The Tsien Lab

Schizophrenia is a highly prevalent disorder with strong genetic components and a high incidence, particularly among the homeless and people with other mental difficulties. One of the major risk factors for a schizophrenia uncovered by genetic studies is variations in the non-coding DNA. This is seen dramatically in the case of CACNA1C that encodes a calcium channel important for brain function, blood pressure, the heartbeat, and digestion. Our group has collaborated with Raquel Moya and Matt Maurano in the Institute of System Genetics to decipher variations in intron three of the CACNA1C gene. In a paper uploaded to a pre-print server

(https://www.medrxiv.org/content/10.1101/2024.03.05.24303780v2) and recently submitted to PNAS, we show how repeating blocks 30 base pairs long in the noncoding DNA show variations in repeat structure displaying strong correlations with disease. Indeed, the repeating blocks are just as likely to be responsible for the disease as any group of single nucleotide polymorphisms (SNPs). To test these ideas, we are engaged in a highly ambitious program of replacing the gene in a mouse with its human counterpart with or without structural variations that are thought to correlate with disease. Working in the mouse, we will be able to test human, genetic variations in the context of real neurons in real brains without the uncertainty encountered by folks working with neurons derived from pluripotent stem cells. 

Two other publications in the pipeline are relevant to the mission of the vulnerable brain. One of them will appear in a book about signaling to the nucleus as part of the molecular machinery supporting memory. We describe how a signaling pathway discovered in our laboratory linking activity in neurons to expression of their genes, may be important for the vulnerable brain.

Another paper, submitted to Molecular Pharmacology, concerns epilepsy and autism, two brain disorders that often go hand in hand. This paper honors Bill Catterall, a colleague and friend for decades who passed away suddenly just this past year. He is well known for proposing that interneurons that release GABA, an inhibitory neurotransmitter, are important for epilepsy and that deficiency of sodium channels in specific types of GABAergic neurons can cause Dravet Syndrome, a devastating form of epilepsy that appears at a young age. Fortunately, Dravet kids respond well to cannabidiol. Our review summarizes our view about how cannabidiol does such an amazing job. Why study a drug that has already been FDA approved, thanks in no small part to the hard work of Orrin Devinsky and others? Because no drug is perfect and knowing how a drug works will enable us to emphasize the best aspects and tune out the side effects.

Upcoming Publications

PNAS

Molecular Pharmacology

Springer (book chapter)