Adgrd1 deficiency reveals increased hippocampal vulnerability and selective behavioral alterations in mice

Synaptic plasticity deficits via aberrant engagement of metaplasticity in the hippocampus of PS19 mice

Tauopathy is characterized by progressive synaptic failure and neuroinflammation, yet the laminar-specific nature of these disruptions remains poorly understood. We investigated hippocampal functional integrity and glial reactivity in 8–10-month-old PS19 (P301S) mice. Electrophysiological recordings in the CA1 stratum radiatum revealed an unexpected increase in basal synaptic transmission despite profound deficits in both maintenance and early induction of the LTP phase. Conversely, the dentate gyrus exhibited reduced basal transmission and impaired LTP maintenance, alongside significant paired-pulse plasticity changes not observed in CA1. Furthermore, we demonstrate that transregional metaplasticity, as driven by prior activity in the stratum oriens (SO) in a way that inhibits subsequent LTP in wild-type mice, is occluded in PS19 mice. These data suggest that the tauopathic hippocampus exists in a “metaplastic” state, which inhibits future LTP. Immunofluorescence studies revealed that while astrogliosis and microglial activation were pan-hippocampal, specific neuroinflammatory markers exhibited striking laminar specificity. Mean fluorescence intensity for the neuroinflammatory astrocyte marker C3 was significantly upregulated only in the SO, and the lysosomal marker CD68 showed heightened occupancy specifically in the SO and stratum lacunosum-moleculare. Our findings indicate that tau pathology does not affect the hippocampus uniformly. Instead, it induces region-specific shifts in synaptic efficacy and a breakdown of metaplastic control that coincides with anatomically localized neuroinflammatory signaling.

Ank3 loss in adult forebrain excitatory neurons disrupts behavior, neuronal activity, membrane proteome, and myelination.

ANK3, encoding the scaffolding protein ankyrin-G, is a major risk gene for bipolar disorder and schizophrenia, but its cellular and circuit-level mechanisms remain poorly defined. Here, we demonstrate that deletion of Ank3 in forebrain excitatory neurons-either prenatally (Ank3-/-:Emx1-Cre) or in adolescence (Ank3-/-:CaMKIIα-Cre) leads to convergent behavioral phenotypes in adulthood, including hyperactivity, reduced anxiety-like behavior, and decreased depression-like responses. Calcium imaging in cultured neurons and acute brain slices revealed that ankyrin-G loss reduces both spontaneous and evoked neuronal activity. Quantitative proteomic profiling of membrane-enriched cortical fractions uncovered widespread remodeling of the synaptic proteome, including upregulation of the kinase Taok2 and unexpected downregulation of myelin basic protein (Mbp), a structural component of oligodendrocyte-derived myelin. Importantly, chronic lithium treatment, known to reverse behavioral abnormalities in Ank3-deficient mice, also restored Mbp expression. Together, our findings identify ankyrin-G as a molecular bridge between excitatory neuronal activity, synaptic structure, and myelin-associated protein expression, revealing a pathway by which ANK3 variants may contribute to neuropsychiatric disease.

Neuronal Ddit4 overexpression in the medial prefrontal cortex reduces synaptic density and impairs cognitive function in mice.

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.

Anoctamin 2 deletion alters dopamine-related signaling and impairs inhibitory behavioral control in mice.

These findings identify ANO2 as a potential modulator of dopamine-related signaling and inhibitory behavioral control, expanding current understanding of calcium-activated chloride channel function in neural circuits relevant to behavioral domains implicated in neuropsychiatric disorders.

The deficiency of KIF2C leads to abnormal distribution of cortical neurons and behavioral deficits in mice

Summary The microtubule-depolymerizing kinesin family member 2C (KIF2C) is highly expressed in neurological tumors and has been implicated in central nervous system (CNS) and psychiatric conditions, but its functions in the CNS remain unclear. To investigate the role of KIF2C in vivo, we generated global Kif2c knockout mice. Kif2c knockout leads to cortical structural abnormalities, selective reduction of deep-layer TBR1 immunoreactivity, and impairments in motor coordination and spatial learning. Single-cell RNA sequencing reveals altered deep-layer neuronal composition, marked by decreased layer 5 intratelencephalic neurons and a relative increase in extratelencephalic projection neurons. Furthermore, Kif2c deficiency drives disorganization of synapse-related gene expression and correlates with widespread expression changes in key developmental signaling pathways. Overall, this study indicates that KIF2C may regulate microtubule dynamics to control deep-layer cortical neuron number and organization and modulate neuronal projections and signaling pathways. This work provides a foundation for understanding the role of KIF2C in neural development.

Increased expression of developmental Nav1.3 promotes hippocampal CA3 hyperexcitability in early-stage 5xFAD mice