- Awarded: 2014
- Award Type: Explorer
- Award #: 311334
Nerve cells communicate with each other via excitatory and inhibitory signals. Growing evidence supports the hypothesis that a neuronal excitation/inhibition imbalance resulting in increased excitation in certain nerve cells in the brain is sufficient to elicit autism-like symptoms. Uwe Rudolph and his colleagues at McLean Hospital and Harvard Medical School focus on receptors for the major inhibitory neurotransmitter in the central nervous system, gamma-aminobutyric acid (GABA).
The activity of most GABA type-A (GABA-A) receptors (those containing the alpha 1, alpha 2, alpha 3 or alpha 5 subunits) is enhanced by benzodiazepine drugs such as diazepam, which have sedative, antianxiety, anticonvulsant and muscle relaxant properties. These drugs increase the inhibitory action of GABA. Specific physiological and pharmacological functions of GABA-A receptor subtypes, as defined by the presence of a specific alpha subunit, have been identified. For example, GABA-A receptors containing the alpha 1 subunit mediate the sedative action and GABA-A receptors containing the alpha 2 subunit mediate the antianxiety-like action of diazepam in mice.
Recently it has been demonstrated that an extremely low dose of the benzodiazepine clonazepam can revert social interaction and cognitive deficits in mice lacking a copy of the SCN1A gene, which are a model of Dravet syndrome (severe myoclonic epilepsy of infancy)1. Rudolph’s group plans to test whether low-dose clonazepam can correct autism-like deficits in the CNTNAP2-deletion mouse model of cortical dysplasia-focal epilepsy syndrome, a syndromic form of autism.
In addition, the group plans to test whether an experimental compound called L-838,417, which enhances GABAergic neurotransmission only at GABA-A receptors containing the alpha 2, alpha 3 or alpha 5 subunits, corrects autism-like deficits in the same mouse model. L-838,417 lacks sedative properties and has a reduced abuse liability in rodents and primates compared with benzodiazepines.