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The neurotrophic factors brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) have been shown to promote excitatory and inhibitory synapse development. However, a quantitative analysis of their influence on connectivity has proven in general difficult to achieve. In this work we use a novel experimental approach based on percolation concepts that provides a quantification of the average number of connections per neuron. In combination with electrophysiological measurements, we characterize the changes in network connectivity induced by BDNF and NT-3 in rat hippocampal cultures. We show that, on the one hand, BDNF and NT-3 accelerate the maturation of connectivity in the network by about 17 h. On the other hand, BDNF and NT-3 increase the number of excitatory input connections by a factor of about two, but without modifying the number of inhibitory input connections. This scenario of a dominant effect on the excitation is supported by the analysis of spontaneous population bursts in cultures treated with either BDNF or NT-3, which show burst amplitudes that are insensitive to the blockade of inhibition. A leaky integrate-and-fire model reproduces the experimental results well.

We investigate the propagation of neural activity along one-dimensional rat hippocampal cultures patterned in lines over multielectrode arrays. Activity occurs spontaneously or is evoked by local electrical or chemical stimuli, with different resulting propagation velocities and firing rate amplitudes. A variability of an order of magnitude in velocity and amplitude is observed in spontaneous activity. A linear relation between velocity and amplitude is identified. We define a measure for neuron activation synchrony and find that it correlates with front velocity and is higher for electrically evoked fronts. We present a model that explains the linear relation between amplitude and velocity, which highlights the role of synchrony. The relation to current models for signal propagation in neural media is discussed.

Jacobi S, Soriano J, Moses E. BDNF and NT-3 increase velocity of activity front propagation in unidimensional hippocampal cultures. J Neurophysiol 104: 2932-2939, 2010. First published July 28, 2010 doi:10.1152/jn.00002.2010. Neurotrophins are known to promote synapse development as well as to regulate the efficacy of mature synapses. We have previously reported that in two-dimensional rat hippocampal cultures, brain-derived neurotrophic factor (BDNF) and neurotrophin-3 significantly increase the number of excitatory input connections. Here we measure the effect of these neurotrophic agents on propagating fronts that arise spontaneously in quasi-one-dimensional rat hippocampal cultures. We observe that chronic treatment with BDNF increased the velocity of the propagation front by about 30%. This change is attributed to an increase in the excitatory input connectivity. We analyze the experiment using the FeinermanGolomb/Ermentrout-Jacobi/Moses-Osan model for the propagation of fronts in a one-dimensional neuronal network with synaptic delay and introduce the synaptic connection probability between adjacent neurons as a new parameter of the model. We conclude that BDNF increases the number of excitatory connections by favoring the probability to form connections between neurons, but without significantly modifying the range of the connections (connectivity footprint). I N T R O D U C T I O NNeurotrophins such as brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) play important roles in neural development and survival. In particular, they were shown to play a critical role in controlling axonal and dendritic growth as well as maintenance of synaptic efficacy (Baker et al. 1998; Bartrup et al. 1997; Bolton et al. 2000; Labele and Leclerc 2000;Morfini et al. 1994;Vicario-Abejon et al. 1998). However, the majority of previously reported effects of the neurotrophins focused on the local changes that they induce in neuron morphology or synaptic connection strength. We have recently shown that in two-dimensional (2D) rat hippocampal cultures, neurotrophins also induce global changes in neural network connectivity (Jacobi et al. 2009). In particular, exposure to BDNF increased excitatory input connectivity, but without modifying the inhibitory connectivity, and that resulted in spontaneous activity bursts whose amplitude was insensitive to the blocking of inhibition.To further assess the relation between neurotrophic effects and neural connectivity, we consider here quasi-one-dimensional (1D) neural cultures, where neural activity propagation is restricted to a single path. One-dimensional neural cultures have emerged in the last years as versatile culturing platforms to investigate the relation between neuronal connectivity, signal propagation, and information coding (Feinerman et al. 2005;Golomb and Ermentrout 1999;Jacobi and Moses 2007;Osan and Ermentrout 2002). The key feature of 1D cultures is that the velocity of activity fronts depends on neural connectivity and specifically on both the synaptic ...

Eytan and Marom [1] recently showed that the spontaneous burst activity of rat neuron cultures includes 'first to fire' cells that consistently fire earlier than others. Here we analyze the behavior of these neurons in long term recordings of spontaneous activity of rat hippocampal and rat cortical neuron cultures from three different laboratories. We identify precursor events that may either subside ('small events') or can lead to a full-blown burst ('pre-bursts'). We find that the activation in the pre-burst typically has a first neuron ('leader'), followed by a localized response in its neighborhood. Locality is diminished in the bursts themselves. The long term dynamics of the leaders is relatively robust, evolving with a halflife of 23-34 hours. Stimulation of the culture can temporarily alter the leader distribution, but it returns to the previous distribution within about 1 hour. We show that the leaders carry information about the identity of the burst, as measured by the signature of the number of spikes per neuron in a burst. The number of spikes from leaders in the first few spikes of a precursor event is furthermore shown to be predictive with regard to the transition into a burst (pre-burst versus small event). We conclude that the leaders play a rôle in the development of the bursts, and conjecture that they are part of an underlying sub-network that is excited first and then act as nucleation centers for the burst.