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Molecular and functional diversity among synapses is generated, in part, by differential expression of neurotransmitter receptors and their associated protein complexes. N -methyl- D -aspartate receptors (NMDARs) are tetrameric ionotropic glutamate receptors that most often comprise two GluN1 and two GluN2 subunits. NMDARs generate functionally diverse synapses across neuron populations through cell-type-specific expression patterns of GluN2 subunits (GluN2A - 2D), which have vastly different functional properties and distinct downstream signaling. Diverse NMDAR function has also been observed at anatomically distinct inputs to a single neuron population. However, the mechanisms that generate input-specific NMDAR function remain unknown as few studies have investigated subcellular GluN2 subunit localization in native brain tissue. We investigated NMDAR synaptic localization in thalamocortical (TC) neurons expressing all four GluN2 subunits. Utilizing super resolution imaging and knockout-validated antibodies, we revealed subtype- and input-specific GluN2 localization at corticothalamic (CT) versus sensory inputs to TC neurons in 4-week-old male and female C57Bl/6J mice. GluN2B was the most abundant postsynaptic subunit across all glutamatergic synapses followed by GluN2A and GluN2C, and GluN2D was localized to the fewest synapses. GluN2B was preferentially localized to CT synapses over sensory synapses, while GluN2A and GluN2C were more abundant at sensory inputs compared to CT inputs. Furthermore, postsynaptic scaffolding proteins PSD95 and SAP102 were preferentially localized with specific GluN2 subunits, and SAP102 was more abundant at sensory synapses than PSD95. This work indicates that TC neurons exhibit subtype- and input-specific localization of diverse NMDARs and associated scaffolding proteins that likely contribute to functional differences between CT and sensory synapses.

Abstract: As animals mature the decay of postsynaptic currents become faster at a variety of synapses. This change is thought to contribute to a refinement of motor co-ordination and to an increase in the precision of sensory perception and cognition. At cholinergic neuromuscular synapses and glycinergic and GABAergic inhibitory synapses, the developmental speeding of synaptic currents depends upon switches of receptor subunits and an ensuing acceleration in the kinetics of channel gating. At glutamatergic excitatory synapses, speeding in the decay time of NMDA receptor (NMDAR)-mediated excitatory postsynaptic currents (NMDA-EPSCs) is also dependent on developmental switches in NMDAR subunits. However, developmental speeding in the kinetics of AMPA receptor (AMPAR)-mediated EPSCs (AMPA-EPSCs) is caused by multiple factors. The decay time of AMPA-EPSCs can be shaped by the kinetics of channel gating or desensitization of AMPA receptors, depending upon the speed of transmitter clearance from the synaptic cleft. During postnatal development AMPAR channel gating and desensitization as well as the transmitter clearance speed up in kinetics. Given that the developmental speeding of synaptic currents play critical roles in the maturation of sensory and motor functions, any defect in this mechanism may seriously affect neuronal function. [Copyright &y& Elsevier]

AbstractThe γ2 subunit is an important functional determinant of GABAA receptors and is essential for formation of high-affinity benzodiazepine binding sites and for synaptic clustering of major GABAA receptor subtypes along with gephyrin. There are two splice variants of the γ2 subunit, γ2 short (γ2S) and γ2 long (γ2L), the latter carrying in the cytoplasmic domain an additional eight amino acids with a putative phosphorylation site. Here, we show that transgenic mice expressing either the γ2S or γ2L subunit on a γ2 subunit-deficient background are phenotypically indistinguishable from wild-type. They express nearly normal levels of γ2 subunit protein and [3H]flumazenil binding sites. Likewise, the distribution, number and size of GABAA receptor clusters colocalized with gephyrin are similar to wild-type in both juvenile and adult mice. Our results indicate that the two γ2 subunit splice variants can substitute for each other and fulfil the basic functions of GABAA receptors, allowing in vivo studies that address isoform-specific roles in phosphorylation-dependent regulatory mechanisms. [ABSTRACT FROM AUTHOR]

The two enantiomers of the putative centrally acting dopamine (DA) autoreceptor agonist 3-(3-hydroxyphenyl)-N- n-propylpiperidine, 3-PPP (Hjorth et al. 1981), were pharmacologically evaluated. An extensive series of biochemical and behavioural experiments unexpectedly revealed that both (+)- and (-)-3-PPP showed clear, but differential, effects on the DA receptors. Thus, (+)-3-PPP is a DA agonist with autoreceptor as well as postsynaptic receptor stimulatory properties. In contrast, although (-)-3-PPP similarly activates DA autoreceptors it acts concomitantly as an antagonist at postsynaptic DA receptors. Moreover, both behavioural and biochemical data on motor activity and DA synthesis and turnover suggest a preferential limbic action for the (-)-enantiomer. These results are discussed in terms of the dual antidopaminergic action of (-)-3-PPP coupled with anatomical differences in the feedback organisation in central (viz, limbic vs striatal) DA systems. It is suggested that compounds like (-)-3-PPP may be of potential clinical utility in the treatment of psychotic disorders, whilst lacking the seriously incapacitating motor dysfunctions produced by current neuroleptic therapy. [ABSTRACT FROM AUTHOR]

It is proposed that the evolutionary origin of the need to sleep is the removal of neurotransmitters (NTs) that escape reuptake and accumulate in brain interstitial fluid (ISF). Recent work suggests that the activity of ionotropic postsynaptic receptors, rapidly initiated by binding of NTs to extracellular sites, is modulated over longer times by adsorption of these NTs to the lipid bilayers in which the receptors are embedded. This bilayer-mediated mechanism is far less molecularly specific than binding, so bilayer adsorption of NTs that have diffused into synapses for other receptors would modulate their activity as well. Although NTs are recycled by membrane protein reuptake, the process is less than 100% efficient; a fraction escapes the region in which these specific reuptake proteins are localized and eventually diffuses throughout the ISF. It is estimated that even if only 0.1% of NTs escape reuptake, they would accumulate and adsorb to bilayers in synapses of other receptors sufficiently to affect receptor activity, the harmful consequences of which are avoided by sleep: a period of efficient convective clearance of solutes together with greatly reduced synaptic activity.