In the developing brain, many glutamate synapses have been found to transmit only NMDA receptor-mediated signaling, that is, they are AMPA-silent. This result has been taken to suggest that glutamate synapses are initially AMPA-silent when they are formed, and that AMPA signaling is acquired through activity-dependent synaptic plasticity. The present study on CA3-CA1 synapses in the hippocampus of the neonatal rat suggests that AMPA-silent synapses are created through a form of activity-dependent silencing of AMPA signaling. We found that AMPA signaling, but not NMDA signaling, could be very rapidly silenced by presynaptic electrical stimulation at frequencies commonly used to probe synaptic function (0.05-1 Hz). Although this AMPA silencing required a rise in postsynaptic Ca(2+), it did not require activation of NMDA receptors, metabotropic glutamate receptors or voltage-gated calcium channels. The AMPA silencing, possibly explained by a removal of postsynaptic AMPA receptors, could subsequently be reversed by paired presynaptic and postsynaptic activity.

Wasling, P., E. Hanse, and B. Gustafsson. Developmental changes in release properties of the CA3-CA1 glutamate synapse in rat hippocampus. J Neurophysiol 92: 2714 -2724, 2004; 10.1152/jn.00464. 2004. Developmental changes in release probability (P r ) and pairedpulse plasticity at CA3-CA1 glutamate synapses in hippocampal slices of neonatal rats were examined using field excitatory postsynaptic potential (EPSP) recordings. Paired-pulse facilitation (PPF) at these synapses was, on average, absent in the first postnatal week but emerged and became successively larger during the second postnatal week. This developmental increase in PPF was associated with a reduction in P r , as indicated by the slower progressive block of the N-methyl-D-aspartate (NMDA) EPSP by the noncompetitive NMDA receptor antagonist MK-801. This developmental reduction in P r was not homogenous among the synapses. As shown by the MK-801 analysis, the P r heterogeneity observed among adult CA3-CA1 synapses is present already during the first postnatal week, and the developmental P r reduction was found to be largely selective for synapses with higher P r values, leaving P r of the vast majority of the synapses essentially unaffected. A reduction in P ves , the release probability of the individual vesicle, possibly caused by reduction in Ca 2ϩ influx, seems to explain the reduction in P r . In vivo injection of tetanus toxin at the end of the first postnatal week did not prevent the increase in PPF, indicating that this developmental change in release is not critically dependent on normal neural activity during the second postnatal week. I N T R O D U C T I O NFollowing their formation, synapses undergo various collective changes, commonly referred to as synaptic maturation. One salient example of such maturation is a developmental decrease in release probability to a single action potential (P r ). This decrease in P r has been documented among glutamate synapses in several regions, including the developing neocortex (Kumar and Huguenard 2001; Reyes and Sakmann 1999), calyx of Held (Iwasaki and Takahashi 2001; Taschenberger et al. 2002), striatum (Choi and Lovinger 1997), and hippocampus (Bolshakov and Siegelbaum 1995; but see Hsia et al. 1998;Muller et al. 1989), suggesting that it represents an essential step in the maturation of the glutamate synapse. In the striatum, patterned neural activity supports the induction of a long-term depression (LTD) that is expressed as a decrease in P r (Choi and Lovinger 1997), suggesting that neural activity may underlie this form of maturation. However, whether inhibition of neural activity or of LTD during a critical period interferes with the maturation of P r has never been directly tested.Studies of hippocampal CA3-CA1 glutamate synapses have shown a considerable P r heterogeneity among the mature synapses (Hessler et al. 1993;Huang and Stevens 1997). During the first postnatal week, however, the synapse population has been described both to have a uniformly high P r (Bolshakov and Siegelbaum 1995)...

Key pointsr The cerebrospinal fluid contains numerous neuromodulators at ambient levels but whether, and how, they affect the activity of central neurons is unknown.r This study provides experimental evidence that human cerebrospinal fluid (hCSF) increases the excitability of hippocampal and neocortical pyramidal neurons.r Hippocampal CA1 pyramidal neurons in hCSF displayed lowered firing thresholds, depolarized resting membrane potentials and reduced input resistance, mimicking properties of pyramidal neurons recorded in vivo.r The excitability-increasing effect of hCSF on CA1 pyramidal neurons was entirely occluded by intracellular application of GTPγS, suggesting that neuromodulatory effects were mediated by G-protein coupled receptors.r These results indicate that the CSF promotes spontaneous excitatory neuronal activity, and may help to explain observed differences in the activity of pyramidal neurons recorded in vivo and in vitro.Abstract The composition of brain extracellular fluid is shaped by a continuous exchange of substances between the cerebrospinal fluid (CSF) and interstitial fluid. The CSF is known to contain a wide range of endogenous neuromodulatory substances, but their collective influence on neuronal activity has been poorly investigated. We show here that replacing artificial CSF (aCSF), routinely used for perfusion of brain slices in vitro, with human CSF (hCSF) powerfully boosts spontaneous firing of CA1, CA3 and layer 5 pyramidal neurons in the rat brain slice. CA1 pyramidal neurons in hCSF display lowered firing thresholds, more depolarized resting membrane potentials and reduced input resistance, mimicking properties of pyramidal neurons recorded in vivo. The increased excitability of CA1 pyramidal neurons was completely occluded by intracellular application of GTPγS, suggesting that endogenous neuromodulators in hCSF act on G-protein coupled receptors to enhance excitability. We found no increase in spontaneous inhibitory synaptic transmission by hCSF, indicating a differential effect on glutamatergic and GABAergic neurons. Our findings highlight a previously unknown function of the CSF in promoting spontaneous excitatory activity, and may help to explain differences observed in the activity of pyramidal neurons recorded in vivo and in vitro.

Previous work implicated the complement system in adult neurogenesis as well as elimination of synapses in the developing and injured CNS. In the present study, we used mice lacking the third complement component (C3) to elucidate the role the complement system plays in hippocampus-dependent learning and synaptic function. We found that the constitutive absence of C3 is associated with enhanced place and reversal learning in adult mice. Our findings of lower release probability at CA3-CA1 glutamatergic synapses in combination with unaltered overall efficacy of these synapses in C3 deficient mice implicate C3 as a negative regulator of the number of functional glutamatergic synapses in the hippocampus. The C3 deficient mice showed no signs of spontaneous epileptiform activity in the hippocampus. We conclude that C3 plays a role in the regulation of the number and function of glutamatergic synapses in the hippocampus and exerts negative effects on hippocampus-dependent cognitive performance.

It is well‐known that the extracellular concentration of calcium affects neuronal excitability and synaptic transmission. Less is known about the physiological concentration of extracellular calcium in the brain. In electrophysiological brain slice experiments, the artificial cerebrospinal fluid traditionally contains relatively high concentrations of calcium (2‐4 mM) to support synaptic transmission and suppress neuronal excitability. Using an ion‐selective electrode, we determined the fraction of ionized calcium in healthy human cerebrospinal fluid to 1.0 mM of a total concentration of 1.2 mM (86%). Using patch‐clamp and extracellular recordings in the CA1 region in acute slices of rat hippocampus, we then compared the effects of this physiological concentration of calcium with the commonly used 2 mM on neuronal excitability, synaptic transmission, and long‐term potentiation (LTP) to examine the magnitude of changes in this range of extracellular calcium. Increasing the total extracellular calcium concentration from 1.2 to 2 mM decreased spontaneous action potential firing, induced a depolarization of the threshold, and increased the rate of both de‐ and repolarization of the action potential. Evoked synaptic transmission was approximately doubled, with a balanced effect between inhibition and excitation. In 1.2 mM calcium high‐frequency stimulation did not result in any LTP, whereas a prominent LTP was observed at 2 or 4 mM calcium. Surprisingly, this inability to induce LTP persisted during blockade of GABAergic inhibition. In conclusion, an increase from the physiological 1.2 mM to 2 mM calcium in the artificial cerebrospinal fluid has striking effects on neuronal excitability, synaptic transmission, and the induction of LTP. Open science badges This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/. Read the Editorial Highlight for this article on page 435.

Pathological hallmarks of Alzheimer's disease (AD) include synaptic and neuronal degeneration and the presence of extracellular deposits of amyloid-beta (Abeta) in senile plaques in the cerebral cortex. Although these brain lesions may be seen also in aged non-demented individuals, the increase in brain Abeta is believed by many to represent the earliest event in the disease process. Accumulating evidence suggests that Abeta, which is highly conserved by evolution, may have an important physiological role in synapse elimination during brain development. An intriguing idea is that this putative function can become pathogenic if activated in the aging brain. Here, we review the literature on the possible physiological roles of Abeta and its precursor protein AbetaPP during development with special focus on electrophysiological findings.

No abstract

No abstract