Fast gabaergic neurotransmission inhibits diversely AMPA and NMDA receptor mediated network dynamics in cortical cultures: A model-driven experimental study

Network burst activity promoted by neuronal populations plays a fundamental role in the formation of a functional network during early development of the neocortex [1]. The synchronous periodic patterns of activity are observed in cerebral cortex in vivo, in cortical slice preparations in vitro, and in dissociated in vitro cortical cell cultures [1,2]. In dissociated cell cultures, the network burst (NB) activity is driven by excitatory neurotransmission, which is primarily mediated by the action of glutamate on two types of glutamatergic ionotropic receptors AMPA and NMDA. Inhibitory neurotransmission is mediated by the action of GABA on GABAergic receptors. GABAergic neurotransmission is thought to control the dynamic pattern formation in neuronal networks by organizing spatially and temporally the network activity rather than only reducing firing probability. The complex interplay and contribution of the excitatory and inhibitory receptors emerging on the level of network dynamics is, however, not well understood [3].

The aim of this study is to examine the diverse role of fast GABAA receptors on shaping the fast AMPA receptor and the slow NMDA receptor mediated recurrent excitatory neurotransmission in initiating, maintaining and terminating the network wide bursts dynamics in three weeks’ old dissociated postnatal rat cortical cultures. In order to study the role of GABAA receptors on AMPA and NMDA receptor driven network burst (NB) structures, the extracellular activity was systematically recorded with microelectrode array technique under several combinations of receptor antagonists such as I. mature control cultures without pharmacology, II. with partial AMPA receptor suppression (NBQX), III. with partial NMDA receptor suppression (D-AP5), IV. with GABAA receptor suppression (PTX), V. disinhibited cultures from II with PTX, and VI. disinhibited cultures from III with PTX. The NB structures are analyzed as burst measures from the detected NBs such as burst length, rising and falling phase, maximum firing rate and burst-size as well as the electrode recruitment at time.

We show the diverse actions of GABAA receptors on shaping the NB structure and overall network dynamics. The action of GABA is shown to dampen the termination of the slowly recruited NBs in NMDA mediated cultures and to dampen the initiation of faster recruited NBs in AMPA mediated NBs in cultures at the end of the third week in vitro. The here presented results can be used to fine-tune data-driven computational network level models of in vitro cell cultures. Well-validated network models can help address the altered involvement of excitatory and inhibitory receptors in cognitive disorders such as schizophrenia and Alzheimer’s disease.