The dendritic architecture determines the inputs in a neuron and its role in the neuronal circuitry. Dendritic arbors are highly dynamic structures, branching and retracting in response to the information received, and stabilized and maintained mainly by postsynaptic signaling.
The so-called dendritic pathologies are a number of diseases that share a feature of neuronal dendritic abnormalities (reviewed in Kaufmann and Moser, 2000). These include changes in dendrite branching patterns, fragmentation of dendrites, retraction or loss of dendrite branching, and changes in spine morphology and number. Dendritic spines are small membranous protrusions from a dendrite with spine head volumes ranging 0.01 μm3 to 0.8 μm3. Spines with strong synaptic contacts typically have a large spine head, which connect to the dendrite via a membranous neck. The most notable classes of spine shapes are “thin”, “stubby”, “mushroom” and “wide”: thin spines have a smaller head and a narrow neck; stubby spines have no obvious constriction between the head and the attachment to the shaft; mushroom spines have a large head and a narrow neck; and wide spines are short in length and characterized by a large neck and a large spine head. Electron microscopy studies have shown that there is a continuum of shapes between these categories. The variable spine shape and volume is thought to be correlated with the strength and maturity of each spine-synapse: the thin and stubby types are considered to be immature forms whereas the mushroom and wide types are considered to be mature forms of spines.
Dendritic abnormalities and specially alterations in dendritic spines have been reported to contribute to several conditions associated with mental retardation, such as Down syndrome (Martinez de Langran, 2012), Angelman syndrome (Dan, 2009; Baudry et al., 2012) and Rett syndrome and to other neurological diseases, such as tuberous sclerosis (Machado-Salas, 1984; Tavazoie et al., 2005 (Chapeau et al., 2009).
The treatment of these dendritic pathologies has been addressed through different approaches without success so far. Treatment of genetic diseases causing mental retardation is mainly focussed on controlling symptoms and any medical conditions derived from said diseases. However, in the last years important efforts have been made to develop therapies targeted to those genes or proteins that have been found to be altered in these conditions. Thus, for example, some studies have shown that restoring MECP2 function, especially by the use of insulin-like growth factor 1 (IGF-1) may be a promising therapy for Rett syndrome. The molecule RG1662, which is an inverse agonist of the GABA-A receptor, a major inhibitory gateway in neuron circuitry, is now under phase I clinical trial in individuals with Down syndrome. Similarly, the mTOR inhibitor rapamycin, which has been found to improve brain function and reduce tumor size in a mouse model of tuberous sclerosis, in under clinical trials.
However, none of these novel therapies has at present proved to fully manage the disease. Therefore, there is still a need in the art for new methods of treatment for diseases associated with neuronal dendritic abnormalities.