Synaptic and cellular changes induced by the schizophrenia susceptibility gene G72 are rescued by N-acetylcysteine treatment.

Genetic studies have linked the primate-specific gene locus G72 to the development of schizophrenia and bipolar disorder. Transgenic mice carrying the entire gene locus express G72 mRNA in dentate gyrus (DG) and entorhinal cortex, causing altered electrophysiological properties of their connections. These transgenic mice exhibit behavioral alterations related to psychiatric diseases, including cognitive deficits that can be reversed by treatment with N-acetylcysteine, which was also found to be effective in human patients. Here, we show that G72 transgenic mice have larger excitatory synapses with an increased amount of N-methyl-d-aspartate (NMDA) receptors in the molecular layer of DG, compared with wild-type littermates. Furthermore, transgenic animals have lower number of dentate granule cells with a parallel, but an even stronger decrease in the number of excitatory synapses in the molecular layer. Importantly, we also show that treatment with N-acetylcysteine can effectively normalize all these changes in transgenic animals, resulting in a state similar to wild-type mice. Our results show that G72 transcripts induce robust alterations in the glutamatergic system at the synaptic level that can be rescued with N-acetylcysteine treatment.

CB1 cannabinoid receptors are enriched in the perisynaptic annulus and on preterminal segments of hippocampal GABAergic axons.

Cannabinoids have been shown to modulate the inhibitory effect of cholecystokinin-containing GABAergic interneurons in the hippocampus via type 1 cannabinoid receptors (CB1 receptor). Although immunohistochemical studies, using pre-embedding techniques, have demonstrated that these receptors are abundant on GABAergic axon terminals, little is known about their exact location relative to the synapse. Here we used two recently developed antibodies against the CB1 receptor to study this question with the postembedding immunogold method, which allows the quantitative examination of receptor distribution along the axonal membrane, even within the synaptic active zone. CB1 receptor positive terminals target both the dendritic and somatic surface of neurons in the CA1 area of the rat hippocampus. We found no difference between these two populations of terminals either in their CB1 receptor density or in the distribution of receptors on their membrane. Recent studies suggest that endocannabinoids play a role in retrograde signaling at these synapses, i.e. signaling molecules diffuse from the postsynaptic membrane to nearby presynaptic terminals. Therefore, we examined the distribution of CB1 receptors on the terminal membranes. We found that they are rare in the synaptic active zone, but are enriched in the perisynaptic annulus, where they can directly influence synaptic calcium channels. Perisynaptic CB1 receptors represent about one tenth of all CB1 receptors in a terminal. In contrast, CB1 receptors have a lower density on the extrasynaptic membrane of terminals far from the postsynaptic cell. We estimated that these terminals contain exceptionally large numbers of CB1 receptors, i.e. a single axon terminal was usually labeled with more than 450 particles. An unexpected finding was that the density of CB1 receptors was significantly higher on preterminal axons than on synaptic terminals. These observations suggest that endocannabinoid signaling may subserve roles other than simply reducing transmitter release from axon terminals.

Large variability in synaptic N-methyl-D-aspartate receptor density on interneurons and a comparison with pyramidal-cell spines in the rat hippocampus.

Pyramidal cells receive input from several types of GABA-releasing interneurons and innervate them reciprocally. Glutamatergic activation of interneurons involves both alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) type glutamate receptors expressed in type I synapses, mostly on their dendritic shafts. On average, the synaptic AMPA receptor content is several times higher on interneurons than in the spines of pyramidal cells. To compare the NMDA receptor content of synapses, we used a quantitative postembedding immunogold technique on serial electron microscopic sections, and analysed the synapses on interneuron dendrites and pyramidal cell spines in the CA1 area. Because all NMDA receptors contain the obligatory NR1 subunit, receptor localisation was carried out using antibodies recognising all splice variants of the NR1 subunit. Four populations of synapse were examined: i). on spines of pyramidal cells in stratum (str.) radiatum and str. oriens; ii). on parvalbumin-positive interneuronal dendritic shafts in str. radiatum; iii). on randomly found dendritic shafts in str. oriens and iv). on somatostatin-positive interneuronal dendritic shafts and somata in str. oriens. On average, the size of the synapses on spines was about half of those on interneurons. The four populations of synapse significantly differed in labelling for the NR1 subunit. The median density of NR1 subunit labelling was highest on pyramidal cell spines. It was lowest in the synapses on parvalbumin-positive dendrites in str. radiatum, where more than half of these synapses were immunonegative. In str. oriens, synapses on interneurons had a high variability of receptor content; some dendrites were similar to those in str. radiatum, including the proximal synapses of somatostatin-positive cells, whereas others had immunoreactivity for the NR1 subunit similar to or higher than synapses on pyramidal cell spines. These results show that synaptic NMDA receptor density differs between pyramidal cells and interneurons. Some interneurons may have a high NMDA receptor content, whereas others, like some parvalbumin-expressing cells, a particularly low synaptic NMDA receptor content. Consequently, fast glutamatergic activation of interneurons is expected to show cell type-specific time course and state-dependent dynamics.

Synaptic effects of identified interneurons innervating both interneurons and pyramidal cells in the rat hippocampus.

GABAergic interneurons sculpt the activity of principal cells and are themselves governed by GABAergic inputs. To determine directly some of the sources and mechanisms of this GABAergic innervation, we have used dual intracellular recordings with biocytin-filled microelectrodes and investigated synaptic interactions between pairs of interneurons in area CA1 of the adult rat hippocampus. Of four synaptically-coupled interneuron-to-interneuron cell pairs, three presynaptic cells were identified as basket cells, preferentially innervating somata and proximal dendrites of pyramidal cells, but one differing from the other two in the laminar distribution of its dendritic and axonal fields. The fourth presynaptic interneuron was located at the border between strata lacunosum moleculare and radiatum, with axon ramifying within stratum radiatum. Action potentials evoked in all four presynaptic interneurons were found to elicit fast hyperpolarizing inhibitory postsynaptic potentials (mean amplitude 0.35 +/- 0.10 mV at a membrane potential of -59 +/- 2.8 mV) in other simultaneously recorded interneurons (n=4). In addition, three of the presynaptic interneurons were also shown to produce similar postsynaptic responses in subsequently recorded pyramidal cells (n=4). Electron microscopic evaluation revealed one of the presynaptic basket cells to form 12 synaptic junctions with the perisomatic domain (seven somatic synapses and five synapses onto proximal dendritic shafts) of the postsynaptic interneuron in addition to innervating the same compartments of randomly-selected local pyramidal cells (50% somatic and 50% proximal dendritic synapses, n=12). In addition, light microscopic analysis also indicated autaptic self-innervation in basket (12 of 12) and bistratified cells (six of six). Electron microscopic investigation of one basket cell confirmed six autaptic junctions made by five of its boutons. Together, these data demonstrate that several distinct types of interneuron have divergent output to both principal cells and local interneurons of the same (basket cells) or different type. The fast synaptic effects, probably mediated by GABA in both postsynaptic interneurons and principal cells are similar. These additional sources of GABA identified here in the input to GABAergic cells could contribute to the differential temporal patterning of distinct GABAergic synaptic networks.

[The creation of post-graduate medical teaching as social phenomenon in the middle of the twentieth century]. / La creation de l'enseignement medical post-universitaire, fait social du milieu du vingtieme siecle.

The explosive improvement in the middle of the twentieth century, in medical learning, induced, in medical practice, an unprecedented mutation. The adjustment of the physicians to this deep modification in each aspect of their practice, became, for the practitioners an absolute need and a deontological duty. From 1947, first in Paris, then, swiftly, all over France, the post-graduate medical teaching was created.

Input-dependent synaptic targeting of alpha(2)-subunit-containing GABA(A) receptors in synapses of hippocampal pyramidal cells of the rat.

Pyramidal cells, expressing at least 14 subunits of the heteropentameric GABA(A) receptor, receive GABAergic input on their soma and proximal dendrites from basket cells, activating GABA(A) receptors and containing either parvalbumin or cholecystokinin and vasoactive intestinal polypeptide. The properties of GABA(A) receptors are determined by the subunit composition, and synaptic receptor content governs the effect of the presynaptic neuron. Using a quantitative electron microscopic immunogold technique, we tested whether the synapses formed by the two types of basket cell show a difference in the subunit composition of GABA(A) receptors. Terminals of one of the basket cells were identified by antibodies to parvalbumin. Synapses made by parvalbumin-negative terminals showed five times more immunoreactivity for the alpha(2) subunit than synapses made by parvalbumin-positive basket cells, whose synapses were frequently immunonegative. This difference is likely to be due to specific GABA(A) receptor alpha subunit composition, because neither synaptic size nor immunoreactivity for the beta(2/3) subunits, indicating total receptor content, was different in these two synapse populations. Synapses established by axo-axonic cells on axon initial segments showed an intermediate number of immunoparticles for the alpha(2) subunit compared to those made by basket cells but, due to their smaller size, the density of the alpha(2) subunit immunoreactivity was higher in synapses on the axon. Because the two basket cell types innervate the same domain of the pyramidal cell, the results indicate that pyramidal cells have mechanisms to target GABA(A) receptors, under presynaptic influence, preferentially to distinct synapses. The two basket cell types act via partially distinct GABA(A) receptor populations.