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ABSTRACT: Schizophrenia is a neurodevelopmental disorder whose clinical features include impairments in perception, cognition and motivation. These impairments reflect alterations in neuronal circuitry within and across multiple brain regions that are due, at least in part, to deficits in dendritic spines, the site of most excitatory synaptic connections. Dendritic spine alterations have been identified in multiple brain regions in schizophrenia, but are best characterized in layer 3 of the neocortex, where pyramidal cell spine density is lower. These spine deficits appear to arise during development, and thus are likely the result of disturbances in the molecular mechanisms that underlie spine formation, pruning, and/or maintenance. Each of these mechanisms may provide insight into novel therapeutic targets for preventing or repairing the alterations in neural circuitry that mediate the debilitating symptoms of schizophrenia. This article is part of a Special Issue entitled: Spine Plasticity and Pathology in Brain Disorders.
Neuroscience 04/2012; · 3.38 Impact Factor
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ABSTRACT: Levels of cannabinoid 1 receptor (CB1R) messenger RNA (mRNA) and protein, which are expressed most heavily in the cholecystokinin class of γ-aminobutyric acid (GABA) neurons, are lower in the dorsolateral prefrontal cortex in schizophrenia, and the magnitude of these differences is strongly correlated with that for glutamic acid decarboxylase 67 (GAD(67)) mRNA, a synthesizing enzyme for GABA. However, whether this correlation reflects a cause-effect relationship is unknown.
Using quantitative in situ hybridization, we measured CB1R, GAD(67), and diacylglycerol lipase alpha (the synthesizing enzyme for the endocannabinoid 2-arachidonoylglycerol) mRNA levels in the medial prefrontal cortex of genetically engineered GAD(67) heterozygous (GAD(67)(+/-)), CB1R heterozygous (CB1R(+/-)), CB1R knockout (CB1R(-/-)), and matched wild-type mice.
In GAD(67)(+/-) mice, GAD(67) and CB1R mRNA levels were significantly reduced by 37% and 16%, respectively, relative to wild-type mice and were significantly correlated across animals (r = .61; p = .01). In contrast, GAD(67) mRNA levels were unaltered in CB1R(+/-) andCB1R(-/-) mice. Expression of diacylglycerol lipase alpha mRNA, which is not altered in schizophrenia, was also not altered in any of the genetically engineered mice.
The findings that reduced GAD(67) mRNA expression can induce lower CB1R mRNA expression support the hypothesis that lower cortical levels of CB1Rs in schizophrenia may partially compensate for deficient GAD(67)-mediated GABA synthesis by reducing endogenous cannabinoid suppression of GABA release.
Biological psychiatry 01/2012; 71(2):114-9. · 8.93 Impact Factor
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ABSTRACT: Deficits in cognitive control, a core disturbance of schizophrenia, appear to emerge from impaired prefrontal gamma oscillations. Cortical gamma oscillations require strong inhibitory inputs to pyramidal neurons from the parvalbumin basket cell (PVBC) class of GABAergic neurons. Recent findings indicate that schizophrenia is associated with multiple pre- and postsynaptic abnormalities in PVBCs, each of which weakens their inhibitory control of pyramidal cells. These findings suggest a new model of cortical dysfunction in schizophrenia in which PVBC inhibition is decreased to compensate for an upstream deficit in pyramidal cell excitation. This compensation is thought to rebalance cortical excitation and inhibition, but at a level insufficient to generate the gamma oscillation power required for high levels of cognitive control.
Trends in Neurosciences 12/2011; 35(1):57-67. · 14.23 Impact Factor
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ABSTRACT: Levels of messenger RNA (mRNA) for the α1 subunit of the GABA(A) receptor, which is present in 60% of cortical GABA(A) receptors, have been reported to be lower in layer 3 of the prefrontal cortex (PFC) in subjects with schizophrenia. This subunit is expressed in both pyramidal cells and interneurons, and thus lower α1 subunit levels in each cell population would have opposite effects on net cortical excitation. We used dual-label in situ hybridization to quantify GABA(A) α1 subunit mRNA expression in calcium/calmodulin-dependent kinase II α (CaMKIIα)-containing pyramidal cells and glutamic acid decarboxylase 65 kDa (GAD65)-containing interneurons in layer 3 of the PFC from matched schizophrenia and healthy comparison subjects. In subjects with schizophrenia, mean GABA(A) α1 subunit mRNA expression was significantly 40% lower in pyramidal cells, but was not altered in interneurons. Lower α1 subunit mRNA expression in pyramidal cells was not attributable to potential confounding factors, and thus appeared to reflect the disease process of schizophrenia. These results suggest that pyramidal cell inhibition is reduced in schizophrenia, whereas inhibition of GABA neurons is maintained. The cell type specificity of these findings may reflect a compensatory response to enhance layer 3 pyramidal cell activity in the face of the diminished excitatory drive associated with the lower dendritic spine density on these neurons.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 06/2011; 36(10):2103-10. · 6.99 Impact Factor
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ABSTRACT: 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 dopamine- and cAMP-regulated phosphoprotein 32 kDa (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.
Neuroscience 02/2010; 167(2):428-38. · 3.38 Impact Factor
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ABSTRACT: Working memory (WM) is a core cognitive process that depends upon activation of D1 family receptors (D1R) and inhibitory interneurons in the prefrontal cortex (PFC). D1R are comprised of the D(1) and D(5) subtypes, and D(5) has a 10-fold higher affinity for dopamine. Parvalbumin (PV) and calretinin (CR) are 2 interneuron populations that are differentially affected by D1R stimulation and have discrete postsynaptic targets, such that PV interneurons provide strong inhibition to pyramidal cells, whereas CR interneurons inhibit other interneurons. The distinct properties of both the D1R and interneuron subtypes may contribute to the "inverted-U" relationship of D1R stimulation and WM ability. To determine the prevalence of D(1) and D(5) in PV and CR interneurons, we performed quantitative double-label immunoelectron microscopy in layer III of macaque area 9. We found that D(1) was the predominant D1R subtype in PV interneurons and was found mainly in dendrites. In contrast, D(5) was the predominant D1R subtype in CR interneurons and was found mainly in dendrites. Integrating these findings with previously published electrophysiological data, we propose a circuitry model as a framework for understanding the inverted-U relationship between dopamine stimulation of D1R and WM performance.
Cerebral Cortex 12/2008; 19(8):1820-34. · 6.54 Impact Factor
