Asymmetric synapses

It is noteworthy that some attempts have been made to visualize synaptic vesicles at an ultrastructural level in the brains of individuals with schizophrenia. In one study, tissue obtained from a temporal lobe biopsy of an individual with schizophrenia (Ong and Garey, 1993) showed many unusual asymmetric synapses, including clumped but numerous, synaptic vesicles located at short synaptic active zones. In another study, electron microscopic examination of the postmortem caudate nucleus revealed swelling of some axon terminals, shrinkage of some axon boutons and fewer synaptic vesicles (Uranova et al., 1996). These observations are similar to a series of prior postmortem electron microscopic studies, where... 

Ultrastructural studies in the striatum showed that D, receptor is present on dendrites and spines (heads and necks) postsynaptic to asymmetrical synapses and on postsynaptic densities on small synapses characteristic of DA terminals. The D, receptor is also... 

Studies at the ultrastructural level in the rat NAc shell showed that 65% of D4 receptors were contained in axons and axon terminals, in plasma and vesicular membranes, while only 22% were located in dendrites and dendritic spines which received input from TH-positive terminals (Svingos et al., 2000). The labeled terminals formed occasionally asymmetrical synapses, and only about 17% of them exhibited TH immunoreactivity. In the NAc, therefore, the D4 receptor appears to be involved in presynaptic rather than postsynaptic functions (Svingos et al., 2000). 

However, not every asymmetrical synapse has a dopamine input onto the same spine. The highest estimates of the fraction of spines that are innervated by dopamine come from Freund et al. (1984) who found that 39% of spines on reconstructed dendrites of a single striatonigral cell received one asymmetrical and one TH-positive symmetrical synapse. In contrast, estimates based on quantitative neuroanatomy, together with some assumptions about the distribution of synapses in the striatal volume give a much smaller fraction. Table 1 summarizes these estimates. 

Fig. 1. A. Morphology of dopamine synapses. Electron micrograph of neostriatal section showing a TH-positive bouton in symmetrical synaptic contact (arrow) with a dendritic spine (S) which receives an asymmetrical synapse on its head from a bouton containing small round vesicles (asterisk) spine apparatus (small arrow). Scale bar 0.2 pm. From Fig. 2F of Freund et al. (1984), with permission. B. Three-dimensional reconstruction of a dopaminergic axon found in a series of 70 sections of the neostriatum, showing the distribution of synaptic sites (arrows). Scale bar 1.0 pm. Modified from Fig. 3C of Groves et al. (1994), with permission.

Dopamine receptor labeling in terminals presynaptic to asymmetrical synapses... 

A similar picture applies to D2 labeling. Generally, a small number of D2 immunoreactive terminals forming asymmetrical synapses have been observed (Sesack et al., 1994 Hersch et al., 1995 Yung et al., 1995), or none at all (Levey et al., 1993). Unfortunately there has been no quantification of the fraction of such terminals which are labeled. However, as for the D1 receptors, their qualitative descriptions suggest only a small fraction of corticostriatal terminals to be D2 positive. 

Fig. 3. Localization of dopamine receptors and transporters in relation to pre- and postsynaptic structures. Dopamine transporter (DAT) and dopamine D2 receptors are localized to dopamine axons, but may be some distance from the sites of synaptic contact. Postsynaptic dopamine D1 and D2 receptors (D1/D2) are localized to postsynaptic densities of symmetrical and asymmetrical synapses, and also dendrites. See text for details.

Ultrastructural studies of the D5 dopamine receptor using immunocytochemistry have revealed that this receptor subtype is highly expressed in the human cortex in pyramidal neurons and their dendrites are present within layers IV-VI (Khan et al., 2000). The D5 dopamine receptor is also localized to the striatum, substantia nigra (both pars compacta and reticulata), the superior colliculus, the thalamus and the pyramidal cells of hippocampus (Khan et al., 2000). In the striatum, electron microscopic analysis indicates that D5 dopamine receptors are present in the spines where asymmetric synapses are formed... 

Fig. 4. Electron micrographs of L-Asp-LI and L-GIu-LI in hippocampus CAl from a hypoglycemic rat subjected to perfusion fixation. The tissue was treated with uranyl acetate before embedding in epoxy resin. The figure shows accumulation of immunoreactivities over synaptic vesicle clusters (sv) versus over cytoplasmic matrix (cm) in terminals making asymmetrical synapses on spines (s). Broken lines mark the houndary between the vesicle-rich and vesicle-poor parts of the terminals. Scale bar = 0.2 pm. (Modified from Gundersen et al., 1998.)...

Our published data also show that behavioral deficits in NL3 R451C mice are associated with an increase in inhibitory synaptic markers, increased evoked excitatory synaptic transmission, increased numbers of inhibitory synaptic puncta above detection threshold, but no change in the number of symmetric or asymmetric synapses by electron microscopy (Tabuchi et al., 2007) (not reproduced here). This increase in inhibitory synaptic function is consistent with the hypothesis that autism-like behaviors may be due to alterations in excitatory to inhibitory balance. 

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