"Although previous studies of Huntington’s disease (HD) have addressed many potential mechanisms of striatal neuron dysfunction and death, it is also known based on clinical findings that cortical function is dramatically disrupted in HD. With respect to disease etiology, however, the specific molecular and neuronal circuit bases for the cortical effects of mutant huntingtin (htt) have remained largely unknown.
In the present work we studied the relation between the molecular effects of mutant htt fragments in cortical cells and the corresponding behavior of cortical neuron microcircuits using a novel cellular model of HD. We observed that a transcript-selective diminution in activity-dependent BDNF expression preceded the onset of a synaptic connectivity deficit in ex vivo cortical networks, which manifested as decreased spontaneous collective burst-firing behavior measured by multi-electrode array substrates. Decreased BDNF expression was determined to be a significant contributor to network-level dysfunction, as shown by the ability of exogenous BDNF to ameliorate cortical microcircuit burst firing.
The molecular determinants of the dysregulation of activity-dependent BDNF expression by mutant htt appear to be distinct from previously elucidated mechanisms, as they do not involve known NRSF/REST-regulated promoter sequences, but instead result from dysregulation of BDNF exon IV and VI transcription. These data elucidate a novel HD-related deficit in BDNF gene regulation as a plausible mechanism of cortical neuron hypoconnectivity and cortical function deficits in HD. Moreover, the novel model paradigm established here is well-suited to further mechanistic and drug screening research applications.
A simple mathematical model is proposed to interpret the observations and to explore the impact of specific synaptic dysfunctions on network activity. Interestingly, the model predicts a decrease in synaptic connectivity to be an early effect of mutant huntingtin in cortical neurons, supporting the hypothesis of decreased, rather than increased, synchronized cortical firing in HD."
Gambazzi L, Gokce O, Seredenina T, Katsyuba E, Runne H, Markram H, Giugliano M, Luthi-Carter R (2010) Diminished activity-dependent brain-derived neurotrophic factor expression underlies cortical neuron microcircuit hypoconnectivity resulting from exposure to mutant huntingtin fragments. J Pharmacol Exp Ther 335:13-22 [PubMed]