Biology subjects

Carrillo, G. L.

Publications and source records attributed to Carrillo, G. L..

3 recordsLinked to original sources

bioRxiv2024

Elevated EGR1 Binding at Enhancers in Excitatory Neurons Correlates with Neuronal Subtype-Specific Epigenetic Regulation

Brain development and neuronal cell specification are accompanied with epigenetic changes to achieve diverse gene expression regulation. Interacting with cell-type specific epigenetic marks, transcription factors bind to different sets of cis-regulatory elements in different types of cells. Currently, it remains largely unclear how cell-type specific gene regulation is achieved for neurons. In this study, we generated epigenetic maps to perform comparative histone modification analysis between excitatory and inhibitory neurons. We found that neuronal cell-type specific histone modifications are enriched in super enhancer regions containing abundant EGR1 motifs. Further CUT&RUN data validated that more EGR1 binding sites can be detected in excitatory neurons and primarily located in enhancers. Integrative analysis revealed that EGR1 binding is strongly correlated with various epigenetic markers for open chromatin regions and associated with distinct gene pathways with neuronal subtype-specific functions. In inhibitory neurons, the majority of genomic regions hosting EGR1 binding sites become accessible at early embryonic stages. In contrast, the super enhancers in excitatory neurons hosting EGR1 binding sites gained their accessibility during postnatal stages. This study highlights the significance of transcription factor binding to enhancer regions, which may play a crucial role in establishing cell-type specific gene regulation in neurons.

neuroscience↗

bioRxiv2022

Complement-dependent loss of inhibitory synapses on pyramidal neurons following Toxoplasma gondii infection

The apicomplexan parasite Toxoplasma gondii has developed mechanisms to establish a central nervous system infection in virtually all warm-blooded animals. Acute T. gondii infection can cause neuroinflammation, encephalitis, and seizures. Meanwhile, studies in humans, non-human primates, and rodents have linked chronic T. gondii infection with altered behavior and increased risk for neuropsychiatric disorders, including schizophrenia. We previously demonstrated that T. gondii infection triggers the loss of perisomatic inhibitory synapses, an important source of inhibition on excitatory pyramidal cells, and a type of synapse that is disrupted in neurological and neuropsychiatric disorders. Similar to other instances of inflammation and neurodegeneration, we showed that phagocytic cells (including microglia and infiltrating monocytes) contribute to the loss of these inhibitory synapses. However, in the case of T. gondii-induced synapse loss, phagocytic cells target and ensheath the cell bodies of telencephalic neurons. Here, we show that these phagocytic cells specifically ensheath excitatory pyramidal neurons, leading to the preferential loss of perisomatic synapses on these neurons. In contrast, inhibitory cortical interneuron subtypes are not extensively ensheathed by phagocytic cells following infection. Moreover, we show that infection induces expression of complement C3 protein by these excitatory neurons and that C3 is required for the loss of perisomatic inhibitory synapses, albeit not through activation of the classical complement pathway. Together, these findings provide evidence that T. gondii infection induces changes in excitatory pyramidal neurons that trigger selective removal of inhibitory perisomatic synapses in the infected neocortex and provide a novel role for complement in remodeling of inhibitory circuits in the infected brain.

neuroscience↗

bioRxiv2019

Toxoplasma induces stripping of perisomatic inhibitory synapses

Infection and inflammation within the brain induces changes in neuronal connectivity and function. The intracellular protozoan parasite, Toxoplasma gondii, is one pathogen that infects the brain and can cause encephalitis and seizures. Persistent infection by this parasite is also associated with behavioral alterations and an increased risk for developing psychiatric illness, including schizophrenia. Current evidence from studies in humans and mouse models suggest that both seizures and schizophrenia result from a loss or dysfunction of inhibitory synapses. In line with this, we recently reported that persistent Toxoplasma gondii infection alters the distribution of glutamic acid decarboxylase 67 (GAD67), an enzyme that catalyzes GABA synthesis in inhibitory synapses. These changes could reflect a redistribution of presynaptic machinery in inhibitory neurons or a loss of inhibitory nerve terminals. To directly assess the latter possibility, we employed serial block face scanning electron microscopy (SBFSEM) and quantified inhibitory perisomatic synapses in neocortex and hippocampus following parasitic infection. Not only did persistent infection lead to a significant loss of perisomatic synapses, it induced the ensheathment of neuronal somata by phagocytic cells. Immunohistochemical, genetic, and ultrastructural analyses revealed that these phagocytic cells included reactive microglia. Finally, ultrastructural analysis identified phagocytic cells enveloping perisomatic nerve terminals, suggesting they may participate in synaptic stripping. Thus, these results suggest that microglia contribute to perisomatic inhibitory synapse loss following parasitic infection and offer a novel mechanism as to how persistent Toxoplasma gondii infection may contribute to both seizures and psychiatric illness.\n\nMAIN POINTSO_LIToxoplasma-infection leads the loss of perisomatic inhibitory synapses\nC_LIO_LIPhagocytic microglia ensheath neuronal somata following Toxoplasma-infection\nC_LIO_LIMicroglia contact and envelop perisomatic nerve terminals, suggesting that Toxoplasma induces synaptic stripping\nC_LI

neuroscience↗