Schizophrenia affects about 1% of the population, causing
hallucinations, depression and impaired thinking and social behavior.
Cognitive problems typically are a major source of dysfunction and
disability in patients and can be among the earliest symptoms.
born to mothers who develop a severe infection, such as influenza or
pneumonia, during pregnancy have a significantly increased risk of
‘Mutations in TMEM108 gene that should enable memories and a sense of direction instead can result in imprecise communication between neurons that contributes to symptoms of schizophrenia.’
Mutations in a gene that should enable memories and a sense of
direction instead can result in imprecise communication between neurons
that contributes to symptoms of schizophrenia, scientists report.
They found that dramatically reducing the amount of protein
expressed by TMEM108, a gene already associated with schizophrenia,
results in fewer, smaller spines, which work like communication fingers
for neurons, said neuroscientist Dr. Lin Mei.
That translates to an impaired ability for neurons to receive
whatever signals surrounding neurons are trying to send and mice
displaying schizophrenia-like behavioral deficits such as impaired
cognition and sense of direction.
"We knew this gene's alteration likely contributed to schizophrenia
and we wanted to better understand how," said Mei, 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 of the study
in the journal PNAS
While some TMEM108 can be found throughout the central nervous
system, it appears to normally cluster in the dentate gyrus, an area in
the brain's hippocampus known to be critical for spatial coding - which
literally provides a sense of direction - as well as emotion and the
ability to learn and remember, which are all affected in schizophrenia.
Dentate gyrus dysfunction also is implicated in psychiatric disorders,
Focusing on this area of the brain, scientists found that expression
of TMEM108 and its protein normally increased in the first few weeks of
life in a mouse - which would equate to the first few years in a human -
critical periods of development that would enable plenty of mature
spines and great communication between neurons.
"This protein is expressed at the highest level during this critical
period," Mei said. "It was low before; it was not very high afterward."
When they made a mouse that consistently expressed only 20%
of the normal level of TMEM108 protein, including during those critical
development periods, it expressed schizophrenia-like behaviors including
problems with direction and memory. Upon closer examination, they found
the total number of spines on the neurons in the dentate gyrus reduced
and the percentage of immature spines high. To further test their
finding, they added more TMEM108 protein, which restored a more normal
They also found that TMEM108 was critical to the expression of AMPA
receptors on the surface of the neurons. AMPA receptors are activated by
the excitatory neurotransmitter glutamate and are important to both how
spines are shaped and how well neurons receive incoming signals for
The good news about the complex interconnectivity is that the
scientists also were able to find a potential future point of
intervention: When they gave a drug that increased AMPA receptor
expression on the cell surface, the spines assumed a more healthy,
mature state. Next steps include seeing whether the more normal spines
and increased receptor expression translate to healthier behavior in
"Morphologically, the mice can be rescued," Mei said. "We hope we
will find that healthy function is restored as well, which could
translate to a new treatment target for this complex, disabling
Spines are like wiry fingers, and each excitatory neuron has
thousands of spines that capture messages from other excitatory neurons,
which helps enable results from making a memory to vision. In good
health, excitatory neurons and their actions are balanced by inhibitory
neurons. The sheer number of spines on excitatory neurons is one of the
ways our brains can handle so much information, Mei said.
It's a dynamic
process as well, as spines, again in a healthy situation, are
continuously forming and maturing; Mei uses the analogies of
mushroom-like mature spines and bean sprout-like immature ones. In
schizophrenia, too many spines remain in the immature state.
AMPA receptors also play a major role in the development and spread
of seizures and are currently a seizure treatment target. TMEM108
mutations also are associated with alcoholism.