Behavioural abnormalities are traditionally thought to
originate in the brain. But a new study by researchers at Albert Einstein
College of Medicine of Yeshiva University has found that inner-ear dysfunction
can directly cause neurological changes that increase hyperactivity.
The study, conducted
in mice, also implicated two brain proteins in this process, providing
potential targets for intervention. The findings were published today in the
online edition of Science.
For years, scientists have observed that many children and
adolescents with severe inner-ear disorders, particularly disorders affecting
both hearing and balance also have behavioural problems, such as hyperactivity.
Until now, no one has been able to determine whether the ear disorders and
behavioural problems are actually linked.
"Our study provides the first evidence that a sensory
impairment, such as inner-ear dysfunction, can induce specific molecular
changes in the brain that cause maladaptive behaviours traditionally considered
to originate exclusively in the brain," said study leader Jean M. Hébert,
PhD, professor in the Dominick P. Purpura Department of Neuroscience and of
genetics at Einstein.
The inner ear consists of two structures, the cochlea (responsible
for hearing) and the vestibular system (responsible for balance). Inner-ear
disorders are typically caused by genetic defects but can also result from
infection or injury.
The idea for the study arose when Michelle W. Antoine, a PhD
student at Einstein at the time, noticed that some mice in Dr Hébert's laboratory
were unusually active – in a state of near-continual movement, chasing their
tails in a circular pattern.
Further investigation revealed that the mice had severe
cochlear and vestibular defects and were profoundly deaf. "We then realised
that these mice provided a good opportunity to study the relationship between
inner-ear dysfunction and behaviour," said Dr Hébert.
The researchers established that the animals' inner-ear
problems were due to a mutation in a gene called Slc12a2, which mediates the
transport of sodium, potassium, and chloride molecules in various tissues,
including the inner ear and central nervous system (CNS). The gene is also
found in humans.
To determine whether the gene mutation was linked to the
animals' hyperactivity, the researchers took healthy mice and selectively
deleted Slc12a2 from either the inner ear, various parts of the brain that
control movement or the entire CNS. "To our surprise, it was only when we
deleted the gene from the inner ear that we observed increased locomotor
activity," said Dr Hébert.
The researchers hypothesised that inner-ear defects cause
abnormal functioning of the striatum, a central brain area that controls
movement. Tests revealed increased levels of two proteins involved in a
signalling pathway that controls the action of neurotransmitters: pERK
(phosphorylated extracellular signal-regulated kinase) and pCREB (phospho-cAMP
response-element binding protein), which is further down the signaling pathway
from pERK. Increases in levels of the two proteins were seen only in the
striatum and not in other forebrain regions.
To discover whether increased pERK levels caused the
abnormal increase in locomotor activity, Slc12a2-deficient mice were given
injections of SL327, a pERK inhibitor. Administering SL327 restored locomotor
activity to normal, without affecting activity levels in controls.
The SL327 injections
did not affect grooming, suggesting that increased pERK in the striatum
selectively elevates locomotor activity and not general activity. According to
the researchers, the findings suggest that hyperactivity in children with
inner-ear disorders might be controllable with medications that directly or
indirectly inhibit the pERK pathway in the striatum.
"Our study also raises the intriguing possibility that
other sensory impairments not associated with inner-ear defects could cause or
contribute to psychiatric or motor disorders that are now considered
exclusively of cerebral origin," said Dr Hébert. "This is an area
that has not been well studied."