Abstract
The modulation of neuronal activity by means of electrical stimulation is a successful therapeutic approach for patients suffering from a variety of central nervous system disorders. Prototypic networks formed by cultured cortical neurons represent an important model system to gain general insights in the input–output relationships of neuronal tissue. These networks undergo a multitude of developmental changes during their maturation, such as the excitatory–inhibitory shift of the neurotransmitter GABA. Very few studies have addressed how the output properties to a given stimulus change with ongoing development. Here, we investigate input–output relationships of cultured cortical networks by probing cultures with and without functional GABAAergic synaptic transmission with a set of stimulation paradigms at various stages of maturation. On the cellular level, low stimulation rates (<15 Hz) led to reliable neuronal responses; higher rates were increasingly ineffective. Similarly, on the network level, lowest stimulation rates (<0.1 Hz) lead to maximal output rates at all ages, indicating a network wide refractory period after each stimulus. In cultures aged 3 weeks and older, a gradual recovery of the network excitability within tens of milliseconds was in contrast to an abrupt recovery after about 5 s in cultures with absent GABAAergic synaptic transmission. In these GABA deficient cultures evoked responses were prolonged and had multiple discharges. Furthermore, the network excitability changed periodically, with a very slow spontaneous change of the overall network activity in the minute range, which was not observed in cultures with absent GABAAergic synaptic transmission. The electrically evoked activity of cultured cortical networks, therefore, is governed by at least two potentially interacting mechanisms: A refractory period in the order of a few seconds and a very slow GABA dependent oscillation of the network excitability.
Highlights
To date electrical stimulation of neuronal structures has become an important therapy for patients suffering from central nervous system disorders such as Parkinson’s disease, epilepsy and deafness [for review see for example Clark (2006), Kringelbach et al (2007), Kipke et al (2008), Moore and Shannon (2009), Lenarz et al (2013)]
We favored gabazine for the chronic blockade, as in experiments where we acutely blocked GABA receptor type A (GABAAR) with bicuculline (5 μM) the network activity recovered from hyper synchronous activity to more clustered and asynchronous activity after washing out the substance, whereas washing out gabazine was more difficult in our hands
We focused on the alterations of these input– output relationships during the maturation as a result of impaired GABAAergic synaptic transmission
Summary
To date electrical stimulation of neuronal structures has become an important therapy for patients suffering from central nervous system disorders such as Parkinson’s disease, epilepsy and deafness [for review see for example Clark (2006), Kringelbach et al (2007), Kipke et al (2008), Moore and Shannon (2009), Lenarz et al (2013)]. Fast GABAergic synaptic transmission, if mature, enables the network to respond to stimuli of higher rates, but with a reduced number of spikes compared to the responses of cultures with blocked GABAARs. This issue is investigated further .
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