GABASYNAPSES

Local interactions between GABAergic and glutamatergic plasticity

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 Obiettivo del progetto (Objective)

'Throughout lifetime a proper balance between excitation and inhibition is crucial for a healthy brain. How exactly this balance between excitation and inhibition is regulated in the brain is not well understood. One intriguing possibility is that glutamatergic and GABAergic synaptic plasticity are not regulated separately, but somehow interact to maintain this balance. In the work proposed here we intend to examine whether plasticity of inhibitory and glutamatergic synapses interact with each other on a very local scale, i.e. within the dendrite. My research has two main objectives. (1) I ask whether excitation affects plasticity of inhibitory axons. I propose to examine at what spatial scale excitatory activity can affect turnover of GABAergic boutons. The area of activity manipulation will be systematically decreased (ranging from global manipulations to activation of individual dendritic inputs) and we will examine how these manipulations affect the formation and loss of GABAergic boutons at the site of manipulation. (2) I propose to examine how local inhibitory synaptic activity affects nearby plasticity of excitatory synapses. Potentiation at individual excitatory synapses will be induced by a glutamate uncaging protocol. A nearby inhibitory synapse (on the same dendrite) will be activated at specific intervals from the plasticity induction protocol and we will test whether this local inhibitory activity affects the induced excitatory plasticity. The proposed research involves the use of advanced imaging techniques, in combination with electrophysiology and using tools from molecular biology. The results of the proposed research will advance our understanding how the balance between excitation and inhibition in the brain is regulated. A better understanding of this crucial balance is fundamental to a wide variety of neuroscience disciplines, from computational and cellular neuroscience to clinical applications.'

Introduzione (Teaser)

Throughout lifetime, a proper balance between nerve excitation and inhibition is crucial for a healthy brain. Understanding this balance is fundamental to a wide variety of neuroscience disciplines.

Descrizione progetto (Article)

In the nervous system, a synapse is a structure that permits a neuron (or nerve cell) to pass signals to another cell. At a synapse, the plasma membrane of the signal-passing neuron comes into close proximity with the membrane of the target cell. In a chemical synapse, electrical activity in the presynaptic neuron is converted into the release of a chemical neurotransmitter that binds to receptors in the membrane of the postsynaptic cell. Chemical synapses can be classified according to the neurotransmitter released: glutamatergic (excitatory), and GABAergic (inhibitory).

Synaptic plasticity is the ability of a synapse to strengthen or weaken over time in response to increases or decreases in their activity, but how how different forms of plasticity are coordinated is not well understood. Glutamatergic and GABAergic synaptic plasticity may not be regulated separately, but somehow interact to maintain a proper balance between excitation and inhibition. The EU-funded 'Local interactions between GABAergic and glutamatergic plasticity' (GABASYNAPSES) project examined interactions between inhibitory and excitatory synapses within neural cells.

To examine the influence of excitatory activity on inhibitory plasticity, researchers studied structural adaptations in inhibitory axons in hippocampal organotypic cultures. They used time-lapse two-photon microscopy to follow presynaptic changes along GFP-labelled inhibitory projections of a nerve cell (axons) under baseline conditions and during enhanced or reduced activity.

Data obtained showed that inhibitory synapses are highly dynamic structures, which are continuously assembled and disassembled and possibly compete with each other along the inhibitory axon. The axons are continuously sampling potential locations for new inhibitory synapses. Axons were found to adjust their sampling behaviour in response to changes in neuronal activity. These new insights into the structural dynamics of inhibitory axons present a highly dynamic picture of inhibition and inhibitory plasticity in neuronal networks.

In a parallel study, the researchers found that dendritic inhibition can be very precise. The effect of an inhibitory synapse strongly depended on the distance and time interval between inhibition and excitation. This suggests that a dendritic inhibitory synapse can affect local excitatory signals and possibly plasticity with high spatial and temporal specificity.

The project results have been presented at international scientific meetings and have led to several publications in peer-reviewed journals.