A selective interplay between aberrant EPSPKA and INaP reduces spike timing precision in dentate granule cells of epileptic rats.

Spike timing precision is a fundamental aspect of neuronal information processing in the brain. Here we examined the temporal precision of input-output operation of dentate granule cells (DGCs) in an animal model of temporal lobe epilepsy (TLE). In TLE, mossy fibers sprout and establish recurrent synapses on DGCs that generate aberrant slow kainate receptor-mediated excitatory postsynaptic potentials (EPSP(KA)) not observed in controls. We report that, in contrast to time-locked spikes generated by EPSP(AMPA) in control DGCs, aberrant EPSP(KA) are associated with long-lasting plateaus and jittered spikes during single-spike mode firing. This is mediated by a selective voltage-dependent amplification of EPSP(KA) through persistent sodium current (I(NaP)) activation. In control DGCs, a current injection of a waveform mimicking the slow shape of EPSP(KA) activates I(NaP) and generates jittered spikes. Conversely in epileptic rats, blockade of EPSP(KA) or I(NaP) restores the temporal precision of EPSP-spike coupling. Importantly, EPSP(KA) not only decrease spike timing precision at recurrent mossy fiber synapses but also at perforant path synapses during synaptic integration through I(NaP) activation. We conclude that a selective interplay between aberrant EPSP(KA) and I(NaP) severely alters the temporal precision of EPSP-spike coupling in DGCs of chronic epileptic rats.

Intracellular calcium regulation by burst discharge determines bidirectional long-term synaptic plasticity at the cerebellum input stage.

Variations in intracellular calcium concentration ([Ca2+]i) provide a critical signal for synaptic plasticity. In accordance with Hebb's postulate (Hebb, 1949), an increase in postsynaptic [Ca2+]i can induce bidirectional changes in synaptic strength depending on activation of specific biochemical pathways (Bienenstock et al., 1982; Lisman, 1989; Stanton and Sejnowski, 1989). Despite its strategic location for signal processing, spatiotemporal dynamics of [Ca2+]i changes and their relationship with synaptic plasticity at the cerebellar mossy fiber (mf)-granule cell (GrC) relay were unknown. In this paper, we report the plasticity/[Ca2+]i relationship for GrCs, which are typically activated by mf bursts (Chadderton et al., 2004). Mf bursts caused a remarkable [Ca2+]i increase in GrC dendritic terminals through the activation of NMDA receptors, metabotropic glutamate receptors (probably acting through IP3-sensitive stores), voltage-dependent calcium channels, and Ca2+-induced Ca2+ release. Although [Ca2+]i increased with the duration of mf bursts, long-term depression was found with a small [Ca2+]i increase (bursts <250 ms), and long-term potentiation (LTP) was found with a large [Ca2+]i increase (bursts >250 ms). LTP and [Ca2+]i saturated for bursts >500 ms and with theta-burst stimulation. Thus, bursting enabled a Ca2+-dependent bidirectional Bienenstock-Cooper-Munro-like learning mechanism providing the cellular basis for effective learning of burst patterns at the input stage of the cerebellum.

NMDA receptor 2 (NR2) C-terminal control of NR open probability regulates synaptic transmission and plasticity at a cerebellar synapse.

The C-terminal domain of NMDA receptor 2 (NR2) subunits has been proposed to play a critical role in regulating NMDA receptor localization and function in postsynaptic densities. However, the mechanism of this regulation is not completely understood. In this paper we show that C-terminal truncation of NR2A and NR2C subunits in mice (NR2A/C(DeltaC/DeltaC)) impairs synaptic transmission and plasticity at the cerebellar mossy fiber-granule cell relay. Activation of synaptic NMDA receptors could be distinguished from that of extrasynaptic receptors by using the glutamate scavenger glutamate pyruvate transaminase and the open channel blocker MK801. NR2A/C(DeltaC/DeltaC) mice exhibited a specific reduction in synaptic NMDA receptor activation attributable to a severalfold decrease in channel open probability but not channel conductance. Immunodetection revealed normal developmental expression of NR subunit proteins. Quantitative immunogold analyses with an antibody to NR1 indicated that the reduction in receptor activation is not attributed to a reduced number of NR1-containing receptors in postsynaptic densities. Thus, NR2A/NR2C subunits and particularly their C termini regulate synaptic NMDA receptor activation and function by enhancing channel open probability, which is critical for long-term potentiation induction.

Long-term potentiation of synaptic transmission at the mossy fiber-granule cell relay of cerebellum.

In the last decade, the physiology of cerebellar neurons and synapses has been extended to a considerable extent. We have found that the mossy fiber-granule cell relay can generate a complex form of long-term potentiation (mf-GrC LTP) following high-frequency mf discharge. Induction. Mf-GrC LTP depends on NMDA and mGlu receptor activation, intracellular Ca(2+) increase, PKC activation, and NO production. The preventative action of intracellular agents (BAPTA, PKC-inhibitors) and of membrane hyperpolarization, and the correlated increase in intracellular Ca(2+) observed using fluorescent dyes, indicate that induction occurs postsynaptically. Expression. Expression includes three components: (a) an increase of synaptic currents, (b) an increase of intrinsic excitability in GrC, and (c) an increase of intrinsic excitability in mf terminals. Based on quantal analysis, the EPSC increase is mostly explained by enhanced neurotransmitter release. NO is a candidate retrograde neurotransmitter which could determine both presynaptic current changes and LTP. NO cascade blockers inhibit both presynaptic current changes and LTP. The increase in intrinsic excitability involves a raise in apparent input resistance in the subthreshold region and a spike threshold reduction. Together with other forms of cerebellar plasticity, mf-GrC LTP opens new hypothesis on how the cerebellum processes incoming information.

LTP regulates burst initiation and frequency at mossy fiber-granule cell synapses of rat cerebellum: experimental observations and theoretical predictions.

Long-term potentiation (LTP) is a synaptic change supposed to provide the cellular basis for learning and memory in brain neuronal circuits. Although specific LTP expression mechanisms could be critical to determine the dynamics of repetitive neurotransmission, this important issue remained largely unexplored. In this paper, we have performed whole cell patch-clamp recordings of mossy fiber-granule cell LTP in acute rat cerebellar slices and studied its computational implications with a mathematical model. During LTP, stimulation with short impulse trains at 100 Hz revealed earlier initiation of granule cell spike bursts and a smaller nonsignificant spike frequency increase. In voltage-clamp recordings, short AMPA excitatory postsynaptic current (EPSC) trains showed short-term facilitation and depression and a sustained component probably generated by spillover. During LTP, facilitation disappeared, depression accelerated, and the sustained current increased. The N-methyl-d-aspartate (NMDA) current also increased. In agreement with a presynaptic expression caused by increased release probability, similar changes were observed by raising extracellular [Ca(2+)]. A mathematical model of mossy fiber-granule cell neurotransmission showed that increasing release probability efficiently modulated the first-spike delay. Glutamate spillover, by causing tonic NMDA and AMPA receptor activation, accelerated excitatory postsynaptic potential (EPSP) temporal summation and maintained a sustained spike discharge. The effect of increasing neurotransmitter release could not be replicated by increasing receptor conductance, which, like postsynaptic manipulations enhancing intrinsic excitability, proved very effective in raising granule cell output frequency. Independent regulation of spike burst initiation and frequency during LTP may provide mechanisms for temporal recoding and gain control of afferent signals at the input stage of cerebellar cortex.

Failure of nicotine-dependent enhancement of synaptic efficacy at Schaffer-collateral CA1 synapses of AD11 anti-nerve growth factor transgenic mice.

Alzheimer's disease is a neurodegenerative disorder characterized by neuronal loss associated with a progressive impairment of cognitive functions. Early consequences of Alzheimer's disease include deficit of cholinergic signalling in particular regions controlling memory processes, such as the cortex and hippocampus, and accumulation of beta-amyloid (Abeta) peptide in neuritic plaques. The cholinergic system depends for its integrity and function on nerve growth factor. Chronic nerve growth factor deprivation in transgenic mice (AD11) engineered to produce recombinant neutralizing anti-nerve growth factor antibodies leads to progressive age-dependent Alzheimer's-like neurodegenerative pathology similar to that found in patients with Alzheimer's disease, associated with a selective loss of cholinergic neurones in the basal forebrain. Here we show that in the hippocampus of 6-month-old AD11 mice, Abeta aggregates started appearing in the CA1 region. The accumulation of Abeta was associated with a loss of cholinergic function at CA3-CA1 synapses. Whereas in wild-type mice nicotine induced a persistent increase of synaptic efficacy via alpha7 nicotine acetylcholine receptors, in AD11 mice this alkaloid failed to modify synaptic strength. Moreover, nicotine failed to transiently enhance the frequency of spontaneous miniature glutamatergic currents (miniature excitatory postsynaptic currents) recorded from CA1 but not from CA3 pyramidal neurones of AD11 mice. However, in CA3 principal cells of AD11 mice, the potentiating effect of nicotine on miniature excitatory postsynaptic currents was prevented when Abeta peptide 1-42 was added to the extracellular solution. These data suggest that in AD11 mice, Abeta interferes with nicotine acetylcholine receptors at the level of presynaptic glutamatergic terminals, inhibiting their function possibly through calcium signalling via presynaptic alpha7 nicotine acetylcholine receptors.

Increased neurotransmitter release during long-term potentiation at mossy fibre-granule cell synapses in rat cerebellum.

During long-term potentiation (LTP) at mossy fibre-granule cell synapses in rat cerebellum synaptic transmission and granule cell intrinsic excitability are enhanced. Although it is clear that changes in granule cell excitability are mediated postsynaptically, there is as yet no direct evidence for the site and mechanism of changes in transmission. To approach this problem, evoked postsynaptic currents (EPSCs) and miniature synaptic currents (mEPSCs) were recorded by patch-clamp in cerebellar slices obtained from P17-P23 rats. LTP was induced by theta-burst stimulation paired with depolarization. During LTP, the EPSCs showed a significant decrease in the coefficient of variation (CV; 28.9 +/- 5.2%, n= 8; P < 0.002), the number of failures (87.1 +/- 41.9%, n= 8; P < 0.04), and the paired-pulse ratio (PPR; 25.5 +/- 4.1% n= 5; P < 0.02). Similar changes were observed by increasing neurotransmitter release (extracellular solutions with high Ca(2+)/Mg(2+) ratio), whereas increases in CV, numbers of failures and PPR occurred when release was decreased (extracellular solutions with low Ca(2+)/Mg(2+) ratio; 10 microm Cl-adenosine). No changes followed modifications of postsynaptic holding potentials, while CV and failures were reduced when the number of active synapses was increased. LTP was prevented by use of solutions with high Ca(2+)/Mg(2+) ratio. Moreover, LTP and the associated CV decrease were observed in the spillover-mediated component of AMPA EPSCs and in NMDA EPSCs. During LTP, mEPSCs did not change in amplitude or variability but significantly increased in frequency (47.6 +/- 16%, n= 4; P < 0.03). By binomial analysis changes in EPSCs were shown to be due to increased release probability (from 0.6 +/- 0.08 to 0.73 +/- 0.06, n= 7; P < 0.02) with a constant number of three to four releasing sites. These observations provide evidence for increased neurotransmitter release during LTP at mossy fibre-granule cell synapses.

Persistent decrease in synaptic efficacy induced by nicotine at Schaffer collateral-CA1 synapses in the immature rat hippocampus.

Neuronal nicotinic acetylcholine receptors (nAChRs) are widely distributed within the brain where they contribute to the regulation of higher cognitive functions. The loss of the cholinergic function in Alzheimer's disease patients, along with the well-known memory enhancing effect of nicotine, emphasizes the role of cholinergic signalling in memory functions. The hippocampus, a key structure in learning and memory, is endowed with nAChRs localized at pre- and postsynaptic levels. In previous work on the immature hippocampus we have shown that, at low probability (P) synapses, activation of alpha7 nAChRs by nicotine or by endogenously released acetylcholine persistently enhanced glutamate release and converted 'presynaptically silent' synapses into functional ones. Here we show that in the same preparation, at high P synapses, nicotine induces long-term depression of AMPA- and NMDA-mediated synaptic currents. This effect was mediated by presynaptic alpha7- and beta2-containing receptors and was associated with an increase in the paired pulse ratio and in the coefficient of variation. High P synapses could be converted into low P and vice versa by changing the extracellular Ca2+/Mg2+ ratio. In these conditions nicotine was able to persistently potentiate or depress synaptic responses depending on the initial P-values. A bi-directional control of synaptic plasticity by nicotine would considerably enhance the computational properties of the network during a critical period of postnatal development thus contributing to sculpt the neuronal circuit.