Newsdesk

http://neurology.thelancet.com Vol 5 April 2006 299

family, the mutation created a malfunction in the potassium channels, causing them to open earlier than normal and close too late. Conversely, in the Filipino family, the mutation prevented the potassium channel from functioning at all (Nat Genet 2006; published online Feb 26. DOI:10.1038/ng1758).

The KCNC3 gene encodes the voltage-gated Shaw channel, which is important for the properties of bursting neurons. Alterations occur in the expression patterns of potassium channels in Huntington’s, Parkinson’s, and Alzheimer’s disease, and neuro-

physiological studies of bursting neurons have implicated voltage-gated potassium channels in human neurodegenerative diseases.

The results of this study show that mutations in the KCN3 channels are suffi cient to cause neurodegeneration, and the researchers suggest that these channels be assessed as mutational and therapeutic targets in bursting neurons in the hippocampus and substantia nigra in conjunction with diseases such as Alzheimer’s.

“The current paradigm is heavily focused on looking at folded proteins”, says Pulst. “This opens up a whole

new class of proteins that can cause neurodegenerative disease or con-tribute to it.”

These fi ndings are likely to stimulate the search for additional mutations in the KCNC3 gene, comments Bernardo Rudy (New York University, NY, USA). “The two mutations found so far occurred in amino acid positions that were already known to be functionally important. It is likely that new mutations will be discovered that will highlight domains of Kv3.3 channels that have not been a focus of interest.”

Roxanne Nelson

Ghrelin is known to aff ect pituitary hormone secretion, appetite, meta-bolism, gastrointenstinal function, and the cardiovascular and immune systems. Now, a team of researchers led by Tamas Horvath (Yale University School of Medicine, CT, USA) reveal an endogenous function of ghrelin that links metabolic control with spatial learning and memory.

Neuronal plasticity within the hippocampal formation has been associated with spatial learning and memory development. Together with the observation that growth hormone secretagogue receptors, or ghrelin receptors, are present in the hippocampal formation, this information “raised the question of whether ghrelin would bind and enter the hippocampus, and whether its presence there indicates that it has a physiologic role in altering neuronal morphology and associated hippo-campal functions”, explains Horvath. Although the eff ect of ghrelin on memory performance has been suggested before, “the authors have extended these data about the eff ect of ghrelin on memory using diff erent experimental approaches”, Susana R de Barioglio (Universidad Nacional de Córdoba, Córdoba, Argentina) told The Lancet Neurology.

Horvath and colleagues analysed the presence of radiolabelled human ghrelin in various parts of mouse brains after peripheral injection. “Our results revealed that circulating ghrelin enters the hippocampal formation”, says Horvath. Furthermore, the distribution of labelled cells and processes suggested that ghrelin binds to processes of hippocampal neurons.

The researchers analysed hippocam-pal tissue from animals that received peripheral administration of either synthetic ghrelin or saline. Assessment of the density of axospinal synapses in the CA1 region of the hippocampus showed that spine synapse density was signifi cantly higher in ghrelin-treated animals than in controls.

In parallel with the changes in synapse number and increased ghrelin concentrations, various behavioural tests known to be dependent, at least in part, on the hippocampus showed enhanced performance of the animals. Horvath’s team used ghrelin-knockout mice to confi rm these data. Mice that lacked ghrelin had fewer spine synapses and underperformed in novel object recognition tests compared with their wild-type littermates. However, ghrelin administration rapidly restored this impairment, indicating that the hormone aff ects

neuronal morphology of brain areas known to be responsible for learning performance and memory function.

These fi ndings “raise the possibility of therapeutic uses of the peptide or its agonists in neurological diseases”, suggests de Barioglio. For example, orally active ghrelin analogues could off er a potential treatment for impaired learning and memory processing that occurs in association with ageing and neurological disorders such as Alzheimer’s disease.

Laura Thomas

An appetite for learning

Ghrelin-like drugs could protect against dementia

Shei

la Te

rry/S

cienc

e Ph

oto

Libr

ary

Rights were not granted to include this image in

electronic media. Please refer to the printed journal.