Contribution of the d-Serine-Dependent Pathway to the Cellular Mechanisms Underlying Cognitive Aging

An association between age-related memory impairments and changes in functional plasticity in the aging brain has been under intense study within the last decade. In this article, we show that an impaired activation of the strychnine-insensitive glycine site of N-methyl-d-aspartate receptors (NMDA-R) by its agonist d-serine contributes to deficits of synaptic plasticity in the hippocampus of memory-impaired aged rats. Supplementation with exogenous d-serine prevents the age-related deficits of isolated NMDA-R-dependent synaptic potentials as well as those of theta-burst-induced long-term potentiation and synaptic depotentiation. Endogenous levels of d-serine are reduced in the hippocampus with aging, that correlates with a weaker expression of serine racemase synthesizing the amino acid. On the contrary, the affinity of d-serine binding to NMDA-R is not affected by aging. These results point to a critical role for the d-serine-dependent pathway in the functional alterations of the brain underlying memory impairment and provide key information in the search for new therapeutic strategies for the treatment of memory deficits in the elderly

The regulation of M1 muscarinic acetylcholine receptor desensitization by synaptic activity in cultured hippocampal neurons1

To better understand metabotropic/ionotropic integration in neurons we have examined the regulation of M1 muscarinic acetylcholine (mACh) receptor signalling in mature (> 14 days in vitro), synaptically-active hippocampal neurons in culture. Using a protocol where neurons are exposed to an EC50 concentration of the muscarinic agonist methacholine (MCh) prior to (R1), and following (R2) a desensitizing pulse of a high concentration of this agonist, we have found that the reduction in M1 mACh receptor responsiveness is decreased in quiescent (+tetrodotoxin) neurons and increased when synaptic activity is enhanced by blocking GABAA receptors with picrotoxin. The picrotoxin-mediated effect on M1 mACh receptor responsiveness was completely prevented by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor blockade. Inhibition of endogenous G protein-coupled receptor kinase 2 by transfection with the non-Gq/11α-binding, catalytically-inactive D110A,K220RG protein-coupled receptor kinase 2 mutant, decreased the extent of M1 mACh receptor desensitization under all conditions. Pharmacological inhibition of protein kinase C (PKC) activity, or chronic phorbol ester-induced PKC down-regulation had no effect on agonist-mediated receptor desensitization in quiescent or spontaneously synaptically active neurons, but significantly decreased the extent of receptor desensitization in picrotoxin-treated neurons. MCh stimulated the translocation of diacylglycerol- sensitive eGFP-PKCε, but not Ca2+/diacylglycerol-sensitive eGFP-PKCβII in both the absence, and presence of tetrodotoxin. Under these conditions, MCh-stimulated eGFP-myristoylated, alanine-rich C kinase substrate translocation was dependent on PKC activity, but not Ca2+/calmodulin. In contrast, picrotoxin-driven translocation of myristoylated, alanine-rich C kinase substrate was accompanied by translocation of PKCβII, but not PKCε, and was dependent on PKC and Ca2+/calmodulin. Taken together these data suggest that the level of synaptic activity may determine the different kinases recruited to regulate M1 mACh receptor desensitization in neurons

Stable Propagation of a Burst Through a One-Dimensional Homogeneous Excitatory Chain Model of Songbird Nucleus HVC

We demonstrate numerically that a brief burst consisting of two to six spikes can propagate in a stable manner through a one-dimensional homogeneous feedforward chain of non-bursting neurons with excitatory synaptic connections. Our results are obtained for two kinds of neuronal models, leaky integrate-and-fire (LIF) neurons and Hodgkin-Huxley (HH) neurons with five conductances. Over a range of parameters such as the maximum synaptic conductance, both kinds of chains are found to have multiple attractors of propagating bursts, with each attractor being distinguished by the number of spikes and total duration of the propagating burst. These results make plausible the hypothesis that sparse precisely-timed sequential bursts observed in projection neurons of nucleus HVC of a singing zebra finch are intrinsic and causally related.Comment: 13 pages, 6 figure

The role of inhibitory feedback for information processing in thalamocortical circuits

The information transfer in the thalamus is blocked dynamically during sleep, in conjunction with the occurence of spindle waves. As the theoretical understanding of the mechanism remains incomplete, we analyze two modeling approaches for a recent experiment by Le Masson {\sl et al}. on the thalamocortical loop. In a first step, we use a conductance-based neuron model to reproduce the experiment computationally. In a second step, we model the same system by using an extended Hindmarsh-Rose model, and compare the results with the conductance-based model. In the framework of both models, we investigate the influence of inhibitory feedback on the information transfer in a typical thalamocortical oscillator. We find that our extended Hindmarsh-Rose neuron model, which is computationally less costly and thus siutable for large-scale simulations, reproduces the experiment better than the conductance-based model. Further, in agreement with the experiment of Le Masson {\sl et al}., inhibitory feedback leads to stable self-sustained oscillations which mask the incoming input, and thereby reduce the information transfer significantly.Comment: 16 pages, 15eps figures included. To appear in Physical Review

Quantitative expression and localization of GABAB receptor protein subunits in hippocampi from patients with refractory temporal lobe epilepsy

This study investigates GABAB protein expression and mRNA levels in three types of specimens. Two types of specimens from patients with temporal lobe epilepsy (TLE), secondary to hippocampal sclerosis, sclerotic hippocampal samples (TLE-HS), and tissue from the structurally preserved non-spiking ipsilateral superior temporal gyrus (TLE-STG) removed from the same patient during epilepsy surgery; and third specimen is hippocampal tissue from individuals with no history of epilepsy (post-mortem controls, PMC). mRNA expression of GABAB subunits was quantified in TLE-HS, TLE-STG and PMC specimens by qRT-PCR. Qualitative and quantitative Western blot (WB) and immunohistochemistry techniques were employed to quantify and localize GABAB proteins subunits. qRT-PCR data demonstrated an overall decrease of both GABAB1 isoforms in TLE-HS compared to TLE-STG. These results were mirrored by the WB findings. GABAB2 mRNA and protein were significantly reduced in TLE-HS samples compared to TLE-STG; however they appeared to be upregulated in TLE-HS compared to the PMC samples. Immunohistochemistry (IHC) showed that GABAB proteins were widely distributed in PMC and TLE-HS hippocampal sections with regional differences in the intensity of the signal. The higher expression of mature GABAB protein in TLE-HS than PMC is in agreement with previous studies. However, these findings could be due to post-mortem changes in PMC specimens. The TLE-STG samples examined here represent a better 'control' tissue compared to TLE-HS samples characterized by lower than expected GABAB expression. This interpretation provides a better explanation for previous functional studies suggesting reduced inhibition in TLE-HS tissue due to attenuated GABAB currents. [Abstract copyright: Copyright © 2017. Published by Elsevier Ltd.

Support for a synaptic chain model of neuronal sequence generation

In songbirds, the remarkable temporal precision of song is generated by a sparse sequence of bursts in the premotor nucleus HVC. To distinguish between two possible classes of models of neural sequence generation, we carried out intracellular recordings of HVC neurons in singing zebra finches (Taeniopygia guttata). We found that the subthreshold membrane potential is characterized by a large, rapid depolarization 5–10 ms before burst onset, consistent with a synaptically connected chain of neurons in HVC. We found no evidence for the slow membrane potential modulation predicted by models in which burst timing is controlled by subthreshold dynamics. Furthermore, bursts ride on an underlying depolarization of ~10-ms duration, probably the result of a regenerative calcium spike within HVC neurons that could facilitate the propagation of activity through a chain network with high temporal precision. Our results provide insight into the fundamental mechanisms by which neural circuits can generate complex sequential behaviours.National Institutes of Health (U.S.) (Grant MH067105)National Institutes of Health (U.S.) (Grant DC009280)National Science Foundation (U.S.) (IOS-0827731)Alfred P. Sloan Foundation (Research Fellowship

Ubiquitous molecular substrates for associative learning and activity-dependent neuronal facilitation.

Recent evidence suggests that many of the molecular cascades and substrates that contribute to learning-related forms of neuronal plasticity may be conserved across ostensibly disparate model systems. Notably, the facilitation of neuronal excitability and synaptic transmission that contribute to associative learning in Aplysia and Hermissenda, as well as associative LTP in hippocampal CA1 cells, all require (or are enhanced by) the convergence of a transient elevation in intracellular Ca2+ with transmitter binding to metabotropic cell-surface receptors. This temporal convergence of Ca2+ and G-protein-stimulated second-messenger cascades synergistically stimulates several classes of serine/threonine protein kinases, which in turn modulate receptor function or cell excitability through the phosphorylation of ion channels. We present a summary of the biophysical and molecular constituents of neuronal and synaptic facilitation in each of these three model systems. Although specific components of the underlying molecular cascades differ across these three systems, fundamental aspects of these cascades are widely conserved, leading to the conclusion that the conceptual semblance of these superficially disparate systems is far greater than is generally acknowledged. We suggest that the elucidation of mechanistic similarities between different systems will ultimately fulfill the goal of the model systems approach, that is, the description of critical and ubiquitous features of neuronal and synaptic events that contribute to memory induction

A reafferent and feed-forward model of song syntax generation in the Bengalese finch

Adult Bengalese finches generate a variable song that obeys a distinct and individual syntax. The syntax is gradually lost over a period of days after deafening and is recovered when hearing is restored. We present a spiking neuronal network model of the song syntax generation and its loss, based on the assumption that the syntax is stored in reafferent connections from the auditory to the motor control area. Propagating synfire activity in the HVC codes for individual syllables of the song and priming signals from the auditory network reduce the competition between syllables to allow only those transitions that are permitted by the syntax. Both imprinting of song syntax within HVC and the interaction of the reafferent signal with an efference copy of the motor command are sufficient to explain the gradual loss of syntax in the absence of auditory feedback. The model also reproduces for the first time experimental findings on the influence of altered auditory feedback on the song syntax generation, and predicts song- and species-specific low frequency components in the LFP. This study illustrates how sequential compositionality following a defined syntax can be realized in networks of spiking neurons

Decreased monosynaptic GABAB-mediated inhibitory postsynaptic potentials in hippocampal CA1 pyramidal cells in the aged rat: pharmacological characterization and possible mechanisms

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