Spatio-temporal configurations of distributed activity in the brain is thought to contribute to the coding of neuronal information and synaptic contacts between nerve cells could play a central role in the formation of privileged pathways of activity. Synaptic plasticity is not the exclusive mode of regulation of information processing in the brain, and persistent regulations of ionic conductances in some specialized neuronal areas such as the dendrites, the cell body, and the axon could also modulate, in the long-term, the propagation of neuronal information. Persistent changes in intrinsic excitability have been reported in several brain areas in which activity is elevated during a classical conditioning. The role of synaptic activity seems to be a determinant in the induction, but the learning rules and the underlying mechanisms remain to be defined. We discuss here the role of synaptic activity in the induction of intrinsic plasticity in cortical, hippocampal, and cerebellar neurons. Activation of glutamate receptors initiates a long-term modification in neuronal excitability that may represent a parallel, synergistic substrate for learning and memory. Similar to synaptic plasticity, long-lasting intrinsic plasticity appears to be bidirectional and to express a certain level of input or cell specificity. These nonsynaptic forms of plasticity affect the signal propagation in the axon, the dendrites, and the soma. They not only share common learning rules and induction pathways with the better-known synaptic plasticity such as NMDA receptor dependent LTP and LTD, but also contribute in synergy with these synaptic changes to the formation of a coherent engram. What Are the Cellular Learning Rules?The most remarkable feature of the brain is its capacity to collect new information from the environment and to store it in order to produce changes in the behavior. Over the last decades, the aim of most neuroscientists in the field of brain plasticity has been to establish learning rules that could account for this storage at the cellular level. The idea that memory storage in the brain results from activity-dependent changes in synaptic strength was developed by Hebb (1949), who proposed that excitatory synapses linking two cells could be strengthened if both cells were active simultaneously. This learning rule has been verified and extended over the last two decades (for review, see Sourdet and Debanne 1999;Abbott and Nelson 2000;Bi and Poo 2001;Sjöström and Nelson 2002). One of the goals of this review is to discuss whether the learning rules and inductions mechanisms defined for synaptic plasticity also apply to other forms of plasticity that affect ion channels in nonsynaptic structures of the neuron. Synaptic and Nonsynaptic PlasticityThe synapse is the anatomical and functional interface between individual nerve cells, and thus occupies a strategic position. It is generally considered as a privileged element involved in short-or long-term modifications of the transmission of neuronal message in the brain. The ...

The cellular substrate for memory is generally attributed to long-lasting changes in synaptic strength. We report here that synaptic or pharmacological activation of the metabotropic glutamate receptor subtype 5 (mGluR5) induces long-term potentiation of intrinsic excitability (LTP-IE) in layer V pyramidal neurons. mGluR5-dependent LTP-IE was associated with a persistent reduction of the afterhyperpolarization (AHP) outward current (IAHP), resulting in the potentiation of EPSP-spike coupling. Apamin occluded induction of LTP-IE, indicating that downregulation of small conductance calcium-dependent potassium (SK) channels mediates this process. In addition to the improved reliability of the input-output function, LTP-IE led to increased temporal precision. The induced reduction of IAHP accelerated the rate of membrane depolarization preceding each action potential and subsequently decreased the jitter of the neuronal discharge. We conclude that mGluR5-dependent LTP-IE not only promotes the spread of excitation in the cortical network but also persistently enhances the temporal fidelity of the neuronal message.

Integration of synaptic excitation to generate an action potential (excitatory postsynaptic potential-spike coupling or E-S coupling) determines the neuronal output. Bidirectional synaptic plasticity is well established in the hippocampus, but whether active synaptic integration can display potentiation and depression remains unclear. We show here that synaptic depression is associated with an N-methyl-D-aspartate receptor-dependent and long-lasting depression of E-S coupling. E-S depression is input-specific and is expressed in the presence of ␥-aminobutyric acid type A and B receptor antagonists. In single neurons, E-S depression is observed without modification of postsynaptic passive properties. We conclude that a decrease in intrinsic excitability underlies E-S depression and is synergic with glutamatergic long-term depression.I ntegration of synaptic inputs to produce an action potential at the axon hillock is a complex operation that depends on two critical factors: the distribution of voltage-gated ion channels in the dendrites and the passive electrical properties upon which these active channels are superimposed (1). Synaptic potentials have been shown to be shaped by intrinsic voltage-gated conductances located in the dendrites and the soma (2), but the dynamics of active synaptic integration remains poorly understood. We addressed here the question as to whether synaptic integration is modified after induction of long-term synaptic potentiation and depotentiation.In the area CA1, homosynaptic long-term potentiation (LTP) of excitatory synaptic transmission is induced by high-frequency stimulation (HFS, 100 Hz) of the afferent fibers (3). In parallel, the probability of discharge of the postsynaptic neurons in response to a given excitatory postsynaptic potential (EPSP) is enhanced (4-7). This second component has been called EPSPto-Spike potentiation (E-S potentiation, E-S P) which is complementary to LTP and functionally important. The reversal of LTP preserves a potential for network plasticity and appears essential for any model of memory (8). Long-term synaptic depotentiation has been reported in the area CA1 (9), but the reversal of E-S P has never been clearly established (10, 11). We show here that E-S depression (E-S D) is expressed concomitantly with long-term depression (LTD). E-S D is largely independent of synaptic inhibition but requires N-methyl-D-aspartate (NMDA) receptor (NMDAR) activation for its induction. We provide evidence for an activity-dependent decrease of the intrinsic excitability of CA1 pyramidal neurons that acts in synergy with LTD. MethodsSlice Preparation. Hippocampal slices (400 m) were obtained from 3-to 6-week-old rats according to institutional guidelines. Slices were cut in a solution (280 mM sucrose͞26 mM NaHCO 3 ͞10 mM D-glucose͞1.3 mM KCl͞1 mM CaCl 2 ͞10 mM MgCl 2 ), and were maintained for 1 h at room temperature in oxygenated (95% O 2 ͞5% CO 2 ) artificial cerebrospinal fluid (ACSF; 125 mM NaCl͞2.5 mM KCl͞0.8 mM NaH 2 PO 4 ͞26 mM NaHCO 3 ͞3 mM CaCl 2 ͞2 mM Mg...

Hyperpolarization-activated (h)-channels occupy a central position in dendritic function. Although it has been demonstrated that these channels are upregulated after large depolarizations to reduce dendritic excitation, it is not clear whether they also support other forms of long-term plasticity. We show here that nearly maximal long-term potentiation (LTP) induced by theta-burst pairing produced upregulation in h-channel activity in CA1 pyramidal neurons. In contrast, moderate LTP induced by spike-timing-dependent plasticity or high-frequency stimulation (HFS) downregulated the h-current (Ih) in the dendrites. After HFS-induced LTP, the h-conductance (Gh) was reduced without changing its activation. Pharmacological blockade ofIhhad no effect on LTP induction, but occluded EPSP-to-spike potentiation, an input-specific facilitation of dendritic integration. Dynamic-clamp reduction ofGhlocally in the dendrite mimicked the effects of HFS and enhanced synaptic integration in an input-selective way. We conclude that dendriticIhis locally downregulated after induction of nonmaximal LTP, thus facilitating integration of the potentiated input.