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Final Report Summary - GABASYNAPSES (Local interactions between GABAergic and glutamatergic plasticity)

Throughout lifetime a proper balance between excitation and inhibition is crucial for a healthy brain. There are well-known neurodevelopmental diseases, such as autism or schizophrenia, in which this balance is disturbed. It is currently not well understood how the balance between excitation and inhibition is regulated in the brain. One intriguing possibility is that glutamatergic and GABAergic synaptic plasticity are not regulated separately, but somehow interact to maintain the balance.

In our research we have examined interactions between inhibitory and excitatory synapses within dendrites.

To examine the influence of excitatory activity on inhibitory plasticity, we studied structural adaptations in inhibitory axons in hippocampal organotypic cultures. We used time-lapse two-photon microscopy to follow changes of presynaptic boutons along GFP-labelled inhibitory axons under baseline conditions and during enhanced or reduced activity. We used post-hoc immunostaining to assess the synaptic nature of the imaged boutons. Our data show that inhibitory synapses are highly dynamic structures, which are continuously being assembled and disassembled and possibly compete with each other along the inhibitory axon. The axons are continuously sampling potential locations for new inhibitory synapses, ‘testing’ new connections and axons adjust their sampling behaviour in response to changes in neuronal activity. These new insights in the structural dynamics of inhibitory axons paint a highly dynamic picture of inhibition and inhibitory plasticity in neuronal networks.

In addition we have established an experimental configuration to examine the effect of individual, identified inhibitory synapses on nearby excitatory synapses within dendrites. We made paired recordings from a CA1 pyramidal cell and a connected interneuron and identified dendritic inhibitory contacts with two-photon microscopy. In this configuration we have experimental control of identified inhibitory synapses within the dendrites of pyramidal cells. Dendritic calcium signals are important determinants of plasticity at excitatory synapses. We determined the influence of individual inhibitory synapses on dendritic calcium signals during postsynaptic action potentials. We found that inhibition strongly depended on the distance and time interval between inhibition and excitation, which suggests that dendritic inhibitory synapses can affect local excitatory plasticity with high spatial and temporal specificity.

Our research results have been presented on international scientific meetings and have led to several publications in peer-reviewed journals. During the course of the ERG grant, the principal investigator, Corette Wierenga, has moved from the Max Planck Institute of Neurobiology in Martinsried (D) to the Utrecht University (NL). She received a VIDI starting grant from the Dutch Organisation for Scientific Research (NWO) and has now a permanent position as Assistant Professor. She will continue her research on interactions between excitatory and inhibitory synapses and their role in neurodevelopmental disorders.

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