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Zusammenfassung:
Various brain regions have distinct and highly conserved ratios of
excitatory and inhibitory neurons. For instance, cerebral cortex typically
includes around 20% of inhibitory neurons. However, it is not
clear whether unphysiological ratios would change collective neuronal
dynamics or jeopardize the balance of excitation and inhibition
on a synaptic level. To investigate this question, we developed a platform
that allowed us to culture hippocampal networks with various
fractions of inhibitory neurons. We also study how cellular composition
affects neuronal dynamics in finite network models with balanced
excitation/inhibition currents and neuronal adaptation.
We used fluorescence-activated cell sorting to isolate inhibitory
and excitatory neurons and seeded them while keeping prescribed
inhibitory percentages. We recorded the calcium dynamics
of these cultures. All of them developed spontaneous network activity
manifested in full network bursts. The cultures with 10–80% of
inhibitory cells showed surprisingly similar mean inter-burst intervals,
which were indistinguishable from unsorted control cultures that usually
contain 20–30% of inhibitory neurons. Fully excitatory and fully inhibitory cultures had significantly longer inter-burst intervals. The
coefficient of variation of inter-burst intervals grew with the number
of inhibitory neurons.
To model the observed effects, we developed a set of networks
with various fractions of excitatory and inhibitory neurons. The networks
were comprised of adaptive leaky integrate-and-fire neurons
driven by slow Poisson input. The relative strength of inhibitory and
excitatory synapses was kept at balance. The model showed that the
stable mean but increasing variance of inter-burst intervals can be
achieved by the balance of excitation and inhibition that regulates
effects of the adaptation. In a fully excitatory network, inter-burst
intervals are determined by the adaptation alone. Adding inhibition
to the network results in stopping bursts before the adaptation completely
silences the activity. This, in turn, allows the next burst to start
earlier, leading to shorter inter-burst intervals with higher variance.
To further compare the behavior of the model and cultures, we disrupted
the excitation/inhibition balance by decreasing the strength of
inhibitory synapses. In the experimental setup, this corresponded to
the application of bicuculline. In the cultures with 10–80% of inhibitory
neurons application of bicuculline led to prolonged interburstintervals
and decreased variability. Under maximum concentration,
the activity of these cultures was generally similar to the fully excitatory
cultures. Similarly, in the model, blocking of inhibition resulted in
stronger adaptation after a burst that led to longer and less variable
inter-burst intervals.
Overall, our results suggest that developed hippocampal cultures with
artificial cellular excitatory and inhibitory composition tend to maintain
the excitation/inhibition balance. This result in a constant mean
activity but a growing variability of bursting in cultures with increasing
numbers of inhibitory neurons.
