This entry to the ModelDB is associated to the paper entitled "Diminished activity-dependent BDNF expression underlies cortical neuron microcircuit hypoconnectivity resulting from exposure to mutant huntingtin fragments", authored by Luca Gambazzi, Ozgun Gokce, Tamara Seredenina, Elena Katsyuba, Heike Runne, Henry Markram, Michele Giugliano and Ruth Luthi-Carter. The model has been developed and implemented by Michele Giugliano (mgiugliano@gmail.com) Abstract: 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. Model information: The model provided here is an ANSI-C source code, intended to be compiled with "gcc" (native under Linux, by CygWin under Windows, by Xcode under Mac OsX). The source code is fully commented and rather simple to grasp, with the aim of providing a useful reference to the interested user. The software is intended (when compiled) to be invoked by some scripting language (e.g. Matlab, or Octave). Libraries and includes are provided. Matlab scripts for data analysis are also provided and commented. The simulation is launched by (Matlab) scripts (analysis*.m), which provide a means to plot results as wells. ---------------------------------------------------------------------------- How to compile the code (from a 'shell' / 'terminal window' / et similia): (see also the source code at /giugliano/source/meanfield.c) Let's assume the present working directory is 'giugliano (i.e. > pwd, returns ..../giugliano) compile by > " gcc -o meanfield source/meanfield.c -lm -O" ---------------------------------------------------------------------------- How to launch the simulation (from a 'shell' / 'terminal window' / et similia): Let's assume the present working directory is 'giugliano (i.e. > pwd, returns ..../giugliano) invoking the program with no input "meanfield" returns the usage.. USAGE: ./meanfield T N C I mext sext Use where T is the life time of the simulation N is the number of (excitatory) neurons C is the probability of random pairwise connection I is the mean synaptic efficacy mext, sext are statistical parameters related to the spontaneous synaptic release Use is the the release probability of short-term (facilitating and) depressing synapses Please refer to the published Supplemental Methods and to references therein, or contact the authors. ---------------------------------------------------------------------------- How to 'play' with the parameters and extract meaningful information: see the way 'schedule_simulation_example.m' is coded.. Michele Giugliano, PhD