PrPC controls via protein kinase A the direction of synaptic plasticity in the immature hippocampus.

The cellular form of prion protein PrP(C) is highly expressed in the brain, where it can be converted into its abnormally folded isoform PrP(Sc) to cause neurodegenerative diseases. Its predominant synaptic localization suggests a crucial role in synaptic signaling. Interestingly, PrP(C) is developmentally regulated and its high expression in the immature brain could be instrumental in regulating neurogenesis and cell proliferation.

The depolarizing action of GABA controls early network activity in the developing hippocampus.

Early in postnatal life γ-aminobutyric acid (GABA), the primary inhibitory transmitter in adults, excites targeted neurons by an outwardly directed flux of chloride which results from the unbalance between the cation-chloride cotransporters NKCC1 and KCC2, involved in chloride uptake and extrusion, respectively. This effect contributes to generate synchronized network activity or giant depolarizing potentials (GDPs) in the developing hippocampus. Here, we review some recent data concerning the mechanisms by which GDPs are generated and their functional role in enhancing synaptic efficacy at poorly developed GABAergic and glutamatergic synapses.

Control of GABA Release at Mossy Fiber-CA3 Connections in the Developing Hippocampus.

In this review some of the recent work carried out in our laboratory concerning the functional role of GABAergic signalling at immature mossy fibres (MF)-CA3 principal cell synapses has been highlighted. While in adulthood MF, the axons of dentate gyrus granule cells release onto CA3 principal cells and interneurons glutamate, early in postnatal life they release GABA, which exerts into targeted cells a depolarizing and excitatory action. We found that GABA(A)-mediated postsynaptic currents (MF-GPSCs) exhibited a very low probability of release, were sensitive to L-AP4, a group III metabotropic glutamate receptor agonist, and revealed short-term frequency-dependent facilitation.

Up-regulation of GLT-1 severely impairs LTD at mossy fibre--CA3 synapses.

Glutamate transporters are responsible for clearing synaptically released glutamate from the extracellular space. By this action, they maintain low levels of ambient glutamate, thus preventing excitotoxic damage, and contribute to shaping synaptic currents. We show that up-regulation of the glutamate transporter GLT-1 by ceftriaxone severely impaired mGluR-dependent long-term depression (LTD), induced at rat mossy fibre (MF)-CA3 synapses by repetitive stimulation of afferent fibres.

At immature mossy fibers-CA3 connections, activation of presynaptic GABA(B) receptors by endogenously released GABA contributes to synapses silencing.

Early in postnatal life correlated GABAergic activity in the hippocampus is thought to play a crucial role in synaptogenesis and in the development of adult neuronal networks. Unlike adulthood, at this developmental stage, mossy fibers (MF) which are the axons of granule cells, release GABA into CA3 principal cells and interneurons. Here, we tested the hypothesis that at MF-CA3 connections, tonic activation of GABA(B) autoreceptors by GABA is responsible for the low probability of release and synapse silencing.

Low expression of Kv7/M channels facilitates intrinsic and network bursting in the developing rat hippocampus.

Early in development, network activity in the hippocampus is characterized by recurrent synchronous bursts, whose cellular correlates are giant depolarizing potentials (GDPs). The propensity for generating GDPs is attributed to GABAergic synaptic transmission being depolarizing and excitatory in neonatal neurons. However, developmental regulation of intrinsic conductances may also influence GDPs generation.

Nicotinic modulation of network and synaptic transmission in the immature hippocampus investigated with genetically modified mice.

The hippocampus, a key structure in learning and memory processes, receives a powerful cholinergic innervation from the septum and contains nicotinic acetylcholine receptors (nAChRs). Early in postnatal development, activation of nAChRs by nicotine or endogenous acetylcholine contributes to enhance synaptic signalling. Here, the patch-clamp technique was used to assess the contribution of alpha7 and beta2-containing (alpha7* and beta2*) nAChRs to nicotine-elicited modulation of GABAergic and glutamatergic activity at the network and single-cell level in the immature hippocampus of wild-type (WT), alpha7-/- and beta2-/- mice.

Reactive oxygen species mediate the potentiating effects of ATP on GABAergic synaptic transmission in the immature hippocampus.

Reactive oxygen species (ROS) constitute important signaling molecules in the central nervous system. They regulate a number of different functions both under physiological conditions and under pathological conditions. Here we tested the hypothesis that in the immature hippocampus ATP, the most diffuse neurotransmitter in the brain, modulates synaptic transmission via ROS.

Studies of the synaptic plasticity of field CA3 of the hippocampus during tetanization of the perforant path.

Studies on living slices of hippocampus-entorhinal cortex formation from adult rats were performed to investigate changes in responses in field CA3 to stimulation of mossy fibers in conditions of perforant path tetanization with different parameters. Tetanization of the perforant path at frequencies of 10 and 100 Hz induced depression of responses in CA3 on testing of this same path. Tetanization of the perforant path at a frequency of 10 Hz and an amplitude subthreshold for potentiating mossy fiber synapses in CA3 became threshold if preceded by tetanization of the perforant path at a frequency of 100 Hz.

GABAergic signaling at mossy fiber synapses in neonatal rat hippocampus.

In the adult rat hippocampus, granule cell mossy fibers (MFs) form excitatory glutamatergic synapses with CA3 principal cells and local inhibitory interneurons. However, evidence has been provided that, in young animals and after seizures, the same fibers can release in addition to glutamate GABA. Here we show that, during the first postnatal week, stimulation of granule cells in the dentate gyrus gave rise to monosynaptic GABAA-mediated responses in principal cells and in interneurons.

Adenosine down-regulates giant depolarizing potentials in the developing rat hippocampus by exerting a negative control on glutamatergic inputs.

Adenosine is a widespread neuromodulator that can be directly released in the extracellular space during sustained network activity or can be generated as the breakdown product of adenosine triphosphate (ATP). Whole cell patch-clamp recordings were performed from CA3 principal cells and interneurons in hippocampal slices obtained from P2-P7 neonatal rats to study the modulatory effects of adenosine on giant depolarizing potentials (GDPs) that constitute the hallmark of developmental networks. We found that GDPs were extremely sensitive to the inhibitory action of adenosine (IC(50) = 0.

ATP contributes to the generation of network-driven giant depolarizing potentials in the neonatal rat hippocampus.

In the immature hippocampus, the so-called 'giant depolarizing potentials' (GDPs) are network-driven synaptic events generated by the synergistic action of glutamate and GABA. Here we tested the hypothesis that ATP, a widely distributed neurotransmitter, directly contributes to the network activity during the first postnatal week. We found that in CA3 pyramidal cells, in the presence of the adenosine antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), ATP produced a transient facilitation of GDPs followed by a depressant effect.

[Study of giant depolarizing activity in the neonatal hippocampal neurones].

Spontaneous oscillatory activity is a general feature of developing neural networks. Early in postnatal development, spontaneous network-driven events, termed giant depolarizing potentials (GDPs), occur synchronously over the entire hippocampus. By performing simulation of hippocampal network with using physiology parameters of the neurons and its network from the present experiments and literature dates, we investigated the participation of the different components of network in the generation of GDPs.

[Study of synaptic plasticity of hippocampal CA3 area as a result of tetanization of perforant path].

Evoked responses in CA3 area to the mossy fibers stimulation were studied after low and high frequency tetanizations of the perforant path. Stimulations of perforant path with 10 and 100 Hz frequencies inducted depression testing through the same path. Subthreshold for potentiation of the mossy fibers inputs to the CA3 tetanization of the perforant path with 10 Hz frequency transformed to threshold one after previous tetanization of the perforant path with 100 Hz frequency.

GABA-mediated giant depolarizing potentials as coincidence detectors for enhancing synaptic efficacy in the developing hippocampus.

Spontaneously occurring neuronal oscillations constitute a hallmark of developmental networks. They have been observed in the retina, neocortex, hippocampus, thalamus, and spinal cord. In the immature hippocampus, the so-called "giant depolarizing potentials" (GDPs) are network-driven synaptic events generated by gamma-aminobutyric acid (GABA), which at this stage is depolarizing and excitatory.

[Modulating influence of adenosine triphosphate on the oscillating properties of hippocampal neurons during early ontogenesis].

Extracellular ATP was used to test the involvement of purinergic P2 receptors in the modulation of GAB Aergic giant depolarizing potentials (GDPs) in rat neonatal hippocampus. Bath application of ATP reduced the GDP frequency in a concentration-dependent manner. The inhibitory effect of ATP persisted in the presence of adenosine P1 receptor antagonist DPCPX indicating the action of ATP on GDPs.