mice after exposure to acute social stress in adulthood. These findings were reflected by an alteration in excitatory and inhibitory synaptic transmission induced by ELA in response to acute social stress. Finally, enhancing the inhibitory network function through transient diazepam treatment during an early developmental sensitive period reversed the ELA-induced social subordination. Collectively, this study significantly advances our understanding of the molecular, physiological, and behavioral alterations induced by ELA, uncovering a previously unknown cell type–specific vulnerability to ELA.

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Ketamine exerts its sustained antidepressant effects via cell-type-specific regulation of Kcnq2

Cited by 54 publications

References 78 publications

A paradigm shift in translational psychiatry through rodent neuroethology

A paradigm shift in translational psychiatry through rodent neuroethology

Neural extracellular matrix regulates visual sensory motor integration

Early life adversity shapes social subordination and cell type–specific transcriptomic patterning in the ventral hippocampus

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