Djurdjica Coss is a professor of biomedical sciences at UC Riverside. CREDIT Coss lab, UC Riverside.

 A University of California, Riverside, study has identified the biological underpinnings of a reproductive disorder caused by the mutation of a gene. This gene mutation also causes Fragile X Syndrome, a leading genetic cause of intellectual impairment and autism.

The researchers found mutations of the Fragile X messenger ribonucleoprotein 1 gene, or FMR1, contribute to premature ovarian failure, or POF, due to changes in neurons that regulate reproduction in the brain and ovaries. The mutation has been associated with early infertility, due to a 25-fold increased risk of POF, but the reasons were unclear. 

POF is the most severe form of premature ovarian aging, which affects about 10% of women and is characterized by an early depletion of ovarian follicles and early menopause. With women postponing reproduction, the chances of infertility increase, including due to FMR1 mutation.

“In the last two or three decades, the median age of first-time mothers in the U.S. and Europe has steadily increased,” said Djurdjica Coss, a professor of biomedical sciences in the UCR School of Medicine who led the research team. “Moreover, premature menopause causes not only early infertility, but also increased risk of cardiovascular disease and osteoporosis. It’s important, therefore, to understand the reasons behind these reproductive disorders and eventually find treatments. Such research can also help better advise women at risk on when to have a child and how to monitor their health outcomes.”

According to the Centers for Disease Control and Prevention, 19% of heterosexual couples in the U.S. experience infertility and need assisted reproductive technology, which can be too costly for many couples.

Coss explained that previous studies concerning the FMR1-mediated reproductive disorders analyzed them exclusively from an endocrine perspective, meaning they studied the changes in hormone levels and how endocrine cells functioned in the ovaries that produce them.

“We took a different approach,” Coss said. “Since the FMR1 gene is highly abundant in neurons, we postulated that neurons that regulate reproduction are affected by the FMR1 mutation, which in turn causes increases in hormone levels. Indeed, we found higher stimulation of neurons in the hypothalamus that regulate reproduction as well as more neurons in the ovaries that contribute to ovarian hormone synthesis.”

To do the research, Coss and her team used transgenic mice that lack the FMR1 gene to emulate the condition in people with a mutation in this gene. They first determined that this mouse model mimics what is observed in women with a FMR1 mutation. They then compared the reproduction-regulating neurons in the ovaries and the brain between these mice and their normal counterparts. They found the changes in function of these neurons led to a more rapid secretion of hormones in young transgenic female mice that later stopped reproducing early. Next, they removed the ovaries from these mice to determine the effect of the FMR1 mutation on just the neurons in the brain. 

“This allowed us to determine that these neurons in the brain, called gonadotropin-releasing hormone neurons, show changes in connectivity that affect how they function,” Coss said. “The increased number of synapses cause them to be faster and have more pulses of hormone secretion.”

Her team also determined that neurons “innervating” the ovaries — supplying the ovaries with nerves — were more abundant in the transgenic mice than in their normal counterparts.

“We think the increases we see in ovarian hormone levels are due to increases in ovarian innervation rather than increases in hormone-producing cells,” Coss said. “The endocrine perspective supports the latter.”

Next, Coss and her team plan to investigate if the effects of FMR1 mutation can be alleviated by partially inhibiting neurons in the ovaries. 

“We anticipate this may normalize ovarian hormone levels, possibly allowing for a normal reproductive lifespan,” Coss said.

The image of the tree is used to illustrate the morphology and function of pyramidal neurons in autism spectrum disorders. These neurons are one of the main integrators of information in the cerebral cortex, with long “branches” and “roots” representing dendrites. The small “leaf-like” projections are the dendritic spines, where the excitatory synapses connect one neuron to another. The blurred sections of the image represent the altered integration and perception of sensory information from the outside world, discovered by Diana E. Mitchell, Soledad Miranda-Rottmann and colleagues. CREDIT © Photo and drawing by Roberto Araya and Soledad Miranda-Rottmann. Photo was taken at Westmount Park, Montreal, Canada.

Results of a new study led by Roberto Araya, a Canadian neuroscientist, biophysicist and researcher at the CHU Sainte-Justine Research Centre, in Montreal, show that in Fragile X syndrome (FXS), the most common cause of autism, sensory signals from the outside world are integrated differently, causing them to be underrepresented by cortical pyramidal neurons in the brain.

This phenomenon could provide important clues to the underlying cause of the symptoms of this syndrome. The research team’s work not only provides insight into the mechanism at the cellular level, but also opens the door to new targets for therapeutic strategies.

The study was published on January 3 in the prestigious journal Proceedings of the National Academy of Sciences.

Autism is characterized by a wide range of symptoms that may stem from differences in brain development. With advanced imaging tools and the genetic manipulation of neurons, the team of researchers at the CHU Sainte-Justine Research Center was able to observe the functioning of individual neurons – specifically pyramidal neurons of cortical layer 5 – one of the main information output neurons of the cortex (the thin layer of tissue found on the surface of  the brain).

The researchers found a difference in how sensory signals are processed in these neurons.

“Previous work has suggested that FXS and autism spectrum disorders are characterized by a hyperexcitable cortex, which is considered to be the main contributor to the hypersensitivity to sensory stimuli observed in autistic individuals,” said  Araya, also a professor in the Department of Neurosciences at Université de Montréal.

“To our surprise, our experimental results challenge this generalized view that there is a global hypersensitivity in the neocortex associated with FXS. They show that the integration of sensory signals in cortical neurons is underrepresented in a murine model of FXS,” added Diana E. Michell, first co-author of the study.

A protein, FMRP, that is absent in the brains of people with FXS modulates the activity of a type of potassium channel in the brain. According to the research group’s work, it is the absence of this protein that alters the way sensory inputs are combined, causing them to be underrepresented by the signals coming out of the cortical pyramidal neurons in the brain.

Soledad Miranda-Rottmann, also first co-author of the study, attempted to rectify the situation with genetic and molecular biology techniques. “Even in the absence of the FMRP protein, which has several functions in the brain, we were able to demonstrate how the representation of sensory signals can be restored in cortical neurons by reducing the expression of a single molecule,” she said.

“This finding opens the door to new strategies to offer support to those with FXS and possibly other autism spectrum disorders to correctly perceive sensory signals from the outside world at the level of pyramidal neurons in the cortex,” concluded Araya.

“Even if the over-representation of internal brain signals causing hyperactivity is not addressed, the correct representation of sensory signals may be sufficient to allow better processing of signals from the outside world and of learning that is better suited to decision making and engagement in action.”

A new study suggests that therapeutic interventions to treat neurodevelopmental disorders may be more effective if done during the early stages of brain development.

“In order to stop the progression of neurodevelopmental disorders, it is important to identify how and when brain circuits are changing during development. Our study identifies when circuits are altered in addition to how brain circuits are corrected,” said the study’s senior author Molly Huntsman, PhD, associate professor at the University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences located on the University of Colorado Anschutz Medical Campus.

The study, published in The Journal of Neuroscience, looks at Fragile X Syndrome (FXS), a pervasive neurodevelopmental disorder and a common cause of intellectual disability, autism and anxiety disorders. 

“Currently, there are no approved or effective therapies targeting specific pathophysiology underlying the clinical manifestations of FXS,” Huntsman said. “We’re hoping to provide answers for when and how to treat FXS to help with therapeutic options eventually.”

The CU Skaggs School of Pharmacy researchers identified potential causal circuit-level changes during a critical period of brain development susceptible to therapeutic intervention. They focused on the amygdala – the brain region where fear and anxiety are processed.

Using a mouse model of FXS, they identified a critical period of increased circuit plasticity occurring in early brain development. They showed that fear-learning emerges in in the brain during these periods of increased plasticity. At the same time, they demonstrated that early intervention ameliorates it.

The results suggest that critical period plasticity in the amygdala is increased and may be shifted to earlier developmental timepoints. This could cause a “maladaptive” form of plasticity and yet one that can be treated with therapeutic intervention at key developmental time points.

Age at the time of treatment, the study said, is important because early pharmacological intervention was shown effective in reducing fear-learning in the mouse model.

“This is highly significant and addresses a critical barrier for understanding how circuits develop in a mouse model of autism and intellectual disability and even more important for therapeutic intervention-directed treatment options,” Huntsman said.

The researchers said future clinical trials should focus on human critical periods of development.

A recently evolved pattern of gene activity in the language and decision-making centers of the human brain is missing in a disorder associated with autism and learning disabilities, a new study by Yale University researchers shows.

“This is the cost of being human,” said Nenad Sestan, associate professor of neurobiology, researcher at Yale’s Kavli Institute for Neuroscience, and senior author of the paper. “The same evolutionary mechanisms that may have gifted our species with amazing cognitive abilities have also made us more susceptible to psychiatric disorders such as autism.”

The findings are reported in the May 11 issue of the journal Cell.

In the Cell paper, Kenneth Kwan, the lead author, and other members of the Sestan laboratory identified the evolutionary changes that led the NOS1 gene to become active specifically in the parts of the developing human brain that form the adult centers for speech and language and decision-making. This pattern of NOS1 activity is controlled by a protein called FMRP and is missing in Fragile X syndrome, a disorder caused by a genetic defect on the X chromosome that disrupts FMRP production. Fragile X syndrome, the leading inherited form of intellectual disability, is also the most common single-gene cause of autism. The loss of NOS1 activity may contribute to some of the many cognitive deficits suffered by those with Fragile X syndrome, such as lower IQ, attention deficits, and speech and language delays, the authors say.

The pattern of NOS1 activity in these brain centers does not occur in the developing mouse brain — suggesting that it is a more recent evolutionary adaptation possibly involved in the wiring of neural circuits important for higher cognitive abilities. The findings of the Cell paper support this hypothesis. The study also provides insights into how genetic deficits in early development, a time when brain circuits are formed, can lead to disorders such as autism, in which symptoms appear after birth.

“This is an example of where the function of genetic changes that likely drove aspects of human brain evolution was disrupted in disease, possibly reverting some of our newly acquired cognitive abilities and thus contributing to a psychiatric outcome,” Kwan said.