Coordination in space and time of excitatory and inhibitory synaptic plasticity at dendritic synapses

For years, GABAergic synapses were considered poorly plastic. However, an increasing body of evidence demonstrated that, similarly to excitatory synapses, inhibitory synapses formed by interneurons onto pyramidal cells can be modulated in response to neuronal activity. The spiking output of a neuron is determined by the opposite but concomitant action of excitation and inhibition. In this view, it is crucial to understand how plasticity at excitatory and inhibitory synapses is coordinated. In this thesis, I will describe two different types of plasticity interplay between excitation and inhibition, in space and time domains. In our previous work (Petrini et al., 2014) we characterized the induction and the expression of postsynaptic inhibitory long term potentiation (iLTP) following the administration of NMDA and CNQX (chemical protocol of induction of iLTP). Here we induced postsynaptic iLTP by administering electrophysiological stimulations intended to better mimic physiological neuronal activity. We observed that the delivery to the postsynaptic neuron of a train of action potentials at frequency of 2Hz, (that we define here low frequency stimulation, LFS) potentiated the amplitude of the inhibitory postsynaptic currents (iPSCs) up to 30 minutes. This particular form of iLTP depended on moderate calcium increase in the postsynaptic neuron and the activation of the Calcium calmodulin kinase II (CaMKII). The concomitant investigation of excitatory transmission revealed the depression of excitatory postsynaptic currents (ePSCs) amplitude thus indicating that LFS induced excitatory (LTD). In order to further study the interaction between excitatory and inhibitory synaptic plasticity, we paired the protocol of iLTP together with simultaneous photorelease of glutamate on a single spine. This particular type of Hebbian stimulation induced LTP at the photostimulated spine (Lee et al., 2009; Matsuzaki et al., 2001, 2004) and LTD on the other spines. In contrast, we observed that the GABAergic synapses located distant from the potentiated spine showed an iLTP while the ones located in a range of 3 micron from the potentiated spine were depressed. Such “inversion of plasticity” was promoted by a massive influx of calcium and the activation of calpain, a protease involved in the cleavage of the gephyrin. In the second part of this thesis, I will show a new type of structural inhibitory short term depression plasticity (siSTD) that occurs during the induction of the plasticity protocol, before the expression of iLTP. In particular, the depolarization of the postsynaptic neuron induced a transient depression of inhibitory synapses that was dependent on the fast activation of the protease calpain. We propose that such “early” calpain activation pathway competes with that of the CaMKII thus defining the extent of long-term inhibitory plasticity.