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.
Autism spectrum disorder (ASD) is characterized by persistent deficits in social communication and the presence of restricted and repetitive behaviors. While ASD has a neurodevelopmental origin, it remains a lifelong condition, yet little is known about how its behavioral and neural features evolve across adulthood. Here, we investigated behavioral, synaptic, and structural alterations across the transition from early to mature adulthood in Cntnap2 knockout mice, a widely used model of ASD. Using a longitudinal behavioral approach combined with electrophysiological recordings and morphological analysis, we show that KO mice exhibit increased stereotyped and repetitive behaviors and reduced exploratory activity at both ages. However, detailed analysis of behavioral patterns revealed age-dependent differences, with early adult KO mice displaying increased behavioral persistence that later evolved into distinct patterns of behavioral sequences. These behavioral changes were associated with alterations in inhibitory synaptic transmission in the dorsolateral striatum (DLS), including changes in spontaneous inhibitory postsynaptic current (sIPSC) frequency and temporal structure. In parallel, mature adult KO mice showed structural remodeling of spiny projection neurons, characterized by increased distal dendritic arborization and age-dependent organization of dendritic spines. Together, our findings demonstrate that ASD-related alterations are not static but evolve across adulthood, revealing a multi-level reorganization of behavioral, synaptic, and structural features. These results highlight the importance of considering adulthood stages in ASD and provide new insights into the dynamic nature of the condition.
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
Males are more commonly diagnosed with autism spectrum disorder (ASD) than females with a ratio of about 4–1. However, the neural mechanisms underlying the sex differences in ASD are unknown. Social deficits are the core symptoms of patients with ASD. Previous studies showed that diminished activity-dependent brain-derived neurotrophic factor (BDNF) signaling induced differential severity of autism-like social preference deficits in male and female mice by using a mouse model with genetic knock-in of human BDNF methionine (Met) allele, which significantly decreased activity-dependent BDNF release without affecting basal BDNF secretion. Here, we investigated the synaptic mechanisms for diminished activity-dependent BDNF-induced differential severity of social preference deficits in males and females. The prefrontal cortex (PFC) is a critical brain region for social behaviors. Whole-cell patch-clamp brain slice recordings showed that diminished activity-dependent BDNF signaling differentially increased the frequency of spontaneous action potentials (sAPs) of pyramidal neurons in the PFC of male and female BDNF+/Met mice. The frequency of sAPs in male BDNF+/Met mice was higher than in female BDNF+/Met mice. Diminished activity-dependent BDNF signaling differentially enhanced excitatory synaptic transmission and dampened inhibitory synaptic transmission of pyramidal neurons at pre- and post- synapses in males and females, which were mediated by dysregulated transcriptional levels of key synaptic genes. Chemogenetic inhibition of pyramidal neurons in the PFC of BDNF+/Met mice was sufficient to ameliorate autism-like social preference deficits in males and females. This study reveals synaptic mechanisms underlying the differential severity of social preference deficit in male and female BDNF+/Met mice, 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
The mineralocorticoid receptor (MR) plays a pivotal role in modulating the neuroendocrine stress response and cognitive function. While recent evidence highlights the importance of MRs in glutamatergic neurons in regulating anxiety-like behavior, the specific contribution of MRs within inhibitory networks remains incompletely understood. To address this gap, we generated a mouse model with targeted ablation of MR in forebrain GABAergic neurons (MRDlx). Comprehensive behavioral profiling revealed a profound, state-dependent cognitive phenotype in male MRDlx mice. Under non-stressful baseline conditions, these mice exhibited impaired object recognition memory, while under aversive learning paradigms, such as the Morris water maze and fear conditioning, they displayed enhanced spatial and contextual memory. Furthermore, male MRDlx mice demonstrated significant behavioral lack of adaptation to 21 days of chronic social defeat stress (CSDS). Notably, these changes were highly sex-influenced, as female MRDlx mice did not exhibit the same baseline cognitive deficits or subsequent stress resistance. Mechanistically, in vitro hippocampal electrophysiological recordings from male mice showed that acute corticosterone (CORT) application, which typically suppresses long-term potentiation (LTP), failed to impair LTP in MRDlx slices, indicating a marked resistance to CORT-induced suppression. Together, our findings suggest that MRs in GABAergic neurons normally function as critical constraints on excitatory synaptic plasticity during high-stress states. Ablating this regulatory mechanism confers robust behavioral and synaptic stress resistance, 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