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Mapping the brain
Can we rescue injured brains?

The Tmem 108 gene forms proteins that enable memory and our sense of direction. But reduced Tmem 108, through mutation, can produce schizophrenia-like symptoms.

Schizophrenia affects about 1 percent of the population, of Americans (about 3.2 million). It causes hallucinations, depression and impairs thinking — and social behavior. Cognitive problems can be a major source of dysfunction and disability, and can be among the earliest symptoms.

Babies born to mothers who developed severe infection in pregnancy, like influenza or pneumonia, have a significantly increased risk of schizophrenia.

Mutations in a gene that enables memory building as well as a sense of direction, induces imprecise communication between neurons and contributes to symptoms of schizophrenia, scientists report.

Dramatically reducing the protein made by the Tmem 108 gene — results in fewer, smaller neural spines, which normally would work like communication antenna between neurons.

This impairs the ability of neurons to receive signals other neurons try to send. Mice then display schizophrenia-like behavioral deficits, such as impaired cognition and an impaired sense of direction.

Adds Lin Mei PhD, chairman of the Department of Neuroscience and Regenerative Medicine at the Medical College of Georgia at Augusta University, Georgia Research Alliance Eminent Scholar in Neuroscience and a corresponding author:"We knew this gene's alteration likely contributed to schizophrenia and we wanted to better understand how."

The work appears in the journal Proceedings of the National Academy of Sciences, PNAS.

While some Tmem 108 proteins can be found throughout the central nervous system, it appears to cluster in the dentate gyrus of the hippocampus. This area is known to be critical to spatial coding - providing a sense of direction - as well as emotions and an ability to learn and remember. Dentate gyrus dysfunction is implicated in many psychiatric disorders.

Focusing on this area of the brain, scientists found that expression of transmembrane protein 108 or Tmem 108 is normally increased in the first few weeks of life in a mouse - equivalent to the first few years in a human. This critical period of development enables neural spines to grow which increases signalling and thus 'communication' between neurons.

Spines are wiry filiments. Each excitatory neuron has thousands of spines that capture messages from other excitatory neurons and create memories. In good health, excitatory neurons and their actions are balanced by inhibitory neurons in a dynamic cycle. The sheer number of spines on excitatory neurons is how our brains create and handle information. Healthy spines are continuously forming and maturing. However, in schizophrenia, too many spines remain in an immature state.

Researchers created a mouse which consistently expressed only 20 percent of the normal level of Tmem 108 protein during critical early development. The pups grew into mice that displayed schizophrenia-like behaviors, including problems with direction and memory. Upon examination, they were found to have reduced spines on their neurons in the dentate gyrus.

Tmem 108 is also critical to the expression of AMPA receptors (or AMPAR) on the surface of the neurons. AMPA receptors are found in many parts of the brain and are the most commonly found receptor in the nervous system. They are activated by the excitatory neurotransmitter glutamate and are important to how spines are shaped which impacts how other neurons receive signals. They also play a major role in the development and spread of seizures and are currently a seizure treatment target. Tmem 108 mutations are also found with alcoholism.

The good news about the Tmem 108 and AMPA receptors interconnectivity is that it gives scientists a potential point of intervention. Now, when they give a drug to increase AMPA receptors on the cell surface, neural spines assume a more healthy and mature state. Next, researchers want to see if they can increase normal spines and receptors into healthier behavior outcomes in schizophrenia-like mice.

"Morphologically, the mice can be rescued. We hope we will find that healthy function is restored as well — which could translate into a new treatment target for this complex, disabling disease."

Lin Mei PhD, Chairman, Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Georgia Research Alliance, USA and Eminent Scholar in Neuroscience.

Neurotransmission in dentate gyrus (DG) is critical for spatial coding, learning memory, and emotion processing. Although DG dysfunction is implicated in psychiatric disorders, including schizophrenia, underlying pathological mechanisms remain unclear. Here we report that transmembrane protein 108 (Tmem108), a novel schizophrenia susceptibility gene, is highly enriched in DG granule neurons and its expression increased at the postnatal period critical for DG development. Tmem108 is specifically expressed in the nervous system and enriched in the postsynaptic density fraction. Tmem108-deficient neurons form fewer and smaller spines, suggesting that Tmem108 is required for spine formation and maturation. In agreement, excitatory postsynaptic currents of DG granule neurons were decreased in Tmem108 mutant mice, indicating a hypofunction of glutamatergic activity. Further cell biological studies indicate that Tmem108 is necessary for surface expression of AMPA receptors. Tmem108-deficient mice display compromised sensorimotor gating and cognitive function. Together, these observations indicate that Tmem108 plays a critical role in regulating spine development and excitatory transmission in DG granule neurons. When Tmem108 is mutated, mice displayed excitatory/inhibitory imbalance and behavioral deficits relevant to schizophrenia, revealing potential pathophysiological mechanisms of schizophrenia.

Key words: dentate gyrus spine glutamatergic transmission AMPA receptors schizophrenia

Dr. Bao-Ming Li, neuroscientist at the Institute of Life Science at China's Nanchang University, is co-corresponding author. Dr. Hui-Feng Jiao, who just completed her graduate work at Nanchang University, which included working in Mei's lab for three years, is first author.

The research was funded by the National Institutes of Health, the U.S. Department of Veterans Affairs and the National Natural Science Foundation of China.
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3D models depicting common shapes of dendritic spines. Longer spines being desireable.
Image Credit: Wikipedia



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