Breakthrough in drug therapy for
28 June, 2007:
An international team, including
Indian neuroscientists, has, for the
first time, reversed symptoms of
mental retardation and autism in mice.
The breakthrough raises hopes of drug
therapy for this disorder that affects
one in 500 children.
Researchers at the National Centre for
Biological Sciences (NCBS) and the
National Institute of Mental Health
and Neuroscience (NIMHANS) in
Bangalore, India, have contributed to
the new finding, according to the
proceedings of the National Academy of
Sciences of the United States.
Scientists at the Massachusetts
Institute of Technology (MIT) in the
United States and Seoul National
University in South Korea are part of
Autism is a developmental disorder
characterised by varying degrees of
deficiencies in communication skills
and social interactions, along with
restricted, repetitive and stereotyped
patterns of behaviour.
A strain of mice, genetically
engineered by Nobel laureate Susumu
Tonegawa and colleagues at the
Massachusetts Institute of Technology,
were manipulated to model ‘fragile X
syndrome (FXS)’ – the leading
inherited cause of mental retardation
and the most common genetic cause of
According to researcher Sumantra
Chatterji at the National Centre for
Biological Sciences, the condition,
tied to a mutated gene in the X
chromosome, causes mild learning
disabilities to severe autism. At
present there is no effective
treatment for FXS and other types of
autism affecting all races and ethnic
groups, Chatterji said.
Chatterji said the team’s findings
have identified a specific enzyme in
the brain, called p21-activated kinase
(PAK), as a potential target for drugs
that may reverse many of the
debilitating symptoms of FXS, and
possibly autism, in children. The
enzyme PAK affects the number, size
and shape of connections between
neurons in the brain.
In the brain, these connections
between neurons are formed by small
protrusions called ‘spines’ which are
spread on branches of neurons called
‘dendrites.’ The numbers and shapes of
dendritic spines are crucial for
normal brain function.
FXS patients have higher numbers of
dendritic spines in their brains, but
each spine is longer and thinner than
in normal individuals.
The team’s analysis showed that
inhibition of PAK activity reverses
the structural abnormality of neuronal
connections seen in FXS mice.
In addition to structural problems,
these abnormal connections between
neurons transmit weaker electric
signals in FXS mice.
Blocking PAK activity also helped
restore electrical signalling between
neurons in the brains of the FXS mice,
The FXS mice also exhibit abnormal
behavioural symptoms like
hyperactivity, purposeless, repetitive
movements and learning difficulties
commonly seen in autistic patients.
These behavioural problems are also
ameliorated in the FXS mice with
reduced PAK activity. The cutting-edge
genetic engineering techniques used by
the collaborators at the MIT created a
unique situation where PAK activity
was blocked only after the
debilitating symptoms of FXS had
already taken hold in the mice.
“That PAK inhibition can reverse
pre-existing symptoms of FXS is very
good news for future design of drugs
for treating fragile X in kids,”
according to Chatterji.
There are known chemical compounds
that inhibit the activity of PAK.
These compounds or new ones targeted
at PAK may greatly facilitate future
development of drugs against FXS, and
possibly autism as well.