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GABAA receptors (GABAARs) are crucial components of our brain's communication system. They are involved in controlling the activity of neurons, including striatal spiny projection neurons (SPNs). However, the exact role of GABAARs in synaptic integration, particularly in adult SPNs, remains less understood. In a recent study, researchers employed a range of techniques using MMRRC mice to provide new insights into the complex interactions between GABAARs and another type of receptor, ionotropic glutamate receptors (iGluRs), in regulating neuron function.
Methods:To explore the role of GABAARs in adult SPNs, the researchers used a combination of molecular, optogenetic, optical, and electrophysiological approaches on ex vivo brain slices from MMRRC mice. Computational tools were also employed to model somatodendritic synaptic integration, which is the process by which neurons combine multiple signals.
Results:The study found that activating GABAARs caused currents with a reversal potential near -60 mV in both juvenile and adult SPNs. Interestingly, this relatively positive reversal potential was not attributed to the expression of a particular protein (NKCC1), but rather to a balance between two other transporters (KCC2 and Cl-/HCO3-cotransporters).
When researchers activated GABAergic synapses, they observed that SPNs became depolarized from their resting down-state. This GABAAR-mediated depolarization worked together with the stimulation of ionotropic glutamate receptors (iGluRs), leading to increased somatic depolarization and dendritic spikes.
Simulations revealed that a diffuse dendritic GABAergic input to SPNs effectively enhanced the response to coincident glutamatergic input. This finding suggests that GABAARs and iGluRs can work in concert to excite adult SPNs when they are in a resting down-state. The inhibitory role of GABAARs appears to be limited to brief periods near the spike threshold.
Implications:The results of this study call for a reevaluation of the role of GABAARs in intrastriatal GABAergic circuits. The discovery that GABAARs can work in conjunction with iGluRs to excite adult SPNs in their resting down-state suggests a more complex role in regulating neuron function than previously thought.
By using MMRRC mice and a variety of techniques, the researchers have provided valuable insights into the intricate interactions between GABAARs and iGluRs in adult brain neurons. This knowledge could potentially lead to a better understanding of various neurological disorders and contribute to the development of more effective treatments.
Conclusion:The study using MMRRC mice has shed light on the complex role of GABAARs in adult striatal spiny projection neurons. By demonstrating that GABAARs can work together with iGluRs to excite adult SPNs in their resting down-state, researchers have opened up new avenues for understanding the regulation of neuronal function and the potential implications for neurological disorders.
Source: https://www.biorxiv.org/content/10.1101/2023.03.14.532627v2
Imagine the genome as a city with different neighborhoods, each having its function. Topologically associating domain (TAD) boundaries are like the fences that separate these neighborhoods, maintaining distinct regulatory territories. Disruption of these boundaries may interfere with regular gene expression and cause diseases, but the full impact remains unclear.
Researchers utilized CRISPR genome editing in mice to investigate the consequences of deleting eight TAD boundaries. All deletions led to noticeable molecular or organismal phenotypes, including chromatin interaction or gene expression changes, reduced viability, and anatomical abnormalities.
In 88% of cases, local 3D chromatin architecture was altered. This included merging TADs and changed contact frequencies within adjacent TADs. Additionally, 63% of the examined loci exhibited increased embryonic lethality or developmental issues. For instance, a TAD boundary deletion near Smad3/Smad6 led to complete embryonic lethality, while another near Tbx5/Lhx5 caused severe lung malformation.
This study highlights the importance of TAD boundary sequences for proper genome function and organism development. It also emphasizes the need to consider the potential pathogenicity of noncoding deletions affecting TAD boundaries in clinical genetics screening. By understanding the impact of TAD boundary disruptions, we can better diagnose and potentially treat genetic disorders.
Source: https://www.nature.com/articles/s42003-023-04819-w#Sec8
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Welcome to the Mutant Mouse Resource & Research Centers (MMRRC) Website
The MMRRC is the nation’s premier national public repository system for mutant mice. Funded by the NIH continuously since 1999, the MMRRC archives and distributes scientifically valuable spontaneous and induced mutant mouse strains and ES cell lines for use by the biomedical research community. The MMRRC consists of a national network of breeding and distribution repositories and an Informatics Coordination and Service Center located at 4 major academic centers across the nation. The MMRRC is committed to upholding the highest standards of experimental design and quality control to optimize the reproducibility of research studies using mutant mice. The MMRRC is supported by the Office of Research Infrastructure Programs (ORIP) in the Office of the Director at NIH. More than 50,000 mutant alleles are maintained as live mice, cryopreserved germplasm, and/or mutant ES cells. Live mice are supplied from a production colony, from a colony recovered from cryopreservation, or via micro-injection of ES cells. An MMRRC facility may offer cryopreserved material for resuscitation at the recipient scientist's institution.