Small molecules open gates to the brain

New tools have been developed which make it possible to chemically shut down nerve cells in the brain at will and study the effects on behaviour. The tools - modified ion channels - mean the causal relationship between individual nerves and behaviour can be directly studied. 

Nerve cells maintain their electrical potentials by building up charge gradients with ions like sodium and calcium. The movement of the ions across nerve membranes is controlled by ligand-gated ion channels (LGICs), so these make interesting handles for controlling nerve function. Upon binding of a small molecule, channels in LGICs open allowing ions to flow into cells - propagating a nerve signal. 

There have been attempts to manipulate LGICs by controlled exposure to agonists before, but it’s difficult. There are problems with getting drug-like molecules to cross the blood-brain barrier and, even if that’s achieved, slow response times often make rigorous behavioural studies impossible. Molecules, such as acetylcholine, do lots of different jobs in the brain, so it’s also usually hard to target specific LGICs without affecting other parts of the brain.

Scott Sternson and colleagues from the Howard Hughes Medical Institute (HHMI), US, have come up with a way of tackling this problem. They looked into modifying the ligand binding domain of the LGIC so that it binds to completely new molecules not normally found in the brain. This avoids activating other LGICs and associated side effects.

Sternson’s team chose to start with a quinuclidinyl benzamide derivative as their model agonist as it is lipophilic enough to enter the brain and binds to acetylcholine sensitive LGICs. They then made a library of analogues of this molecule and created three new LGICs that responded to these chemicals. 

’The biological questions we’re interested in revolve around the neural mechanisms which motivate hunger,’ says Sternson, ’so we will be using [these tools] to test the causal relationship between neural activity and that.’ 

In a proof of concept experiment, Sternson delivered the new LGICs to specific sites in mouse brains using either genetic modification or viral vectors. The nerves he chose are implicated in hunger, and when activated caused an extreme hunger response and voracious eating. However, on dosing with ligands complementary to the new LGICs, the mice stopped feeding. Holding the LGICs open stops the signal to eat more from getting through to the brain.

Although Sternson is currently studying hunger specifically, he says he ’wanted to devise a very general solution for manipulating neurones’. Although delivery of the tools to specific sites in the brain is sometimes tricky, they could potentially be used to silence a range of neural pathways and assess the behavioural impacts.

Hagan Bayley, professor of chemical biology at Oxford University, UK, says the work has been ’expertly executed at every stage,’ and that these ’engineered LGICs are certain to be extremely useful tools for many aspects of neuroscience, especially for behavioural studies in transgenic animals. [They] may also have additional applications in biotechnology: for example, as sensors of small molecules.’ 

Josh Howgego