Parvalbumin-Immunoreactive Axon Terminals in Macaque Monkey and Human Prefrontal Cortex: Laminar, Regional, and Target Specificity of Type I and Type II Synapses DARLENE S. MELCHITZKY, 1 SUSAN R. SESACK, 1,2 AND DAVID A. LEWIS 1,2 * 1 Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania 15213 2 Department of Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania 15213 ABSTRACT In sensory regions of primate neocortex, the calcium-binding protein parvalbumin (PV) is present in axon terminals that form both Gray’s type I (asymmetric) and type II (symmetric) synapses. Those terminals forming type I synapses appear to arise from relay nuclei in the thalamus, whereas those forming type II synapses derive from cortical local circuit neurons. However, whether PV is present in both of these two types of terminals in the association regions of the primate prefrontal cortex (PFC) is not known. In the present study, PV- immunoreactive (IR) axon terminals in the superficial layers (layers 2–3a) of monkey PFC area 9 were found to form exclusively type II synapses onto the dendritic spines (44%), shafts (39%), or somata/axon initial segments (17%) of pyramidal neurons. In contrast, in the middle layers (layers 3b–4), 52% of the PV-IR axon terminals formed type I synapses, and 79% of these terminals contacted dendritic spines. However, in the adjacent area 46, only 12% of the PV-IR terminals in the middle layers formed type I synapses. In addition, the PV-IR axon terminals forming type I synapses were 50% larger than those terminals forming type II synapses. Similar to the macaque monkey, in area 9 of the human PFC, PV-IR axon terminals forming type I synapses onto dendritic spines were found in the middle layers. These findings indicate that PV-IR axon terminals in macaque monkey and human PFC are likely to have both intrinsic and extrinsic sources. In addition, the laminar, regional, and target specificity of the labeled terminals forming type I synapses suggests that they arise from PV-IR neurons in the mediodorsal thalamic nucleus. J. Comp. Neurol. 408:11–22, 1999.  1999 Wiley-Liss, Inc. Indexing terms: asymmetric synapse; mediodorsal thalamic nucleus; schizophrenia In the prefrontal cortex (PFC), as well as in other areas of the primate neocortex, the calcium-binding protein parvalbumin (PV) is expressed in a subpopulation of -aminobutyric (GABA)-containing nonpyramidal neu- rons, including wide-arbor neurons and chandelier cells (Celio, 1986; DeFelipe et al., 1989; Conde ´ et al., 1994; Gabbott and Bacon, 1996). Consistent with these observa- tions, ultrastructural investigations have shown that PV- immunoreactive (PV-IR) axon terminals form Gray’s type II (symmetric) synapses (Gray, 1959) onto the dendritic shafts, dendritic spines, and somata of pyramidal cells (Blu ¨ mcke et al., 1991; DeFelipe and Jones, 1991; Williams et al., 1992), the known postsynaptic targets of basket or wide-arbor neurons (Freund et al., 1983; Lund and Lewis, 1993). Furthermore, the characteristic axon terminals of chandelier cells, which form symmetric synapses onto the axon initial segments of pyramidal cells (DeFelipe et al., 1985), have been demonstrated to be immunoreactive for PV (Blu ¨ mcke et al., 1991; Williams et al., 1992). In layer 4 of macaque monkey visual and somatosensory cortices, some PV-IR axon terminals form Gray’s type I (asymmetric) synapses (Blu ¨ mcke et al., 1991; DeFelipe and Jones, 1991), suggesting that PV also may be present in the excitatory projections from the thalamus that Grant sponsor: U.S. Public Health Service; Grant numbers: MH00519, MH45156, and MH43784. *Correspondence to: David A. Lewis, M.D., Western Psychiatric Institute and Clinic, Biomedical Science Tower, W1651, 3811 O’Hara Street, Pitts- burgh, PA15213. E-mail: lewis@cortex.psychiatry.pitt.edu Received 24 August 1998; Revised 1 December 1998; Accepted 13 December 1998 THE JOURNAL OF COMPARATIVE NEUROLOGY 408:11–22 (1999)  1999 WILEY-LISS, INC.