Afferent specific role of NMDA receptors for the circuit integration of hippocampal neurogliaform cells.

Appropriate integration of GABAergic interneurons into nascent cortical circuits is critical for ensuring normal information processing within the brain. Network and cognitive deficits associated with neurological disorders, such as schizophrenia, that result from NMDA receptor-hypofunction have been mainly attributed to dysfunction of parvalbumin-expressing interneurons that paradoxically express low levels of synaptic NMDA receptors. Here, we reveal that throughout postnatal development, thalamic, and entorhinal cortical inputs onto hippocampal neurogliaform cells are characterized by a large NMDA receptor-mediated component. This NMDA receptor-signaling is prerequisite for developmental programs ultimately responsible for the appropriate long-range AMPAR-mediated recruitment of neurogliaform cells. In contrast, AMPAR-mediated input at local Schaffer-collateral synapses on neurogliaform cells remains normal following NMDA receptor-ablation. These afferent specific deficits potentially impact neurogliaform cell mediated inhibition within the hippocampus and our findings reveal circuit loci implicating this relatively understudied interneuron subtype in the etiology of neurodevelopmental disorders characterized by NMDA receptor-hypofunction.Proper brain function depends on the correct assembly of excitatory and inhibitory neurons into neural circuits. Here the authors show that during early postnatal development in mice, NMDAR signaling via activity of long-range synaptic inputs onto neurogliaform cells is required for their appropriate integration into the hippocampal circuitry.

Structural requirements for activation of the glycine coagonist site of N-methyl-D-aspartate receptors expressed in Xenopus oocytes.

Five structural features important for activation of the glycine recognition site on N-methyl-D-aspartate (NMDA) receptors were identified by structure-activity studies of more than 60 glycine analogues in voltage-clamped Xenopus oocytes injected with rat brain mRNA. First, sterically unhindered and ionized carboxyl and amino termini were essential for action at this site. Second, an increase in the interterminal separation by greater than one carbon (e.g., beta-alanine) markedly attenuated activity at this site. Third, activity at the glycine site was stereoselective. The D-isomers of alanine and serine were approximately 20 and 30 times more potent than the L-isomers. Fourth, only small sterically unobtrusive substitutions at the alpha-carbon could be tolerated. alpha-Methyl (D-alanine) and alpha-cyclopropyl (1-amino-cyclopropane carboxylic acid) (ACC) substitutions were effective as agonists but most larger aliphatic and aromatic alpha-carbon substitutions were simply inactive. Glycine, D-alanine, and ACC probably have only a two-point attachment to the receptor. Finally the alpha-carbon substituent of D-serine is envisioned as binding to a third site on the receptor probably via hydrogen bonding of the omega-terminal hydroxyl group. Thus, serine, an hydroxymethyl substitution of glycine, permitted activation of NMDA receptor-mediated currents, whereas isosteric substitutions incapable of hydrogen bonding (e.g., 2-aminobutyric acid) were inactive. Additionally, the position and size of the hydroxyl-containing group is critical for agonist action; D-threonine, DL-homoserine, and hydroxyphenolic substitutions at the alpha-carbon were all inactive. Halogenated analogs of a size comparable to D-serine but capable only of proton acceptance at the omega-terminus (beta-fluoro-D-alanine and beta-chloro-D-alanine) possessed agonist action, whereas an analog capable of only proton donation (1,2-diaminopropionic acid) was inactive. Full concentration-response curves were constructed for those analogs displaying greater than 25% of the effect of glycine when tested at 3 microM. With the exception of (R)-(+)cycloserine and beta-fluoro-D-alanine, all compounds were nearly full agonists and had Hill coefficients not significantly different from unity. The order of relative potency of the active analogs was ACC greater than glycine greater than D-serine greater than D-alanine greater than beta-fluoro-D-alanine greater than (R)-(+)-cycloserine greater than L-serine greater than L-alanine. Molecular modelling of a series of active and inactive analogs with close structural relation to glycine was undertaken. These results were complementary to those data obtained from the electrophysiological investigation.(ABSTRACT TRUNCATED AT 400 WORDS)