NMDA receptor activation can alter synaptic strength, cause cell death, and may modulate the release of glutamate and other neurotransmitters. Using a specific and selective antiserum directed against the R1 subunit of the NMDA receptor, we examined (1) whether NMDA receptors in the adult rat visual cortex are exclusively postsynaptic or also presynaptic and (2) whether NMDA-R1 subunits are incorporated into the plasma membrane prior to, contemporaneously, or following the formation of synapses during postnatal development. By light microscopy, NMDA-R1 immunoreactivity in the adult visual cortex is easily detectable within perikarya and proximal dendrites in laminae 2-6. Many of them have the morphological features of pyramidal neurons. In addition, fine punctate labeling is evident throughout the neuropil. Electron microscopy reveals these puncta to reside at postsynaptic densities of axospinous junctions and at fine astrocytic processes and axon terminals. In the deeper laminae, the majority of labeled profiles are astrocytic. Visual cortices of animals in their first postnatal week show concentrated immunoreactivity in a few nonpyramidal neurons within laminae that have just differentiated from the cortical plate. Electron microscopy reveals diffuse labeling along the plasma membrane of dendritic shafts lacking morphologically identifiable synaptic junctions or appositions to axons. Immunoreactivity is detectable in dendritic processes by postnatal day (PND) 2, in axonal processes by PND 4, and in astrocytic profiles by PND 14. Immunoreactivity also is detectable along the postsynaptic membrane of presumably transient axosomatic junctions. At all ages, the prevalence of NMDA-R1-immunoreactive profiles is lamina 1 > 4/5 > 6/6B. These results provide the cellular basis for NMDA receptors' participation in (1) postsynaptic membrane excitability, (2) regulation of transmitter release, (3) and, in the deeper laminae, astrocyte responses. During development, NMDA-R1 subunits are associated with the plasma membrane prior to axons' arrival while clustering of receptors to junctions may be promoted by axonal contact. Finally, spatial segregation of axonal growth cones may be mediated by NMDA-R1 subunits on these axonal processes.
A series of electron microscopic immunocytochemical studies was performed to analyze subcellular sites for noradrenergic modulation in monkey prefrontal cortex. One out of 12 noradrenergic varicosities, identified by dopamine beta-hydroxylase immunocytochemistry within single ultrathin sections, forms morphologically identifiable junctions with small dendrites and spines. Accordingly, alpha2-adrenergic receptors, almost all of which are of the A-subtype, that occur in spines are localized discretely over postsynaptic membranes. alpha2-Adrenergic receptors are also found at sites along axons, dendritic shafts and astrocytic processes lacking morphologically identifiable synaptic junctions, suggesting that these receptors are activated by volume transmission. In particular, axonal alpha2-adrenergic receptors occur mostly at pre-terminal regions, suggesting that axo-axonic interactions may mediate reduction of neurotransmitter release at sites other than axo-spinous junctions by closing voltage-dependent calcium channels. These results indicate that noradrenergic modulation of prefrontal cortex involves synaptic interactions at spines of pyramidal neurons and nonsynaptic volume transmission to glia, dendritic shafts and axons.
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