A New Therapeutic Approach For Huntington’s Disease Found

Huntington’s disease is associated with a genetic anomaly characterized by excessive repeats of the trinucleotide CAG in the huntingtin (Hdh) gene. This leads to disease progression that eventually encompasses a wide range of severe motor disturbances and cognitive deficits. Among the early symptoms are learning impairments. Researchers at the University of California – Irvine used this observation to study the effect of brain-derived neurotrophic factor (BDNF), a positive modulator of memory encoding, during the onset of Huntington’s disease.

Hippocampal slices were prepared from two mouse models that have 92 and 111 CAG repeats inserted into the huntingtin gene, as well as from wild-type mice. Electrophysiological traits of neurons in these slices, which were taken prior to the onset of motor disturbances, found no discernable differences with low-frequency stimulation or with paired-pulse facilitation, which tests for neurotransmitter mobilization. However, the HD knock-in mice differed from the controls following theta burst stimulation (TBS), which mimics the natural events leading to long-term potentiation (LTP) and memory formation. TBS elicited a muted initial response from the HD knock-in mice, which then decayed more rapidly than observed in the wild-type animals. Moreover, the rate of decay was consistently faster in the mutant models, regardless of the intensity of the initial response. Thus, the abnormal huntingtin gene severely impairs the stabilization of LTP.

A key response to TBS is actin polymerization in dendritic spines, since that serves to stabilize the potentiated state. To examine the effect of TBS on this step in the memory formation process, rhodamine-conjugated phalloidin was used to stain the hippocampal slices after stimulation, for subsequent histochemical analyses. (Phalloidin is a toxin that binds specifically to polymeric actin.) The results show that excessive repeats of CAG in the huntingtin gene are associated with markedly lower (five-fold) actin polymerization.

One of the characteristics of Huntington’s disease is abnormally low levels of BDNF and its TrkB receptor in the neocortex and hippocampus. The two mouse models used in this study exhibited a similar BDNF deficit. Infusion of the neurotrophin for 60 minutes prior to electrophysiological testing had no impact on baseline activity in either mutant or wild-type tissue slices. However, it did significantly alter the response to TBS by the HD knock-in mice, while having no effect on the wild-type mouse. BDNF fully restored LTP and significantly elevated the level of dendritic actin polymerization in the HD models.

The results suggest that BDNF may prove valuable as a therapy for Huntington’s disease, although attempts to deliver it have met with limited success. Thus, the latest study sets the stage for another avenue. Ampakines, which have been found to increase the levels of BDNF in the hippocampus, might afford a new therapeutic approach.

Message posted by: Keith Markey