Serotonergic modulation of LTP at excitatory and inhibitory synapses in the developing rat visual cortex.

The stability and efficacy of neuronal circuits are achieved through a detailed balance between pyramidal cell and interneuron activities. Interestingly, the neocortical excitatory-inhibitory (E-I) balance is actively maintained at the soma of Layer 5 pyramidal neurons which receive 20% of excitation and 80% of inhibition after dendritic integration, and this is not affected by changes in synaptic strength. To infer the role of serotonergic neuromodulation on the activity-dependent maintenance of the E-I balance, we performed continuous voltage clamp measurements of stimulation-locked conductance dynamics in Layer 5 pyramidal neurons before and after long-term potentiation (LTP) induction, together with chronic or acute manipulation of serotonin function. When a theta-burst stimulation was applied in Layer 2/3 of 5-HT depleted cortical slices (after in vivo treatment with the tryptophan hydroxylase inhibitor p-chlorophenylalanine (pCPA)), or after in vitro perfusion of the potent 5-HT1A receptor antagonist WAY-100,635, we observed a persistent shift of the ratio between excitation and inhibition toward more inhibition. This was due to a strong LTP of inhibition co-aligned with a weak LTP of excitation, whereas the same protocol caused a similar potentiation of excitatory and inhibitory inputs when applied in control slices. In contrast, neither excitatory nor inhibitory postsynaptic currents were potentiated when LTP protocols were delivered in the presence of either the selective serotonin reuptake inhibitor citalopram or the 5-HT1A receptor agonist 8-OH-DPAT. This is the first demonstration that serotonergic neuromodulation is crucial for the maintenance of the neocortical E-I balance during high-frequency regimes.

Roles of nitric oxide in the homeostatic control of the excitation-inhibition balance in rat visual cortical networks.

The level of excitability of cortical neurons depends on the balance between their excitatory and inhibitory inputs (excitation/inhibition [E/I] balance). In the cortex, the E/I balance received by a neuron is dynamically maintained through a coordinated regulation of the strength of these inputs, described in term of homeostatic plasticity. Using a method allowing the determination of the E/I balance in rat cortical layer 5 pyramidal neurons (L5-PNs, the main output stage of the cortex), while keeping the interactions between excitatory and inhibitory networks functional, we examined the effects of high or low frequency of stimulation (HFS or LFS) protocols in layer 4 (in order to mimic thalamo-cortical entries) on the E-I level of the neuronal network. We previously showed that the E/I balance of L5-PNs remains stable due to a dual potentiation or dual depression of E and I after HFS or LFS protocols. Here, using a specific neuronal nitric oxide synthase (nNOS) inhibitor, we show that the related potentiation or depression of E and I (underlying homeostatic plasticity processes) required nNOS activation. We also show that application of an unspecific blocker of nitric oxide synthase (NOS) or a nitric oxide (NO) scavenger induces an increase of the E/I balance suggesting a role for a tonic NO synthesis in the regulation of the network activity. It is concluded that, in the cortex, a phasic NO effect (due to activation of nNOS) is required for the induction of homeostatic plasticity processes whereas a tonic NO signal is involved in the regulation of a set-point value for the E/I balance.