Dopamine synaptic complex with pyramidal neurons in primate cerebral cortex.

Abstract

Dopamine (DA)-containing projections to the cerebral cortex are considered to play an important role in cognitive processes. Using a recently developed monoclonal antiserum directed against DA and an antibody directed against tyrosine hydroxylase in combination with Golgi impregnation and electron microscopy, we have observed that DA and tyrosine hydroxylase afferents establish symmetric membrane specializations with the soma, dendritic shafts, and spines of identified pyramidal cells in the prefrontal, cingulate, and motor cortex of primates. The axospinous contacts invariably formed part of a synaptic complex in which the dendritic spine of a pyramidal neuron was the target of both a DApositive symmetric and an unlabeled asymmetric bouton. This arrangement allows direct DA modulation of the overall excitability of cortical projection neurons by altering local spine responses to excitatory inputs. Dopamine (DA) has been implicated in a wide range of cognitive and affective behaviors and its importance for diseases affecting thought processes, such as schizophrenia, has been repeatedly stressed (1). Although the highest brain concentrations of DA are found in the caudate nucleus, this neurotransmitter is also present in the cerebral cortex, particularly in areas like the prefrontal cortex (2, 3) that are involved in emotional and cognitive processing. In rodents (4) and nonhuman primates (5), experimental depletion of DA has, in fact, been shown to result in cognitive deficits.A more complete understanding of DA's role in cortical function will require detailed knowledge about the cortical targets of DA afferents. The DA innervation of the primate prefrontal cortex has so far been studied only at the light microscopic level (6, 7). These studies reveal rich plexuses of DA-containing fibers in specific layers of the prefrontal cortex in monkeys (6, 7) and humans (8). However, definitive information on the postsynaptic structures innervated by these fibers is lacking. Accordingly, the goal of the present study was to provide ultrastructural data on the nature, distribution, and postsynaptic targets of dopaminergic boutons in the primate neocortex. We have used a recently available monoclonal antiserum directed against DA developed in one of our laboratories (9) as well as an antibody to its rate-limiting enzyme, tyrosine hydroxylase (TH) (10), and combined these methods with Golgi impregnation and electron microscopy (EM) to visualize DA synapses in the primate cortex. MATERIALS AND METHODSFive adult male rhesus monkey (Macaca mulatta) were deeply anesthetized and transcardially perfused using the fixative of Van Eden et al. (11) for DA and that of Somogyi and Takagi (12) for TH. After perfusion, blocks of tissue were taken from the dorsal bank of the principal sulcus (Walker's area 46), the anterior cingulate gyrus (Brodmann's area 24), and the primary motor cortex (Brodmann's area 4) (see Fig. 1) and were then sectioned perpendicular to the pial surface on a vibratome or cryostat. The sections were stai...

Catechol O-Methyltransferase (COMT) mRNA Expression in the Dorsolateral Prefrontal Cortex of Patients with Schizophrenia

“…The majority of dopaminergic terminals synapse on pyramidal neurons, while dopaminergic contacts on nonpyramidal neurons are much less dense and are irregularly distributed (Goldman-Rakic et al, 1989;Krimer et al, 1997;Smiley and Goldman-Rakic, 1993). Consistent with this, our present data show higher levels of COMT mRNA in pyramidal than in small, presumably nonpyramidal neurons.…”

“…Previous anatomical studies in monkey (Goldman-Rakic et al, 1989;Krimer et al, 1997;Lewis, 1992;Smiley and Goldman-Rakic, 1993) and human (Akil et al, 1999;Lewis, 1992) brain have demonstrated that dopaminergic projections to DLPFC are highly organized and distributed in a bilaminar manner at high densities in the superficial (I/II) and deep layers (V/VI), whereas the distribution is more uniform in the dorsomedial region of this cortical area. The majority of dopaminergic terminals synapse on pyramidal neurons, while dopaminergic contacts on nonpyramidal neurons are much less dense and are irregularly distributed (Goldman-Rakic et al, 1989;Krimer et al, 1997;Smiley and Goldman-Rakic, 1993).…”

GABAergic Interneurons Implications for Understanding Schizophrenia and Bipolar Disorder

“…Some of these monoaminergic fibers seem to project directly to nonpyramidal cells of the cortex and probably influence the activity of GABAergic neurons. For example, GABA neurons in rat medial prefrontal cortex receive direct inputs from dopaminergic fibers (Goldman-Rakic et al 1989;Verney et al 1990;Benes et al 1993). Consistent with this, nonpyramidal cells have been found to express both D1 and D2 receptor binding activities (Vincent et al 1993Davidoff and Benes 1998) or their associated messenger RNAs (Huntley et al 1992).…”

Dopaminergic signaling in dendritic spines

“…A significant subpopulation of spines [15] is simultaneously contacted by both dopaminergic and glutamatergic varicosities [15][16], forming the "striatal microcircuit" or "synaptic triad" [17]. Similar DA innervation architecture is also observed in pyramidal neurons in the cortex and hippocampus, and magnocellualar neurons of basolateral amygdale [17,32]. This "triad" architecture can serve as a heterosynaptic co-incidence detector by which activation of the DA terminal selectively influences the simultaneously active converging glutamatergic input at the level of individual spines.…”