Prion protein (PrP) plays a crucial role in prion disease, but its physiological function remains unclear Mice with gene deletions restricted to the coding region of PrP have only minor phenotypic deficits, but are resistant to prion disease We generated double transgenic mice using the Cre–loxP system to examine the effects of PrP depletion on neuronal survival and function in adult brain Cre‐mediated ablation of PrP in neurons occurred after 9 weeks We found that the mice remained healthy without evidence of neurodegeneration or other histopathological changes for up to 15 months post‐knockout However, on neurophysiological evaluation, they showed significant reduction of afterhyperpolarization potentials (AHPs) in hippocampal CA1 cells, suggesting a direct role for PrP in the modulation of neuronal excitability These data provide new insights into PrP function Furthermore, they show that acute depletion of PrP does not affect neuronal survival in this model, ruling out loss of PrP function as a pathogenic mechanism in prion disease and validating therapeutic approaches targeting PrP.

Neural networks are more than the sum of their parts, but the properties of those parts are nonetheless important. For instance, neuronal properties affect the degree to which neurons receiving common input will spike synchronously, and whether that synchrony will propagate through the network. Stimulus-evoked synchrony can help or hinder network coding depending on the type of code. In this Perspective, we describe how spike initiation dynamics influence neuronal input-output properties, how those properties affect synchronization, and how synchronization affects network coding. We propose that synchronous and asynchronous spiking can be used to multiplex temporal (synchrony) and rate coding and discuss how pyramidal neurons would be well suited for that task.

Prescott SA, Ratté S, De Koninck Y, Sejnowski TJ. Pyramidal neurons switch from integrators in vitro to resonators under in vivolike conditions. J Neurophysiol 100: 3030 -3042, 2008. First published October 1, 2008 doi:10.1152/jn.90634.2008. During wakefulness, pyramidal neurons in the intact brain are bombarded by synaptic input that causes tonic depolarization, increased membrane conductance (i.e., shunting), and noisy fluctuations in membrane potential; by comparison, pyramidal neurons in acute slices typically experience little background input. Such differences in operating conditions can compromise extrapolation of in vitro data to explain neuronal operation in vivo. For instance, pyramidal neurons have been identified as integrators (i.e., class 1 neurons according to Hodgkin's classification of intrinsic excitability) based on in vitro experiments but that classification is inconsistent with the ability of hippocampal pyramidal neurons to oscillate/resonate at theta frequency since intrinsic oscillatory behavior is limited to class 2 neurons. Using long depolarizing stimuli and dynamic clamp to reproduce in vivo-like conditions in slice experiments, we show that CA1 hippocampal pyramidal cells switch from integrators to resonators, i.e., from class 1 to class 2 excitability. The switch is explained by increased outward current contributed by the M-type potassium current I M , which shifts the balance of inward and outward currents active at perithreshold potentials and thereby converts the spike-initiating mechanism as predicted by dynamical analysis of our computational model. Perithreshold activation of I M is enhanced by the depolarizing shift in spike threshold caused by shunting and/or sodium channel inactivation secondary to tonic depolarization. Our conclusions were validated by multiple comparisons between simulation and experimental data. Thus even so-called "intrinsic" properties may differ qualitatively between in vitro and in vivo conditions.