It is demonstrated that dysbindin-1 deficiency drives distinct, female-specific vulnerabilities in behavioral and molecular alterations relevant to neuropsychiatric conditions, providing insight into the sex-dependent pathophysiology of social and cognitive deficits in preclinical models of schizophrenia.
Abstract
Schizophrenia is a complex neuropsychiatric disorder associated with genetic variants of the dystrobrevin-binding protein 1 (Dtnbp1) gene. While cognitive deficits in male Dtnbp1 mutant mice are well-documented, the impact of this mutation on female subjects remains underexplored. This study investigated the behavioral and molecular effects of Dtnbp1 deficiency in male and female knockout (Dys-/-) mice, highlighting sex-specific cognitive, social, and molecular signaling impairments relevant to schizophrenia. Female Dys-/- mice exhibited an anxiolytic phenotype with intact threat memory and normal novel object recognition memory. However, they displayed profound deficits in temporal order recognition memory and multiple domains of social behavior. Conversely, male Dys-/- mice largely maintained normal social recognition. Molecular analyses revealed dysregulation of the dopaminergic system specifically in the prefrontal cortex (PFC) of female Dys-/- mice. This dysfunction was characterized by reduced mRNA expression of the dopamine receptors D1 (Drd1) and D2 (Drd2), as well as aberrant activity of canonical (DARPP-32) and noncanonical (GSK3β) signaling pathways. Collectively, these findings demonstrate that dysbindin-1 deficiency drives distinct, female-specific vulnerabilities in behavioral and molecular alterations relevant to neuropsychiatric conditions, providing insight into the sex-dependent pathophysiology of social and cognitive deficits in preclinical models of schizophrenia.
It is demonstrated that ASD-related alterations are not static but evolve across adulthood, revealing a multi-level reorganization of behavioral, synaptic, and structural features.
Mathieu Thabault, Cloé Fernandes-Gomes, Cloé Alcaraz et al.· Neurobiology of Disease· 0 citations
Chronic stress exposure causes neurobiological and behavioral changes that resemble those reported in psychiatric conditions such as major depressive disorder (MDD). Preclinical stress models and studies using postmortem tissue from MDD patients have shown that DNA Damage-Inducible Transcript 4 (Ddit4) is increased in the prefrontal cortex (PFC). This is important because DDIT4 negatively regulates the mammalian target of rapamycin (mTOR) pathway, which may lead to behavioral deficits through diminished neuroplasticity and PFC function. Our prior studies indicate that coordinated neuron-microglia interactions contribute to synaptic remodeling in the PFC. The present studies aimed to test the hypothesis that increased neuronal Ddit4 expression is sufficient to drive structural remodeling of PFC neurons, in part by provoking microglia activation, and this leads to behavioral and cognitive deficits. To this end, we bilaterally infused AAV5-hSyn1-Ddit4-tdTomato or a control vector into the PFC of male Thy1-GFP and C57BL/6 mice and examined molecular, cellular, and behavioral endpoints. Mice with Ddit4 overexpression (Ddit4-OV) showed no change in passive stress coping yet exhibited a deficit in temporal order memory. Immunohistology analyses showed a decrease in dendritic spine density of Ddit4-OV mice. However, we found no changes in microglia count, microglia size, or nearest neighbor distance. Bulk RNA sequencing of Ddit4-OV PFC revealed increases in transcripts involved with dendrite and synapse function and decreases in transcripts involved with mitochondrial function, implicating mTOR dysregulation. Altogether, these results indicate that Ddit4 overexpression recapitulates some of the broad molecular, cellular, and behavioral adaptations observed following chronic stress exposure through a cell-autonomous mechanism.Significance Statement This work provides more context for the neurobiological effects of neuronal DNA Damage-Inducible Transcript 4 (Ddit4). Ddit4, an inhibitor of the mammalian target of rapamycin (mTOR) pathway, exhibits increased expression in the prefrontal cortex (PFC) of both rats exposed to pre-clinical chronic stress models and humans diagnosed with major depressive disorder (MDD). Our findings demonstrate that Ddit4 overexpression specifically in neurons is sufficient to reduce spine density in the PFC, impair temporal order memory, and induce transcriptional changes associated with stress and depression. These results indicate that neuronal Ddit4 can disrupt PFC function and cognitive performance in a cell-autonomous manner.
Alexander M. Kuhn, Kelly E. Bosis, Madeline M Mairose et al.· eNeuro· 0 citations
Repetitive behaviors are classically associated with autism spectrum disorder and obsessive compulsive disorder, but also occur prominently in attention-deficit/hyperactivity disorder (ADHD), yet the underlying mechanisms remain poorly understood. Our recent work identified ADHD-like behaviors in Cry1Δ11 mice, in which a mutation in a core circadian gene Cry1 produces a CRY1Δ11 protein that fails to inhibit the Gαs subunit, leading to hyperactive signaling of dopamine D1 receptor (DRD1). Although this dysregulation was initially reported in the ventral striatum, we hypothesized that similar mechanisms might be present in the dorsal striatum, a brain region critically involved in the generation of repetitive behaviors and densely populated by DRD1-expressing medium spiny neurons (MSNs). Here, we demonstrate that Cry1Δ11 mice exhibit robust repetitive behaviors, including excessive self-grooming and stereotyped rearing, which are associated with increased activity of DRD1-MSNs in the dorsolateral striatum. Chemogenetic manipulation further revealed that activation of these neurons induces excessive self-grooming, whereas their inhibition reduces such behavior, indicating bidirectional control over repetitive action. Critically, systemic administration of the DRD1 antagonist SCH23390 fully rescued both neuronal hyperactivity and behavioral abnormalities in mutant mice. Together, our findings establish a direct mechanistic link among a core circadian gene mutation, striatal dopaminergic hyperactivity, and repetitive behaviors, thereby identifying aberrant DRD1 signaling in the dorsolateral striatum as a promising target for therapeutic intervention.
Xiran Liu, Dengfeng Liu, Bingyu Long et al.· Translational Psychiatry· 0 citations
Results suggest that Adgrd1 plays a key role in maintaining hippocampal resilience and regulating motivational behaviors through integrated molecular and circuit-level mechanisms.
Inés Martínez-Soria, Pol Picón-Pagès, A. P. Pérez González et al.· bioRxiv· 0 citations
Synaptic mechanisms underlying the differential severity of social preference deficit in male and female BDNF+/Met mice are revealed, which provides a potential neural basis for sex differences in male and female ASD patients with and without the BDNF Val66Met SNP.
Kaijie Ma, Maria Webb, Samuel S Newton et al.· Frontiers in Neuroscience· 0 citations
These findings suggest that MRs in GABAergic neurons normally function as critical constraints on excitatory synaptic plasticity during high-stress states, underscoring that adaptive stress responses rely on a finely tuned, cell-type-specific balance of corticosteroid signaling within limbic microcircuits.
Huanqing Yang, V. Kovářová, Alena O. Godunova et al.· Neurobiology of Stress· 0 citations
