UI study may explain gene's role in major psychiatric disorders, suggest new treatments

A new study from the University of Iowa and Weil Cornell Medicine of Cornell University shows that a genetic risk factor for five major psychiatric diseases may also be linked to the death of newborn brain cells. At the same time, the research suggests a compound currently being developed for use in humans may prevent these cells from dying.

In 2013, the largest genetic study of psychiatric illness to date found that mutations in the gene called CACNA1C are a risk factor in five major forms of neuropsychiatric disease—schizophrenia, major depression, bipolar disorder, autism, and attention deficit hyperactivity disorder (ADHD). All five conditions are also associated with high levels of anxiety. Now, researchers have discovered a new and unexpected role for CACNA1C that may both explain its association with these neuropsychiatric diseases and suggest new approaches to treat them.

The new study, recently published in eNeuro, showed that the loss of the CACNA1C gene from the forebrain of mice resulted in decreased survival of newborn neurons in the hippocampus—one of only two regions in the adult brain where new neurons are continually produced, a process known as neurogenesis. The death of these hippocampal neurons has been linked to a number of psychiatric conditions, including schizophrenia, depression, and anxiety.

Andrew Pieper

“We have identified a new function for one of the most important genes in psychiatric illness,” says Andrew Pieper, co–senior author of the study, professor of psychiatry at the UI Carver College of Medicine, and member of the Pappajohn Biomedical Institute at the UI. “It mediates survival of newborn neurons in the hippocampus, part of the brain that is important in learning, memory, mood, and anxiety.”

The scientists were also able to restore normal neurogenesis in mice lacking the CACNA1C gene by using a “neuroprotective” compound called P7C3-A20, which Pieper’s group discovered and which is currently under development as a potential therapy for neurodegenerative diseases. The finding suggests that P7C3 compounds may also be potential therapies for these neuropsychiatric conditions, which affect millions of people worldwide and which are often difficult to treat.

Pieper’s co–lead author, Anjali Rajadhyaksha, is an associate professor of neuroscience in the Department of Pediatrics and in the Feil Family Brain and Mind Research Institute at Weill Cornell Medicine, as well as director of the Weill Cornell Autism Research Program. She studies the role of the Cav1.2 calcium channel that the CACNA1C gene encodes. The Cav1.2 calcium channel is an important component of reward pathways and is affected in various neuropsychiatric disorders. 

“Genetic risk factors that can disrupt the development and function of brain circuits are believed to contribute to multiple neuropsychiatric disorders. Adult newborn neurons may serve a role in fine-tuning rewarding and environmental experiences, including social cognition, which are disrupted in disorders such as schizophrenia and autism spectrum disorders,” Rajadhyaksha says. “The findings of this study provide a direct link between the CACNA1C risk gene and a key cellular deficit, providing a clue into the potential neurobiological basis of CACNA1C-linked disease symptoms.”

Several years ago, Rajadhyaksha and Pieper created genetically altered mice whose forebrains are missing the CACNA1C gene. The team discovered that the animals have very high levels of anxiety.

“That was an exciting finding because all of the neuropsychiatric diseases in which this gene is implicated are associated with symptoms of anxiety,” says Pieper, who also holds appointments in the UI Department of Neurology, the Free Radical and Radiation Biology Program in the Department of Radiation Oncology, Holden Comprehensive Cancer Center, and the Iowa City VA Health Care System.

By studying neurogenesis in the mice, the research team has shown that loss of the CACNA1C gene from the forebrain decreases the survival of newborn neurons in the hippocampus—only about half as many hippocampal neurons survive in mice without the gene compared to normal mice. Loss of the CACNA1C gene also reduces the production of brain-derived neurotropic factor (BDNF), an important protein that supports neurogenesis.

The findings suggest that loss of the CACNA1C gene disrupts neurogenesis in the hippocampus by lowering the production of BDNF.

Pieper had previously shown that the “P7C3-class” of neuroprotective compounds bolsters neurogenesis in the hippocampus by protecting newborn neurons from cell death. When the team gave the P7C3-A20 compound to mice that lacked the CACNA1C gene, the mice’s neurogenesis rose to normal levels. Notably, the cells were protected despite the fact that the BDNF levels remained abnormally low, demonstrating that P7C3-A20 bypassed the BDNF deficit and independently rescued hippocampal neurogenesis.

Pieper says the next step will be to determine if the P7C3-A20 compound could treat the mice’s anxiety symptoms. If so, it’s possible that drugs based on this compound might help patients with major forms of psychiatric disease.

“CACNA1C is probably the most important genetic finding in psychiatry. It probably influences a number of psychiatric disorders, most convincingly bipolar disorder and schizophrenia,” says Jimmy Potash, professor and DEO of psychiatry at the UI, who was not involved in the study. “Understanding how these genetic effects are manifested in the brain is among the most exciting challenges in psychiatric neuroscience right now.”

In addition to Pieper and Rajadhyaksha, the research team included Anni Lee, Héctor De Jesús-Cortés, Zeeba Kabir, Whitney Knobbe, Madeline Orr, Caitlin Burgdorf, Paula Huntington, Latisha McDaniel, Jeremiah Britt, Franz Hoffmann, and Daniel Brat.

The research was supported in part by grants from the Hartwell Foundation and the Weill Cornell Autism Research Program. Pieper holds patents on the P7C3 family of neuroprotective compounds.