Metabotropic glutamate receptors (mGluRs) mediate important modulatory glutamatergic influences throughout the brain. However, the specific localization and functions of group I mGluR subtypes (mGluR1alpha and mGluR5) in cortical neurotransmission are not well known, particularly in primates. To address this issue, we used immunoelectron microscopy to compare the subcellular localizations of mGluR1alpha and mGluR5 in the prefrontal cortex of macaque monkeys. Both receptor subtypes were found in a variety of subcellular compartments, including spines, dendrites, preterminal axons, axon terminals, and glia; however, quantitative differences were found in the relative abundance of labeled elements for each receptor. The mGluR1alpha-immunoreactive (-IR) elements were overwhelmingly the spines and dendrites, with labeled terminals, axons, and glia seen more rarely. The mGluR5-IR elements were also mostly spines and dendrites, but the proportion of labeled unmyelinated axons, terminals, and glia was higher than for mGluR1alpha-IR elements. Double labeling with SMI-32 and parvalbumin confirmed that both receptors were found in pyramidal cell and interneuron dendrites. The localization of mGluR1alpha to pyramidal cells in primate cortex contrasts with reports that mGluR1alpha is found almost exclusively in interneurons in rodent cortex. By using double labeling, we found no evidence for mGluR1alpha or mGluR5 in dopaminergic afferents to prefrontal cortex. The data presented here provide an anatomical substrate for a differential role of mGluR1alpha and mGluR5 in post-and presynaptic actions of glutamate in primate prefrontal cortex. They further suggest differences in the cortical distribution of group I mGluRs between primates and rodents.

Thrombospondins are extracellular-matrix glycoproteins implicated in the control of synaptogenesis and neurite growth. Previous microarray studies suggested that one gene of this family, thrombospondin 4 (THBS4), was upregulated during human brain evolution. Using independent techniques to examine thrombospondin expression patterns in adult brain samples, we report approximately 6-fold and approximately 2-fold greater expression of THBS4 and THBS2 messenger RNA (mRNA), respectively, in human cerebral cortex compared with chimpanzees and macaques, with corresponding differences in protein levels. In humans and chimpanzees, thrombospondin expression differences were observed in the forebrain (cortex and caudate), whereas the cerebellum and most nonbrain tissues exhibited similar levels of the 2 mRNAs. Histological examination revealed THBS4 mRNA and protein expression in numerous pyramidal and glial cells in the 3 species but humans also exhibited very prominent immunostaining of the synapse-rich cortical neuropil. In humans, additionally, THBS4 antibodies labeled beta-amyloid containing plaques in Alzheimer's cases and some control cases. This is the first detailed characterization of gene-expression changes in human evolution that involve specific brain regions, including portions of cerebral cortex. Increased expression of thrombospondins in human brain evolution could result in changes in synaptic organization and plasticity, and contribute to the distinctive cognitive abilities of humans, as well as to our unique vulnerability to neurodegenerative disease.

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The actions of dopamine D1 family receptors (D1R) depend upon a signal transduction cascade that modulates the phosphorylation state of important effector proteins, such as glutamate receptors and ion channels. This is accomplished both through activation of protein kinase A (PKA) and the inhibition of protein phosphatase-1 (PP1). Inhibition of PP1 occurs through PKA-mediated phosphorylation of DARPP-32 or the related protein inhibitor-1 (I-1), and the availability of DARPP-32 is essential to the functional outcome of D1R activation in the basal ganglia. While D1R activation is critical for prefrontal cortex (PFC) function, especially working memory, the functional role played by DARPP-32 or I-1 is less clear. In order to examine this more thoroughly, we have utilized immunoelectron microscopy to quantitatively determine the localization of DARPP-32 and I-1 in the neuropil of the rhesus monkey PFC. Both were distributed widely in the different components of the neuropil, but were enriched in dendritic shafts. I-1 label was more frequently identified in axon terminals than was DARPP-32, and DARPP-32 label was more frequently identified in glia than was I-1. We also quantified the extent to which these proteins were found in dendritic spines. DARPP-32 and I-1 were present in small subpopulations of dendritic spines, (4.4 and 7.7% and respectively), which were substantially smaller than observed for D1R in our previous studies (20%). Double-label experiments did not find evidence for colocalization of D1R and DARPP-32 or I-1 in spines or terminals. Thus, at the least, not all prefrontal spines which contain D1R also contain I-1 or DARPP-32, suggesting important differences in D1R signaling in the PFC compared to the striatum. Corresponding author: E. Chris Muly, Yerkes National Primate Research Center, 954 Gatewood Rd. NE, Atlanta, GA 30329, telephone (404) 727-9603, facsimile (404) 727-3278, emuly@emory.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptNeuroscience. Author manuscript; available in PMC 2011 May 5. The functional effects of activating D 1 or D 5 , the dopamine D1 family receptors (D1R), depend on a complex signal transduction pathway. The basic scheme of D1R signal transduction involves the coupling of D1R to G αs to activate adenylyl cyclase (AC) and produce cyclic AMP (cAMP) which, in turn, activates protein kinase A (PKA). PKA phosphorylates a variety of substrate proteins, and it is the altered phosphorylation of key signaling proteins that accounts for much of the effects of D1R stimulation. The actions of PK...