bioRxiv Subject Collection: Neuroscience's Journal
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Thursday, February 27th, 2025
| Time |
Event |
| 9:54a |
Activation of KCC2 during development alleviates cognitive, behavioral, and neural excitability in adult CDKL5-deficient mice
Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a developmental and epileptic encephalopathy (DEE) characterized by severe drug-resistant epileptic disorders beginning in early childhood, along with cognitive and social impairments in later childhood and adulthood. Existing pharmacological therapies for CDD primarily focus on anti-seizure medications, which often have associated sedative side effects. In addition, there are currently no effective treatments for cognitive or behavioral impairments associated with this disorder. Postnatal development expression of CDKL5 has a similar timeline as the developmental activity of the potassium chloride co-transporter (KCC2), the maturation of which is a prerequisite for the developmental switch to fast synaptic hyperpolarizing inhibition mediated by g-aminobutyric acid type A receptors (GABAAR). This developmental GABA switch is determined by changes in the phosphorylation of multiple residues in KCC2. During this initial postnatal period, dramatic changes occur as major neuronal circuits are formed, laying down the initial pathways important for memory consolidation and behavioral processing. Currently, a knowledge gap exists in understanding KCC2 dysfunction in CDD.
In adult Cdkl5 KO mice we found aberrant KCC2 phosphorylation and expression, such that KCC2 phosphorylation profile appeared immature. We examined the developmental changes in KCC2 and observed significant alterations in the phosphorylation of key residues and decreased KCC2 expression from p14 to p21. Because KCC2 loss-of-function has been strongly correlated with excessive neuronal excitation, cognitive and behavioral impairments, we examined seizure susceptibility, spatial memory, and social interaction in adult Cdkl5 KO mice following once daily administration of the KCC2 activator (OV350), or vehicle, to infant Cdkl5 KO mice. We found that adult Cdkl5 KO mice are more susceptible to kainate-induced seizures, show poor sociability and deficits in spatial learning and memory compared to WT mice. Twelve days of OV350 treatment as infants (p10 to p21) prevented the development of benzodiazepine-resistant seizures and alleviated cognitive and behavioral deficits in adult Cdkl5 KO mice. In contrast, 12 days of OV350 treatment in adult Cdkl5 KO mice had limited ability to alleviate cognitive and behavioral deficits. In summary, this study demonstrates that enhancing KCC2 function may be a potential therapeutic target for CDD and other DEEs. However, early intervention during critical developmental windows is crucial for optimal outcomes. | | 9:54a |
Activity of Human-Specific Interlaminar Astrocytes in a Chimeric Mouse Model of Fragile X Syndrome
Astrocytes, a type of glial cells, have multiple roles in regulating neuronal development and homeostasis. In addition to the typical mammalian astrocytes, in the primate cortex interlaminar astrocytes are located in the superficial layer and project long processes traversing multiple layers of the cerebral cortex. Previously, we described a human stem cell based chimeric mouse model where interlaminar astrocytes develop. Here, we utilized this model to study the calcium signaling properties of interlaminar astrocytes. To determine how interlaminar astrocytes could contribute to neurodevelopmental disorders, we generated a chimeric mouse model for Fragile X syndrome. We report that FXS interlaminar astrocytes exhibit hyperexcitable calcium signaling and cause an increase in dendritic spine dynamics. | | 9:54a |
Characterizing massa intermedia morphology in schizophrenia: associations with aging, neuropsychological functioning, and atypical hippocampal development
The massa intermedia (MI) is a midline structure connecting the left and right thalamus that typically develops during the 2nd trimester of pregnancy. Missing and smaller MI has been linked to neurodevelopmental disorders, including schizophrenia (SZ), and subtle deficits in cognition. However, findings are inconsistent and the association between MI and other anatomical variants linked to atypical brain development in SZ, including incomplete hippocampal inversion (IHI), is unclear. Presence/absence and morphology of the MI were ascertained on structural T1-weighted MRI images obtained at 3T in SZ (n = 223) and healthy individuals (n = 194) and compared between groups. Associations between MI morphology, cognitive function, and incomplete hippocampal inversion (IHI) were assessed. Prevalence of missing MI was 1.7% and did not differ between groups. MI was significantly smaller in SZ (p <.001). However, follow-up analyses revealed that smaller MI size in SZ was due to a significant Diagnosis x Age interaction characterized by a stronger negative age effect in SZ. IHI was significantly more common in individuals with missing MI. Neurocognition was not correlated with MI size when controlling for age and diagnosis. Stronger effects of age on MI size in SZ suggests that abnormal MI size measured in adulthood may not be a reliable static indicator of atypical neurodevelopment, but may reflect disease progression or accelerated aging. Missing MI was rare in our sample. Conversely, missing MI is associated with IHI suggesting a shared neurodevelopmental disruption in the 2nd trimester. | | 9:54a |
Direct pathway bias and altered striatal neurogenesis in human iPSC models of 16p11.2 CNVs: Evidence from single-cell and functional analyses
Striatal medium spiny neurons (MSNs) control motor, cognitive, and social domains via direct (dMSNs) and indirect (iMSNs) basal ganglia pathways. Recent genomic analyses implicate striatal circuit dysfunction in neurodevelopmental disorders (NDDs) and highlight MSNs as a newly recognised cell type affected in schizophrenia, yet much NDD research still focuses on cortical interneurons and glutamatergic neurons, leaving MSN involvement understudied. Here, we use human iPSC-derived MSNs to demonstrate high-fidelity striatal development and explore 16p11.2 copy number variants (CNVs) - mutations predisposing carriers to autism spectrum disorder, schizophrenia, intellectual disability and other NDD conditions featuring basal ganglia deficits. By profiling both 16p11.2 duplication and deletion MSNs, we uncover reciprocal changes in MSN neurogenesis kinetics that converge on a dMSN fate bias. These shifts correspond to altered calcium signalling and enhanced firing upon direct-pathway activation. Our findings reveal a previously unappreciated role for MSN subtype imbalances in NDD pathogenesis and open new avenues for therapeutic intervention. | | 9:54a |
Inhibitory and disinhibitory VIP IN-mediated circuits in neocortex
Cortical GABAergic interneurons (INs) are comprised of distinct types that provide tailored inhibition to pyramidal cells (PCs) and other INs, thereby enabling precise control of cortical circuit activity. INs expressing the neuropeptide vasoactive-intestinal peptide (VIP) have attracted attention recently following the discovery that they predominantly function by inhibiting dendritic-targeting somatostatin (SST) expressing INs, thereby disinhibiting PCs. This VIP-SST disinhibitory circuit motif is observed throughout the neocortex from mice to humans, and serves as a key mechanism for top-down (feedback) and context-dependent information processing. Thus, VIP IN-mediated disinhibition has been found to play an important role in sensory processing, control of executive functions, attention, sensorimotor integration and other cortico-cortical and thalamocortical feedback interactions. Furthermore, VIP INs have been implicated in mediating the effects of reinforcement signals, both reward and aversive, via their responsiveness to neuromodulators such as acetylcholine (ACh), and in facilitating synaptic plasticity and learning. While it is evident from transcriptomic analyses that VIP INs are a molecularly heterogeneous group, the physiological significance of this diversity is unclear at present. Here, we have characterized the functional diversity of VIP INs in the primary somatosensory cortex by leveraging intersectional genetic approaches to study distinct VIP IN subtypes. We found that VIP INs can be divided into four different populations: a group that expresses the Ca2+-binding protein calretinin (CR), two distinct groups that express the neuropeptide cholecystokinin (CCK), and a group that does not express either CR or CCK (non-CCK non-CR; or nCCK nCR). VIP neurons in each group exhibit different laminar distributions, axonal and dendritic arbors, intrinsic electrophysiological properties, and efferent connectivity, VIP/CR INs target almost exclusively SST INs, VIP/nCCK nCR INs also mainly target SST INs but also have connections to parvalbumin (PV) expressing INs. These two groups have essentially no connectivity to pyramidal cells (PCs). On the other hand, the two types of VIP/CCK INs target PCs, but differ in the degree to which synaptic release from each type is modulated by endocannabinoids. We also found that long-range inputs differentially recruit distinct VIP IN groups. Intriguingly, we find that distinct VIP IN populations target distinct SST INs subtypes in turn, indicating the presence of specialized VIP-SST disinhibitory subcircuits. Activation of distinct VIP IN subpopulations in vivo results in differential effects on the cortical network, thus providing evidence for modularity in VIP IN-mediated actions during cortical information processing. | | 9:54a |
Critical Period Plasticity is Associated withResilience to Short Unpredictable Stress
Exposure to stress can increase the risk of depression in susceptible individuals, but not in resilient ones. Resilience to stress decreases with age, parallel to drastic changes in the quality of brain plasticity from juvenile to old age, suggesting that the type of plasticity found in the maturing brain promotes resilience. To indirectly test this, we administered short unpredictable stress to adult male and female mice, as well as to adolescent mice and mice that lack SynCAM 1 and display extended adolescent-like, critical period plasticity in the brain. We found that short unpredictable stress robustly increased core body temperature in all groups of mice, indicative of stress-induced hyperthermia (SIH) and confirming the efficacy of the stress paradigm. However, depressive-like behavior as measured though tail suspension test was increased in adult mice only, supporting that the type of plasticity found in the maturing brain promotes resilience to stress. All three groups of mice showed a mild increase in locomotor activity after stress, suggesting that the quality of plasticity does not correlate with resilience to anxiety-like phenotypes. Our study hence provides further evidence for the protective role of developmental plasticity during stress and points to new mechanisms that promote resilience to stress-induced depression. | | 5:46p |
AIRUS: a simple workflow for AI-assisted exploration of scientific data
The development "reasoning" large language models (LLMs) seems poised to transform data analysis in all fields of science. This note describes a simple, iterative workflow termed AIRUS (AI Research Under Supervision), that allows working scientists, including those who lack extensive AI or programming expertise, to immediately start taking advantage of these capabilities. In the proposed workflow, a researcher uses an LLM to generate hypotheses, produce code, interpret results, and refine its approach in repeated cycles, only intervening when necessary. This can be run by simple cut-and-paste of code and results between web-based LLMs and an online Jupyter notebook. We demonstrate the workflow with two examples: one analysis of synthetic data, and one analysis of data from the International Brain Lab. |
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