Martinez Vizcaino, N. | Search bioRxiv

bioRxiv2026

Multimodal profiling and intersectional genetics reveal CA1 border inhibitory neuron diversity and postnatal emergence of retrosplenial connectivity

Inhibitory neurons (INs) at the stratum radiatum/stratum lacunosum-moleculare border of hippocampal CA1 comprise diverse populations, including long-range-projecting neurons that innervate the retrosplenial cortex (RSCtx). However, their molecular organization and developmental connectivity remain poorly understood. Here, we combine multimodal transcriptomic profiling, intersectional genetics, and retrograde tracing to characterize CA1 border INs. We identified two major caudal ganglionic eminence-derived, Cxcl14-enriched populations distinguished by Syt6/Cck-related and Ntng1-expressing transcriptional profiles. We then generated a Cxcl14-Cre mouse line that, when combined with an IN-specific viral enhancer, provides genetic access to CA1 border INs. Retrograde labeling established that CA1 INs projecting to the RSCtx belong to the Ntng1-expressing population, and that this long-range projection emerges during postnatal mouse development, between postnatal days 3 and 5. Finally, analysis of genes encoding cell-surface proteins, key regulators of connectivity, revealed distinct expression profiles in RSCtx-projecting and SYT6-positive INs. Together, these findings establish a molecular and developmental framework for CA1 border IN diversity and provide a genetic strategy for investigating the assembly and function of these inhibitory circuits.

neuroscience↗

bioRxiv2020

Lipid metabolic stress in development defines which genetically-susceptible DYT-TOR1A mice develop disease

There has been enormous progress defining the genetic landscape of disease. However, genotypes rarely fully predict neurological phenotypes, and we rarely understand why. TOR1A +/{Delta}gag that causes dystonia with ~30% penetrance is a classic case. Here we show, in inbred mice, that +/{Delta}gag affects embryonic brain lipid metabolism with sex-skewed reduced penetrance. Penetrance is affected by environmental context, including maternal diet. The lipid metabolic defect resolves during post-natal development. Nevertheless, we discover dystonia-like symptoms in ~30% of juvenile female Tor1a+/{Delta}gag mice, and prevent these symptoms by genetically suppressing abnormal lipid metabolism. We conclude that Tor1a+/{Delta}gag embryos poorly buffer metabolic stress in utero, resulting in a period of abnormal metabolism that hardwires the brain for dystonia in later life. The data show unexpected and profound impacts of sex, and thus highlight the importance of examining male and female animal models of disease. Significance StatementThe genetic landscape of neurological disease is relatively well mapped. However, we typically cannot explain why some mutations only cause disease in a subset of individuals. A classic case is DYT-TOR1A dystonia that only develops in 30% of TOR1A+/{Delta}gag carriers. We now find that ~30% of inbred female Tor1a+/{Delta}gag mice develop abnormal brain lipid metabolism as embryos, while males are spared. The percentage is affected by maternal diet. Further, this period of abnormal lipid metabolism causes dystonia-like symptoms in juvenile mice. These data show how an environmentally-sensitive event of development defines which genetically-susceptible individuals develop disease in later life. They also highlight the importance of examining male and female animal models of disease.

neuroscience↗