Presynaptic NMDA Receptors Mediate IPSC Potentiation at GABAergic Synapses in Developing Rat Neocortex

NMDA receptors are traditionally viewed as being located postsynaptically, at both synaptic and extrasynaptic locations. However, both anatomical and physiological studies have indicated the presence of NMDA receptors located presynaptically. Physiological studies of presynaptic NMDA receptors on neocortical GABAergic terminals and their possible role in synaptic plasticity are lacking.We report here that presynaptic NMDA receptors are present on GABAergic terminals in developing (postnatal day (PND) 12-15) but not older (PND21-25) rat frontal cortex. Using MK-801 in the recording pipette to block postsynaptic NMDA receptors, evoked and miniature IPSCs were recorded in layer II/III pyramidal cells in the presence of AMPA/KA receptor antagonists. Bath application of NMDA or NMDA receptor antagonists produced increases and decreases in mIPSC frequency, respectively. Physiologically patterned stimulation (10 bursts of 10 stimuli at 25 Hz delivered at 1.25 Hz) induced potentiation at inhibitory synapses in PND12-15 animals. This consisted of an initial rapid, large increase in IPSC amplitude followed by a significant but smaller persistent increase. Similar changes were not observed in PND21-25 animals. When 20 mM BAPTA was included in the recording pipette, potentiation was still observed in the PND12-15 group indicating that postsynaptic increases in calcium were not required. Potentiation was not observed when patterned stimulation was given in the presence of D-APV or the NR2B subunit antagonist Ro25-6981.The present results indicate that presynaptic NMDA receptors modulate GABA release onto neocortical pyramidal cells. Presynaptic NR2B subunit containing NMDA receptors are also involved in potentiation at developing GABAergic synapses in rat frontal cortex. Modulation of inhibitory GABAergic synapses by presynaptic NMDA receptors may be important for proper functioning of local cortical networks during development

Altered white matter architecture in BDNF Met carriers

Brain-derived neurotrophic factor (BDNF) modulates the pruning of synaptically-silent axonal arbors. The Met allele of the BDNF gene is associated with a reduction in the neurotrophin's activity-dependent release. We used di ffusion-weighted imaging to construct structural brain networks for 36 healthy subjects with known BDNF genotypes. Through permutation testing we discovered clear di fferences in connection strength between subjects carrying the Met allele and those homozygotic for the Val allele. We trained a Gaussian process classi fier capable of identifying the subjects' allelic group with 86% accuracy and high predictive value. In Met carriers structural connectivity was greatly increased throughout the forebrain, particularly in connections corresponding to the anterior and superior corona radiata as well as corticothalamic and corticospinal projections from the sensorimotor, premotor and prefrontal portions of the internal capsule. Interhemispheric connectivity was also increased via the corpus callosum and anterior commissure, and extremely high connectivity values were found between inferior medial frontal polar regions via the anterior forceps. We propose that the decreased availability of BDNF leads to de cifits in axonal maintenance in carriers of the Met allele, and that this produces mesoscale changes in white matter architecture

Distribution and localization of the GABAB receptor

The functional GABAB receptors (GABABRs) are formed by obligate heteromers composed of two principal subunits named GABAB1 and GABAB2. In Drosophila melanogaster three GABAB subunits have been identified: GB1, GB2 and GB3. The GB1 and GB2 subunits need to be co-expressed in Xenopus oocytes or in mammalian cell lines to produce functional GABABRs. A subfamily of potassium channel tetramerization domain-containing (KCTD8, 12, 12b, and 16) proteins that are constituents of native GABABRs were recently identified. KCTDs show a temporal and spatial distribution pattern that may contribute to the heterogeneity of native GABABRs and their pharmacological properties. Of several isoforms of the GABAB1 subunit identified to date, the most abundant in the brain are the isoforms 1a and 1b; they are co-expressed with the subunit GABAB2 and their expression differs across brain and neuronal populations. GABAB1a localizes to glutamatergic terminals and is necessary for hetero-receptor function. Both isoforms 1a and 1b are detected in dendrites, but only GABAB1b in spine heads. Electron microscopy studies show that in the central nervous system (CNS), GABAB1 and GABAB2 are both pre and postsynaptic, but mostly localize to postsynaptic sites. The GABAB1(a/b) and GABAB2 subunits show an overlapping pattern of distribution throughout the CNS with certain exceptions (i.e. caudate-putamen and cerebellum). GABABRs are also detected in Schwann cells, in several peripheral tissues, and in non-neuronal cells (cardiomyocytes and airway smooth muscle). The widespread distribution of GABABRs in the CNS and the periphery reflects their physiological, pathophysiological, and pharmacological relevance