Long-Term Enhancement of Neuronal Excitability and Temporal Fidelity Mediated by Metabotropic Glutamate Receptor Subtype 5

The role of a neuron in neural processing is ultimately determined by whether or not it fires an action potential in a given context. Studies on synaptic plasticity have focused primarily on changes in EPSPs, and not on whether plasticity translates into changes in firing. However, this issue has been addressed by examining EPSP-spike (E-S) potentiation, which enhances the ability of an EPSP of a fixed slope to elicit spikes after long-term potentiation (LTP). Although LTP is thought to underlie learning and memory, E-S potentiation could play an equally important role by potentiating the neuronal input-output function. Here, we used a combined experimental and theoretical approach to examine both the mechanisms underlying E-S potentiation as well as the role of inhibition in shaping the input-output function of neurons. Whereas previous studies examined tetanus-LTP, in which inhibitory synapses may have undergone plasticity, here we examined pairing-induced associative LTP. We determined that although intact inhibition was necessary for pairinginduced E-S potentiation, inhibitory plasticity was not. We further established using computer simulations that a primary mechanism of E-S potentiation was a change in the relative recruitment and latency of inhibitory neurons. Although these studies do not exclude the presence of additional mechanisms of E-S potentiation that may be engaged depending on the induction protocol, they do establish that under intact pharmacology, LTP of the Schaffer collateral to CA1 pyramidal neuron synapses will produce E-S potentiation as a result of changes in the balance and timing of excitation and inhibition.

Section: Discussionmentioning

confidence: 99%

Timing and Balance of Inhibition Enhance the Effect of Long-Term Potentiation on Cell Firing

Marder

Buonomano²

2004

“…Removing I D increases this voltage trajectory and, in turn, improves the fidelity of AP generation. This novel rule may also account for the SK-dependent precision of the second spike (Sourdet et al, 2003) (but see Wolfart et al, 2001;Deister et al, 2009) and for the I h -dependent control of rebound spike , since these currents also control the voltage trajectories leading to spike generation. Furthermore, this rule is compatible with the enhanced precision produced by the amplification of fast afterhyperpolarizations by autaptic contacts in neocortical interneurons (Bacci and Huguenard, 2006).…”

Section: Ion Channels Control the Temporal Precision Of Aps: A Novel Lawmentioning

confidence: 99%

“…But outward K ϩ current can also decrease AP precision. For instance, activation of SK channels by the first AP reduces the rate of depolarization leading to the second spike and increases its temporal jitter (Sourdet et al, 2003). Thus, a clarification of the rules by which outward K ϩ currents sculpt AP precision is needed.…”

Section: Introductionmentioning

confidence: 99%

Spike-Time Precision and Network Synchrony Are Controlled by the Homeostatic Regulation of the D-Type Potassium Current

Cudmore¹,

Fronzaroli-Molinières²,

Giraud³

et al. 2010

128

Homeostatic plasticity of neuronal intrinsic excitability (HPIE) operates to maintain networks within physiological bounds in response to chronic changes in activity. Classically, this form of plasticity adjusts the output firing level of the neuron through the regulation of voltage-gated ion channels. Ion channels also determine spike timing in individual neurons by shaping subthreshold synaptic and intrinsic potentials. Thus, an intriguing hypothesis is that HPIE can also regulate network synchronization. We show here that the dendrotoxin-sensitive D-type K ϩ current (I D ) disrupts the precision of AP generation in CA3 pyramidal neurons and may, in turn, limit network synchronization. The reduced precision is mediated by the sequence of outward I D followed by inward Na ϩ current. The homeostatic downregulation of I D increases both spike-time precision and the propensity for synchronization in iteratively constructed networks in vitro. Thus, network synchronization is adjusted in area CA3 through activity-dependent remodeling of I D .

“…Even here tradeoffs are possible, especially for plasticity induced under naturalistic conditions (i.e., natural spike trains rather than stereotyped induction protocols). Whereas large NMDA currents bias synapses toward potentiation, spike-triggered adaptation biases them toward depression by reducing firing rates and temporal fidelity (Sourdet et al, 2003) and increasing mem- Figure 9. Spatially extended spiking activity provoked by excessive NMDA currents is suppressed by increased intrinsic adaptation.…”

Section: Homeostatic Compensationmentioning

confidence: 99%

Synaptic and Intrinsic Balancing during Postnatal Development in Rat Pups Exposed to Valproic Acidin Utero

Walcott¹,

Higgins²,

Desai³

2011

Valproic acid (VPA) is among the most teratogenic of commonly prescribed anticonvulsants, increasing the risk in humans of major malformations and impaired cognitive development. Likewise, rats exposed prenatally to VPA exhibit a variety of neuroanatomical and behavioral abnormalities. Previous work has shown that pyramidal neuron physiology in young VPA-exposed animals is marked by two strong abnormalities: an impairment in intrinsic neuronal excitability and an increase in NMDA synaptic currents. In this study, we investigated these abnormalities across postnatal development using whole-cell patch recordings from layer 2/3 neurons of medial prefrontal cortex. We found that both abnormalities were at a peak soon after birth but were gradually corrected as animals matured, to the extent that normal excitability and NMDA currents had been restored by early adolescence. The manner in which this correction happened suggested coordination between the two processes. Using computational models fitted to the physiological data, we argue that the two abnormalities trade off against each other, with the effects on network activity of the one balancing the effects of the other. This may constitute part of the nervous system's homeostatic response to teratogenic insult: an attempt to maintain stability despite a strong challenge.