Biology subjects

Pletnikov, M. V.

Publications and source records attributed to Pletnikov, M. V..

4 recordsLinked to original sources

bioRxiv2024

Circulating extracellular microRNAs in the blood promote sociability in mice

Extracellular vesicles (EVs) are cell-derived small membrane vesicles and circulate throughout the body, but the impact of circulating EVs on brain function and behavior remains elusive. Here, we report that wild-type (WT) mouse blood, particularly EVs, increases sociability in socially impaired immunodeficient Rag1-/- mice, mimicking the effects of WT T cell transfer. These EVs localized to neurons and regulated PKC{varepsilon} expression, GABAA receptor synaptic localization, and inhibitory postsynaptic signaling in prefrontal cortex (PFC) pyramidal neurons. Injection of Rag1-/- EVs supplemented with miR-23a-3p and miR-103-3p enhanced synaptic function and sociability in Rag1-/- mice. T cells secreted miR-23a-3p via EVs, and Mir23a-/- T cells failed to increase sociability. Similar beneficial effects of WT blood EVs were observed in additional mouse models with sociability deficits, Cntnap2-/- and Shank3-/- mice. These findings uncover a previously unrecognized role of EV miRNAs in mediating immune modulation of synaptic function and social behavior, revealing a novel molecular pathway for immune-neuron communication.

neuroscience↗

bioRxiv2023

Microglial cannabinoid receptor type1 mediates social memory deficits produced by adolescent THC exposure and 16p11.2 duplication

Adolescent cannabis use increases the risk for cognitive impairments and psychiatric disorders. Cannabinoid receptor type 1 (Cnr1) is expressed not only in neurons and astrocytes, but also in microglia, which shape synaptic connections during adolescence. Nonetheless, until now, the role of microglia in mediating the adverse cognitive effects of delta-9-tetrahydrocannabinol (THC), the principal psychoactive constituent of cannabis, has been unexplored. Here, we report that adolescent THC exposure produces microglial apoptosis in the medial prefrontal cortex (mPFC), which was exacerbated in the mouse model of 16p11.2 duplication, a representative copy number variation (CNV) risk factor for psychiatric disorders. These effects are mediated by microglial Cnr1, leading to reduction in the excitability of mPFC pyramidal-tract neurons and deficits in social memory in adulthood. Our findings highlight the importance of microglial Cnr1 to produce the adverse effect of cannabis exposure in genetically vulnerable individuals.

neuroscience↗

bioRxiv2021

Experimental and computational analysis of calcium dynamics in 22q11.2 deletion model astrocytes

Intracellular calcium dynamics in spontaneously active cells such as neurons or astrocytes is an information-rich readout of the physiological state of the cell. Methods for deriving mechanistic information from biological time courses, as well as for algorithmically extracting cellular activity time courses from imaging data, have significantly advanced in recent years but been mostly applied to neuronal data. At the same time, the role for astrocytes, a type of glial brain cells, in cognition and psychiatric diseases remains poorly understood. Using calcium imaging, computer vision, and Bayesian kinetic inference, we analyze calcium dynamics in primary astrocytes derived from control or Df1/+ mice, a model of 22q11.2 deletion syndrome (DiGeorge syndrome). Inference of highest-likelihood molecular kinetic characteristics from the intracellular calcium time courses pinpoints a significant change in the activity of the sarcoendoplasmic reticulum calcium ATPase (SERCA). Applying a SERCA inhibitor to the control cells reproduces the differences detected in the deletion-bearing cells. Our work identifies for the first time the molecular changes driving the calcium kinetics in 22q11.2 deletion model astrocytes. We conclude that Bayesian kinetic inference is a useful tool for mechanistic dissection of a complex cellular phenotype, calcium dynamics, in glial cells. This method has the potential to facilitate formulation of specific hypotheses concerning the underlying molecular mechanisms, prioritization of experiments testing such hypotheses, and, in the future, individualized functional molecular diagnostics.

systems biology↗

bioRxiv2019

Neuronal histone methyltransferase EZH2 regulates neuronal morphogenesis, synaptic plasticity, and cognitive behavior of mice

Recent studies showed that in the nervous system histone methyltransferase EZH2-mediated trimethylation of histone H3 lysine 27 (H3K27me3) acts to regulate neural stem cell proliferation and fate specificity through silencing different gene sets. Here we explored the function of EZH2 in early post-mitotic excitatory neurons by generating a neuronal specific Ezh2 conditional knockout mouse line. The results showed that lack of neuronal EZH2 led to delayed neuronal migration, more complex dendritic arborization, and significantly increased dendritic spine density. RNA-sequencing (RNA-seq) experiments comparing control and Ezh2 knockout neurons revealed that neuronal EZH2 regulated genes related to neuronal morphogenesis. In particular, Pak3 was identified as a target gene suppressed by EZH2 and H3K27me3, and expression of dominant negative PAK3 reversed Ezh2 knockout-induced higher dendritic spine density. Lastly, lack of neuronal EZH2 resulted in impaired memory behaviors in adult mice. Our results demonstrated that neuronal EZH2 played important roles in controlling multiple steps of neuronal morphogenesis during development, which had long-lasting effects on cognitive function in adult mice.

neuroscience↗