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The Journal of Neuroscience, July 30, 2003, 23(17):6856-6865
Previous Article | Next Article
Brain-Derived Neurotrophic Factor Is Required for the Maintenance of Cortical Dendrites
Jessica A. Gorski, Steven R. Zeiler, Susan Tamowski, andKevin R. Jones Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, Colorado 80309
Abstract
Top
Abstract
Introduction
Brain-derived neurotrophic factor (BDNF) is thought to be involved in neuronal survival, migration, morphological and biochemical differentiation, and modulation of synaptic function in the CNS. In the rodent cortex, postnatal BDNF expression is initially low but subsequently increases to reach maximal levels around weaning. Thus, BDNF expression peaks at a time when both structural and functional maturation of cortical circuitry occurs. Although the function of BDNF has been probed using many approaches, its requirements during this phase of life have not previously been examined genetically. To test the in vivo requirements for BDNF during this important phase of development we generated early-onset forebrain-specific BDNF mutant mice. Although these mice undergo forebrain-restricted deletion of BDNF by Cre-mediated recombination during embryogenesis, they are healthy, and we did not detect the loss of specific cortical excitatory or inhibitory neurons. However, the neocortex of 5-week-old mice was thinner, attributable at least partly to neuronal shrinkage. Importantly, although visual cortical layer 2/3 neurons in the mutants initially developed normal dendrite structure, dendritic retraction became apparent by 3 weeks of age. Thus, our observations suggest that cortically expressed BDNF functions to support the maintenance of cortical neuron size and dendrite structure rather than the initial development of these features. This is consistent with a role for BDNF in stabilizing the "survival" of circuitry during the phase of activity-dependent reorganization of cortical connectivity.
Key words: BDNF; dendrite; cortex; morphology; Cre-lox; neurotrophin; mouse; mutant
Introduction
BDNF, a secreted neurotrophin, regulates aspects of neuronal survival, migration, morphological and biochemical differentiation, and synaptic function (Bibel and Barde, 2000; Huang and Reichardt, 2001
In vitro studies have demonstrated that BDNF has survival-promoting activity on cortical neurons through a calcium-dependent mechanism (Finkbeiner, 2000
Studies of null BDNF and TrkB mutant mice have suggested relatively subtle BDNF requirements in the survival of most cortical neurons, but have indicated functions in the migration and differentiation these cells (Klein et al., 1993
3-4 weeks of age) forebrain-restricted TrkB mutant mice suggested that some cortical excitatory neurons are lost after dendritic retraction over a period of several weeks (Xu et al., 2000
Although analysis of prenatal BDNF requirements is feasible using null mutant mice, and later adult requirements for BDNF have been indirectly probed using late-onset TrkB mutants, the initial genetic requirements of the BDNF-TrkB signaling system in the cortex during the period when BDNF expression rises dramatically have not been examined. To test these requirements specifically, we generated early-onset forebrain-restricted BDNF mutant mice. Notably, we were unable to detect specific cortical neuron losses, and layer II/III pyramidal neurons initially developed normal soma size and basal dendritic tree complexity. However, these cells subsequently shrank in size and lost dendritic complexity at
Materials and Methods
Generation of the BDNFlox targeting construct. The 5' lox site was inserted into a DraIII site in the 5' untranslated region (UTR), 14 bp downstream of the exon V splice acceptor site and 18 bp upstream of the initiation codon (Hohn et al., 1990Isolation of mouse strain. The linearized targeting construct was electroporated into D3 embryonic stem cells (Doetschman et al., 1985
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Figure 1. Generation of forebrain-restricted BDNF mutant mice. A, Diagram of the BDNFlox allele. Exon V, the BDNF coding exon, is shown schematically at the top [open bar, 5'-UTR; shaded bar, pro region (a portion of the BDNF procursor protein removed by proteolytic processing); filled bar, mature hormone region], flanked by lox sites (filled triangles), and followed by lacZ (hatched bar), an SV40 intron-polyA (open bar), and an FRT-flanked PGK neomycin (open bar with triangles). Location of the splice acceptor (SA) is denoted by a narrow. B, Diagram of the BDNFlox allele after Cre-mediated recombination. BDNF-coding sequences in exon V are excised and lacZ is brought downstream of the splice acceptor site and under control of BDNF promoters. C, X-gal stained 10 µm coronal section through Emx1IREScre; BDNFlox/+ brain. D, X-gal stained 10 µm coronal section through BDNFlacZ/+ brain. E, Growth of wild-type (WT), Emx1IREScre; BDNFlox/+, BDNFneo/+ heterozygous (Hz), and Emx-BDNFKO mice (KO). Emx-BDNFKO mice weigh significantly less at 3, 4, 5, and 6 weeks of age. *p < 0.05. F, Tibia bone length measured for 5-week-old mice (n >10 mice per genotype). No significant differences were detected between genotypes. G, BDNF protein quantitated by ELISA, expressed as nanograms of BDNF protein per gram of wet tissue, in extracts of brain structures from 5-week-old mice (n = 3 mice per genotype). BDNF was not detected (nd) in the visual cortex and hippocampus of Emx-BDNFKO mice. visc, Visual cortex; hipp, hippocampus; thal, thalamus; mid/hind, midbrain/hindbrain.
Genetics and genotyping. All animal procedures were conducted in accord with U.S. Public Health Service guidelines and with the approval of the University of Colorado Institutional Animal Care and Use Committee. Two BDNFlox strains were isolated from independent embryonic stem cell clones, and the structure of the targeted locus was confirmed by DNA blot analysis (Fig. 1 B). To eliminate the PGK-neomycin selectable marker, BDNFlox mice were mated to the FLP-4917 Flp recombinase-expressing transgenic strain (Dymecki, 1996
BDNF protein ELISA. BDNF protein was quantitated using the BDNF Emax ImmunoAssay System (Promega, Madison, WI). Tissue was dissected and weighed and protein was extracted and quantitated following the manufacturer's protocol, except for a change in lysis buffer (to 50 m M Tris-HCl, 0.6 M NaCl, 0.2% Triton X-100, 1% BSA, 0.1 M benzothonion chloride, 1 m M benzamidine, 0.1 m M PMSF, pH 7.4). All samples from an individual animal were run in triplicate, and the resulting quantities were averaged.
Determination of cortical layer thickness. Mice were heavily sedated by the intraperitoneal injection of 14 µl/g avertin (0.025 gm 2,2,2 tribromoethylalcohol, 0.025 ml tertamyl alcohol in PBS) and transcardially perfused with 4% paraformaldehyde in 0.1 M phosphate buffer, pH 7.4. The brains were either cryoprotected overnight in 22% sucrose in 0.1 M phosphate buffer and sectioned coronally at 40 µm on a cryostat (Leica, Nussloch, Germany) or postfixed for over 12 hr and sectioned at 50 µm with a vibrating microtome (Leica). Sections were collected into PBS, washed in 0.5 M Tris, pH 7.5, mounted on slides (Superfrost; Fisher Scientific, Pittsburgh, PA), and counterstained with cresyl violet, (0.2% cresyl violet, 0.5% acetic acid, 0.01 M sodium acetate, and 0.02 M sodium hydroxide) and coverslipped with Permount (Fisher Scientific). Primary somatosensory and visual cortices [identified as per Franklin and Paxinos (1997
Neuron counts and density determination. Alternating 50 and 500 µm vibratome sections were prepared as above. A block
Diolistics. Diolistics was performed as described in Gan et al. (2000
Biocytin analysis of dendritic complexity. Layer II/III neurons were retrogradely filled as described previously (Xu et al., 2000
Cells were reconstructed and drawn using a camera lucida drawing tube at 400x magnification, and a modified Sholl analysis (Sholl, 1953
Cell counts using immunocytochemical markers. Cryostat (40 µm) or vibratome (50 µm) sections, prepared as described above, were collected into PBS, incubated in block (Tris-buffered saline, 0.4% Triton X-100, 1% glycine, 1% bovine serum albumin, and 1% normal goat serum) for 4 hr at room temperature, and then incubated in primary antibody for 2 d at 4°C. Primary antibodies specific for
-galactosidase (1:1000, ICN Pharmaceuticals, Auroria, OH; or 1:2000, from C. Yee and T. Finger, University of Colorado Health Sciences Center, Denver, CO), NeuN (1:1000, Molecular Probes), Calretinin (1:1000), Calbindin (1:200), GABA (1:500, Sigma, St Louis, MO), NPY (1:1000, Incstar, Minneapolis, MN), S100 (1:500, DAKO, Glostrup, Denmark), SCIP (1:100, a gift from Dr. G. Lemke, Salk Institute, San Diego, CA) and ER81 (1:500, a kind gift from Dr. T. M. Jessell, Columbia University, New York, NY).
Sections were washed three times in TBST (Tris-buffered saline, 0.4% Triton X-100) for 5 min and incubated in Alexa 488 goat anti-mouse IgG antibody (1:200, Molecular Probes) and Alexa 546 goat anti-rabbit IgG antibody (1:200, Molecular Probes) for 2 hr at room temperature. Sections were washed twice in TBST, once in TBS and once in 0.5 M Tris, pH 7.5, before mounting on Superfrost slides and coverslipped with Fluoro-mount (Fisher Scientific), or they were incubated in 0.2 M KCl, pH 2, for 2 min, incubated in 0.0001% Bisbenzamide in 0.2 M KCl, pH 2, for 45 sec, washed in 0.2 M KCl, pH 2, for 2 min and then rinsed in 0.5 M Tris, pH 7.5, before coverslipping as above. Images were captured using a microscope (Leica) running Openlab software (Improvision).
Calbindin- and parvalbumin-positive cells were counted in three strips of primary visual cortex 1200 µm wide at 100x magnification. Immunopositive cells were counted across the entire thickness of the cortex, except for Calbindin, for which only layers IV-VI were counted because Calbindin is also expressed in pyramidal neurons in layers II/III. Between five and eight strips per animal of primary visual cortex 335 µm wide, at 100x magnification, were used to count the ratio of GABA, SCIP, and ER81-positive cells to NeuN-positive cells. Counts were performed blind to the animal's genotype. One-way ANOVA with a Tukey post hoc test was used to determine statistical significance.
Results
Generation of early forebrain-restricted BDNF mutant mice
To enable the generation of tissue-specific BDNF mutant mice using the Cre-site-specific DNA recombinase, lox sites were inserted into exon V, the BDNF protein-coding exon. A trimerized polyadenylation signal was inserted upstream of the 3' lox site, and an E. coli lacZ gene was inserted downstream (Fig. 1A). Cre-mediated recombination deletes the polyadenylation signals, allowing lacZ transcription and translation in place of BDNF (Fig. 1B). Mice homozygous for BDNFlox (BDNFlox/lox) are viable and fertile, and in 5-week-old BDNFlox/lox mice BDNF protein concentration in visual cortex and hippocampus was not significantly different from wild-type (n = 4 mice/genotype, p > 0.05).To produce forebrain-restricted BDNF mutant mice, BDNFlox/+ mice were mated to Emx1IREScre/+; BDNFneo/+ mice. Emx1IREScre/+ mice, heterozygous for the Emx1IREScre allele, express Cre recombinase by embryonic day 10.5 in the precursors of cortical and hippocampal excitatory neurons and glia, causing recombination between lox sites, without expression in most subcortical structures and peripheral tissues (Gorski et al., 2002
Extent and specificity of the early forebrain-restricted BDNF mutation
Although we previously characterized the timing, tissue, and cell-type specificity of Emx1IREScre-mediated recombination using Cre-dependent reporter mouse strains (Gorski et al., 2002To further determine the efficacy of the Emx-BDNFKO mutation, BDNF protein from the brains of 5-week-old mice was quantified. BDNF protein was undetectable in the visual cortex and hippocampus of Emx-BDNFKO mice (Fig. 1G) (n = 3 mice/genotype, p < 0.001). Although BDNF protein in thalamus and midbrain/hindbrain structures of Emx-BDNFKO mice was reduced compared with wild-type mice (p < 0.01), only the cortex and hippocampus were significantly different compared with heterozygous mice (p < 0.05), indicating that the subcortical reductions are attributable mostly to the Emx-BDNFKO mice having one BDNFneo allele. Thus, these data document an effectively complete loss of BDNF in the cortex and hippocampus of Emx-BDNFKO mice, and reductions comparable to those found in heterozygotes in the thalamus and midbrain/hindbrain.
General characteristics of Emx-BDNFKO mice
Emx-BDNFKO mutant mice often opened their eyes 1 d later than their littermates, at P15 instead of P14, suggesting that they mature slightly more slowly than their littermates. At the ages of 3 and 5 weeks Emx-BDNFKO mice weighed less than their littermates (Fig. 1E). However, between 2 and 12 weeks, there was not a significant difference in tibia length between genotypes, indicating that skeletal growth was not affected, and by 8 weeks of age the body weights of wild-type and Emx-BDNFKO mutant mice were not significantly different (Fig. 1F). Beyond 16 weeks of age, Emx-BDNFKO mice developed mild obesity (35% increase in body mass at 16 weeks compared with wild-type, p < 0.05, n = 10). BDNFneo/+ mice developed more severe obesity and at a younger age, by 8 weeks (80% increase in body mass at 8 weeks compared with wild-type, p < 0.05, n = 10) as reported previously (Lyons et al., 1999Of eight mutants allowed to age, two died between 12 and 14 months, 5 between 14 and 16 months, and 1 at 18 months of age, suggesting a shortening of lifespan. Emx-BDNFKO mice exhibited poor fecundity; only two litters were born from 20 matings in which an Emx-BDNFKO male was paired with a wild-type female or vice versa (10 matings each way). Emx-BDNFKO males appeared more aggressive than normal and neither males nor females built normal nests. Detailed behavioral analysis of Emx-BDNFKO mice has documented that although abnormalities were not detected in tests for ataxia and anxiety, there are substantial deficits in spatial and nonspatial learning (Gorski et al., 2003
Cortical volume is reduced but cell losses are not apparent
Despite the behavioral deficits exhibited by Emx-BDNFKO mice, initial examination of their brains revealed relatively normal cytoarchitecture. Given the evidence supporting a role for BDNF/TrkB signaling in the survival, differentiation, and function of cortical neurons, we analyzed more carefully the cortical anatomy of Emx-BDNFKO mice. The cortex of 5-week-old Emx-BDNFKO mice was thinner than in control mice (Fig. 2A-F). Somatosensory cortical thickness was reduced by 12% (p < 0.001, n = 3) and visual cortical thickness was reduced by 17% (p < 0.001, n = 3). Determination of the absolute number of neurons in specific cortical regions is impractical, thus, we quantified neuronal density. A 22% increase in neuron density was found in layer II/III of Emx-BDNFKO visual cortex compared with wild-type (Fig. 2C) (p < 0.01, n = 3), suggesting that thinning of the cortex is attributable at least partly to shrinkage of neurons. Layers IV-VI showed a trend toward increased density that was not statistically significant (Fig. 2G).
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Figure 2. Cortical thinning in Emx-BDNFKO mice. Cresyl violet-stained 50 µm coronal sections of visual (A-C) and somatosensory (D-F) cortices from 5-week-old WT, Hz, and KO mice. Cortical thickness is reduced in KO mice, but the cytoarchitecture appears generally normal and barrels are apparent in somatosensory cortex (D-F). G, Neuronal density in visual cortex of 5-week-old mice (n = 3 mice per genotype). Neurons are distributed more densely in layer II/III of KO mice (p < 0.05).
Late-onset forebrain-restricted TrkB mutant mice were reported to lose some excitatory neurons in layer V, between 6 and 10 weeks of age, several weeks after the loss of TrkB (Xu et al., 2000
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Figure 3. Absence of detectable neuronal or glial losses at 5 weeks of age. A-F, (20 µm) of layer V of primary visual cortex processed for ER81 (A, C, E) or SCIP (B, D, F) immunocytochemistry. G-I, Coronal sections primary visual cortex sections (10 µm) processed for S100 and NeuN immunoreactivity. Quantitation of ER81 and SCIP-positive layer V neurons relative to NeuN-positive cells (J), ratio of S-100-positive astrocytes to NeuN-positive neurons (K), and the ratio of total cells to NeuN-labeled neurons (L) revealed no differences between the genotypes (p > 0.05, n = 3 mice per genotype).
To test whether cortically produced BDNF is involved in promoting the migration, chemical differentiation, and/or survival of cortical inhibitory interneurons, we examined the distribution of GABA-, calbindin-, parvalbumin-, neuropeptide Y (NPY) and calretinin-expressing cells in the somatosensory and visual cortices of 3- and 5-week-old mice. No differences in the qualitative pattern of immunostaining (Fig. 4A), or in the number of GABA-, calbindin-, or parvalbumin-expressing cells were detected between genotypes (Fig. 4B,C). Thus, as determined using these methods, BDNF was not required for the migration, proliferation, survival, and biochemical differentiation of most cortical inhibitory interneurons through 5 weeks of age.
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Figure 4. Apparently normal biochemical differentiation of cortical inhibitory neurons. A, Coronal sections (40 µm) of primary visual cortex from 3-week-old mice processed for parvalbumin, calbindin, NPY, and calretinin immunoreactivity revealed no gross differences in expression pattern. B, Quantification of calbindin- and parvalbumin-positive neurons from primary visual cortex of 2-, 3-, and 5-week-old WT and KO mice revealed no differences between the genotypes (p > 0.05, n = 3 mice per genotype). C, The ratio of GABA+/NeuN+ neurons is not significantly different at 5 weeks of age (p > 0.05, n = 3 mice per genotype).
The cortex is highly populated with astrocytes and oligoden-drocytes, and these cells are known to express the truncated TrkB receptor (Frisen et al., 1993
BDNF is required for the maintenance of neuronal morphology
Reduced neuron soma size or reduced extent of dendritic arborization could contribute to cortical thinning. Because layer II/III had significantly increased neuron density at 5 weeks of age (Fig. 2C), we studied layer II/III neurons. At 5 weeks of age, the soma area was reduced by 29 and 24% in Emx-BDNFKO mice compared with wild-type and heterozygotes, respectively (p < 0.001). This result indicated that soma shrinkage contributed to cortical thinning, but did not discriminate between two possibilities; either a failure in the initial development of soma size or the development of normal soma size followed by contraction. To distinguish between these possibilities, we analyzed soma size at two younger ages. At 2 weeks of age the neuron soma area was not significantly different between the genotypes (p > 0.7) (Fig. 5A-C), but at 3 weeks of age there was a 28 and 22% decrease in soma area in Emx-BDNFKO mice compared with wild-type and heterozygous mice, respectively (p < 0.001 and p < 0.05, respectively). Between 2 and 5 weeks of age, the soma size did not change significantly in the wild-type and heterozygous mice. Notably, the soma area shrank between 2 and 3 weeks of age in Emx-BDNFKO mice (p < 0.001), and again between 3 and 5 weeks (p < 0.05) in these animals. Thus, BDNF is not required for layer II/III pyramidal neuron somas to grow to their full size, but is necessary for the maintenance of soma size between 14 and 35 d of age.
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Figure 5. BDNF is required for the maintenance of layer II/III pyramidal neuron morphology. Examples of DiI labeled visual cortical layer II/III pyramidal neurons from 2-week-old (A-C) and 5-week-old (D-F) mice and biocytin-filled and camera lucida-reconstructed layer II/III visual cortical pyramidal neurons from 5-week-old mice (G-I). J, Soma area of layer II/III neurons at 2, 3, and 5 weeks of age (n = 3 mice per genotype, 15 cells per mouse). K, Number of primary dendrites from 2-, 3-, and 5-week-old mice. *p < 0.05; **p < 0.01; n = 3 mice per genotype, 15 cells per mouse. L, Number of branch points per primary dendrites for 2- and 5-week-old mice (n = 3 mice per genotype, 15 cells per mouse). M, Number of branches per dendrite order for 2- and 5-week-old mice. *p < 0.05; **p < 0.01; n = 3 mice per genotype, 15 cells per mouse. H, Modified Sholl analysis of layer II/III pyramidal neurons from 5-week-old mice. *p < 0.05; **p < 0.01; n = 3 mice per genotype, 7 cells per mouse. Data in J-L were obtained from neurons visualized through diolistic labeling, with the exception that biocytin-filled and camera lucida-reconstructed neurons were used for some of the 5-week-old animals for comparison (-b). Data in M and N were obtained from biocytin-filled and camera lucida-reconstructed neurons. O, Soma areas measured from calbindin (calb) and parvalbumin (parv)-positive cortical neurons from 3-week-old mice revealed a significant difference between Emx-BDNFKO and control genotypes. **p < 0.01; ***p < 0.01; n = 3 mice per genotype, 55-75 cells per mouse. P-R, BDNF expression during postnatal cortical development as detected by X-gal staining of 40 µm sections from BDNFlacZ/+ mice. Postnatal ages are indicated at the bottom.
Next, we analyzed the number of primary dendrites, which increases rapidly during the first two postnatal weeks in rats to beyond the adult level before declining slightly (Miller, 1988
Several reports have described BDNF influences on the branching of cortical dendrites. Thus, we analyzed basal dendrite branching in layer II/III. At 2 weeks of age there was no difference in the number of branch points per primary dendrite between the genotypes, but by 5 weeks of age there was a 29% reduction compared with wild-type and a 34% reduction compared with heterozygotes (p < 0.05) (Fig. 5L). Analysis of branch points per dendrite order revealed significant differences between genotypes (main effect for genotype F(2,9) = 29.03, p < 0.0001) (Fig. 5i), with intermediate to distal dendrites most affected. Modified Sholl analysis revealed a decrease in basal dendritic arbor complexity at 40 µm and greater distances from the neuron soma (Fig. 5O) (p < 0.001), also indicating that distal dendritic branching is more severely affected than proximal branching. In combination, these data revealed that cortical BDNF is not required for the initial elaboration of layer II/III neuron basal dendrites, but is required for the maintenance of the dendritic tree.
As described above, we did not detect cortical BDNF requirements for the survival or biochemical differentiation of specific excitatory and inhibitory neurons, but found that cortical BDNF is required for the maintenance of the size of layer II/III excitatory neurons. We were curious whether there might be a similar requirement of BDNF for maintenance of interneuron size. We measured the soma area of cortical inhibitory neurons and found that at 3 weeks of age the soma area of calbindin-positive neurons from layers IV-VI was reduced by 20% (p < 0.001) compared with both wild-type and heterozygous littermates (Fig. 5i). The soma of parvalbumin-positive neurons was reduced by
Discussion
Lack of a detected requirement for neuronal survival
Several reports have indicated that BDNF/TrkB signaling supports the survival of cortical neurons in vitro and in vivo (Ghosh et al., 1994Interneuron differentiation
In vitro and in vivo studies have suggested that BDNF may influence the maturation of GABAergic inhibitory interneurons (Marty et al., 1997CaMKII (
BDNF is required for maintenance of neuronal morphology
Our results support the hypothesis that BDNF expression in the developing forebrain is necessary for the maintenance of the anatomical characteristics of cortical neurons, both soma size and dendritic structure. Neuronal soma size has been correlated with both advancing neuronal development and increased neural activity. The molecular regulation of soma size is not well understood. Signaling through Ras G-protein and Akt protein kinase has been shown to affect cell size in multiple organisms and cell types, including murine cortical neurons (Heumann et al., 2000The processes of initial dendrite formation and branching occurred normally in the absence of cortical BDNF through the first two postnatal weeks. Thus, any influence of the low levels of BDNF present in the visual cortex before 2 weeks of age on layer II/III pyramidal neuron development is limited. However, when BDNF expression normally rises dramatically in the cortex between 2 and 3 weeks of age (Timmusk et al., 1994
Similarly, in another in vivo study, Xu et al. (2000
Previous studies of the effects of added BDNF on dendrites in cultured cortical slices have been interpreted mostly in the context of roles for BDNF-TrkB signaling in initiating dendrite growth (McAllister et al., 1995
Although some of the specific anatomical abnormalities in layer II/III of Emx-BDNFKO mice are similar to predictions from BDNF effects on cultured cortical slices, others are different. Similar to our findings, Niblock et al. (2000
The mechanism by which BDNF exerts its stabilizing effect on dendrite morphology is uncertain. BDNF-TrkB signaling might regulate the stability of dendrites directly. For example, TrkB signaling could regulate the activity of members of the Rho family of GTPases, known to modify dendrite number, form, and stability in a variety of neural types including cortical neurons (Threadgill et al., 1997
Alternatively, BDNF could influence dendritic structure indirectly through modulating synaptic activity. The levels and/or patterns of neuronal activity could be perturbed in the absence of BDNF. Both the development and the stability of dendritic form is sensitive to neural activity and is influenced by the process of synaptogenesis (Cline, 2001
Regardless of whether BDNF directly or indirectly influences dendrite structure, our results indicate that the essential function for cortical BDNF is not to support neuronal survival, the classic neurotrophic function, or to regulate the initial growth of cortical dendritic trees, as suggested by in vitro studies. Instead, cortical BDNF appears to support the "survival" of dendritic structure that is generated through BDNF-independent mechanisms. This requirement for dendrite maintenance occurs during the period of life when BDNF expression normally rises (between eye opening and weaning in murine visual cortex). This is particularly intriguing considered in the context of models of activity-dependent development of circuitry. In such models, an initially exuberant and relatively nonspecific set of connections is formed and then subsequently refined through a process in which connections are selected based upon Hebbian rules (Katz and Shatz, 1996
Footnotes
Received Mar. 25, 2003; revised Jun. 3, 2003; accepted Jun. 6, 2003.This work was supported by a Burroughs-Wellcome New Investigator in Pharmacology Award and grants from the American Cancer Society, the Colorado Council for Research and Creative Work, and Muscular Dystrophy Association (K.R.J.). We thank Chris Bassett, Tom Fuller-Rowel, Decha Sermwittawayong, Morgan Skurky-Thomas, and Tiffany Talley for technical support; Dr. Susan Dymecki for the FLP mouse strain; Anirvan Ghosh and Louis Reichardt for helpful suggestions; Jessica Hanover, Naomi Ruff, and Michael Stryker for their assistance with the biocytin injection procedures; Drs. Greg Lemke, Cindy Yee, Tom Finger, and Thomas Jessell for providing anti-SCIP, -
Correspondence should be addressed to Dr. Kevin R. Jones, 347 UCB, Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, CO 80309. E-mail: krjones{at}stripe.colorado.edu.
Copyright © 2003 Society for Neuroscience 0270-6474/03/236856-10$15.00/0
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