Neuronal Plasticity the Arbor Way—Watching Dendritic Remodeling in the Neocortex
9 January 2005. The word "plasticity" means different things to different people. One of the more common uses refers to the inherent ability of neuronal circuits to change and adapt to their environment, but there are numerous candidates for the molecular and morphological processes underlying this the remodeling of circuits. It could be a subtle molecular rearrangement that changes the flux through specific circuits, or it could be as dramatic as completely rewiring the axons and dendrites of the neuronal circuitry. Scientists think of these plasticities as functional versus structural, and while there is evidence that both can occur in the mammalian neocortex, the latter has only been consistently demonstrated after injury or some kind of external manipulation. But in the December 27 PLoS Biology, Elly Nedivi and colleagues at MIT reported that dendrites in the mouse neocortex spontaneously expand and contract, a finding that might change the way some scientists view neuronal plasticity.
First author Wei-Chung Allen Lee and colleagues detected the structural plasticity when they used the powerful resolution of the two-photon microscope to visualize individual neurons inside the brains of 4- to 6-week-old living mice. Focusing their objectives on layer 2/3 of the visual cortex, they were surprised to see that all was not static. Images taken from exactly the same place, but at different times, revealed that dendrites, those arborlike branches that receive input from other neurons, appeared and disappeared with regularity.
Lee and colleagues monitored six pyramidal cells (named because of their shape) and eight nonpyramidal cells for three to 10 weeks. They found that each of the nonpyramidal cells had at least one, and as many as seven dynamic dendrite tips. In one neuron, four of 28 dendrite tips examined changed length. One of these branches extended by 16 μM over a 4-week period, while another extended by about 10 μM. In another nonpyramidal neuron, a single dendrite extended out of the field of view of the microscope. From age 11 to 13 weeks, that dendrite grew more than 90 μM. Overall, the authors found that about 14 percent (35 out of 259) of monitored dendrites grew (3 percent), retracted (2 percent), or did both (9 percent). By contrast, none of the 124 monitored pyramidal dendrites were dynamic, however, leaving the authors to conclude that “while dendritic branches of pyramidal cells remain stable, nonpyramidal interneurons in these layers are dynamic, exhibiting a range of structural changes on a week-to-week basis.” The authors found that the interneurons in question were γ-aminobutyric acid-, or GABAergic inhibitory neurons.
While this data indicates that the dendritic arbor can undergo spontaneous remodeling, the overall changes are small—only 1 to 5 percent of the total length of the dendritic arbor. This may explain why previous studies on remodeling have been inconsistent (for a review, see Chklovskii et al., 2004), but more importantly, it also raises questions of functional significance. “The functional test is a very hard one to pass,” said Karel Svoboda at the Howard Hughes Medical Institute at Cold Spring Harbor Laboratory in New York. He and other researchers, including Wen-Biao Gan at New York University School of Medicine, work to address this issue by looking at the dynamics of neuronal spines, which harbor the synapses that many neurons use to communicate with each other. Using this method, both groups have shown that spines turn over in pyramidal neurons of the cortex in response to stimuli. With electron microscopy, Svoboda’s lab also showed that these spines do have synapses (see SRF related news story). Both groups also reported early last year that, though there are both persistent and transient spines in the pyramidal neurons of adult mice, the spines become more stable as the animals age (see Holtmaat et al., 2005 and Zuo et al., 2005). Many nonpyramidal dendrites do not contain spines. Despite this, Lee and colleagues were able to monitor the spines on one neuron, finding them to be motile. However, it is not clear if any new spines formed, or if any existing spines disappeared during the growth and retraction of the dendrites.—Tom Fagan.
Allen Lee W-C, Huang H, Feng G, Sanes JR, Brown EN, So PT, Nedivi E. Dynamic remodeling of dendritic arbors in GABAergic interneurons of adult visual cortex. PLoS Biology. February 2006;4:e29. Abstract
Comments on News and Primary Papers
Primary Papers: Dynamic Remodeling of Dendritic Arbors in GABAergic Interneurons of Adult Visual Cortex.Comment by: Patricia Estani
Submitted 9 February 2006
Posted 9 February 2006
I recommend this paper
Comments on Related News
Related News: Dendritic Spine Research—Putting Meat on the BonesComment by: Amanda Jayne Law, SRF Advisor
Submitted 13 February 2006
Posted 13 February 2006
The formation of dendritic spines during development and their structural plasticity in the adult brain are critical aspects of synaptogenesis and synaptic plasticity. Actin is the major cytoskeletal source of dendritic spines, and polymerization/depolymerization of actin is the primary determinant of spine motility and morphogenesis. Some, but not all, postmortem studies in schizophrenia have identified reduced dendritic spine density in neurons of the hippocampal formation and dorsolateral prefrontal cortex (for review, see Honer et al., 2000); however, little is known about the underlying pathogenic mechanisms affecting synaptic function in the disease.
Many different factors and proteins are known to control dendritic spine development and remodeling (see Ethell and Pasquale, 2005). Comprehensive investigation of the effectors and signaling pathways involved in regulating actin dynamics may provide insight into the molecular mechanisms mediating altered cortical microcircuitry in the disease.
David Lewis and colleagues have previously reported reduced spine density in the basilar dendrites of pyramidal neurons in laminar III of the DLPFC (though this is not clearly a laminar-specific finding). In their current study, Hill et al. extended these investigations to examine gene expression levels for members of the RhoGTPase family of intracellular signaling molecules (e.g., Cdc42, Rac1, RhoA, Duo), and Debrin, an F-actin binding protein, all of which are critical signal transduction molecules involved in spine formation and maintenance. Their aim was to determine whether alterations in the expression of one of more molecules may underlie the reduced spine density seen in the disorder. Hill et al. report that reductions in Cdc42 and Duo mRNA are observed in the DLPFC in schizophrenia and correlate with spine density on deep layer III pyramidal neurons. This paper provides preliminary evidence that "gene expression levels of certain mRNAs encoding proteins known to be key regulators of dendritic spines are reduced in the DLPFC in schizophrenia." However, the paper also reports that these two mRNAs are reduced in lamina where significant reductions in spine density are not observed in schizophrenia. These results may suggest, as the authors discuss, that reduced expression of Cdc42 and Duo might contribute to, but is not sufficient to cause reduced, spine density.
Synaptic dysfunction has received increasing attention as a key feature of schizophrenia’s neuropathology and possibly its genetic etiology (Law et al., 2004). Neuregulin 1 (NRG1), a lead schizophrenia susceptibility gene, is known to be a critical upstream regulator of signal transduction pathways modulating cytoskeletal dynamics, playing pivotal roles in synapse formation and function. We have previously reported that isoform-specific alterations of the NRG1 gene and its primary receptor, ErbB4, are apparent in the brain in schizophrenia and related to genetic risk for the disease (Law et al, 2005a, Law et al, 2005b). Altered NRG1/ErbB4 signaling in schizophrenia may be a pathway to aberrant cortical neurodevelopment and synaptic function via dysregulation of specific intracellular signaling pathways linked to actin. The lack of significant alterations in gene expression levels for proteins such as Rac1 and RhoA in the DLPFC (gray matter, as reported by Hill and colleagues) in schizophrenia might be because the primary defect may not lie with the expression of these molecules but with the upstream modulation of their function and activity. Therefore, investigation of the proteins themselves, their phosphorylation status and activity, will be useful in understanding how genes effect molecular pathways that mediate biological risk for schizophrenia. The study of intracellular signaling cascades may be a route to a closer understanding of the biological mechanisms underpinning the association of genes such as NRG1 and ErbB4 with schizophrenia and their relationship to its neuropathology.
Ethell IM, Pasquale EB. Molecular mechanisms of dendritic spine development and remodeling.
Prog Neurobiol. 2005 Feb;75(3):161-205. Epub 2005 Apr 2. Review.
Honer G, Young C, and Falkai P, 2000. Synaptic Pathology in the Neuropathology of Schizophrenia, Progress and interpretation. Oxford University Press, edited by Paul J Harrison and Gareth W. Roberts, pp105-136.
Law AJ, Weickert CS, Hyde TM, Kleinman JE, Harrison PJ. Reduced spinophilin but not microtubule-associated protein 2 expression in the hippocampal formation in schizophrenia and mood disorders: molecular evidence for a pathology of dendritic spines.
Am J Psychiatry. 2004 Oct;161(10):1848-55.
Law, 2005a. Soc Neurosci Abstract, SFN Annual Meeting, Washington DSC, 2005.
Neuregulin1 and schizophrenia: A pathway to altered cortical circuits.
Also See SfN 2005 research news: Cortical Deficits in Schizophrenia: Have Genes, Will Hypothesize.
Law 2005b ACNP Abstract, Neuropsychopharmacology, vol. 30, Supplement 1.
SNPing away at NRG1 and ErbB4 gene expression in schizophrenia.
View all comments by Amanda Jayne Law