Calretinin-positive L5a pyramidal neurons in the development of the paralemniscal pathway in the barrel cortex
© Liu et al.; licensee BioMed Central Ltd. 2014
Received: 28 June 2014
Accepted: 4 November 2014
Published: 18 November 2014
The rodent barrel cortex has been established as an ideal model for studying the development and plasticity of a neuronal circuit. The barrel cortex consists of barrel and septa columns, which receive various input signals through distinct pathways. The lemniscal pathway transmits whisker-specific signals to homologous barrel columns, and the paralemniscal pathway transmits multi-whisker signals to both barrel and septa columns. The integration of information from both lemniscal and paralemniscal pathways in the barrel cortex is critical for precise object recognition. As the main target of the posterior medial nucleus (POm) in the paralemniscal pathway, layer 5a (L5a) pyramidal neurons are involved in both barrel and septa circuits and are considered an important site of information integration. However, information on L5a neurons is very limited. This study aims to explore the cellular features of L5a neurons and to provide a morphological basis for studying their roles in the development of the paralemniscal pathway and in information integration.
1. We found that the calcium-binding protein calretinin (CR) is dynamically expressed in L5a excitatory pyramidal neurons of the barrel cortex, and L5a neurons form a unique serrated pattern similar to the distributions of their presynaptic POm axon terminals.
2. Infraorbital nerve transection disrupts this unique alignment, indicating that it is input dependent.
3. The formation of the L5a neuronal alignment develops synchronously with barrels, which suggests that the lemniscal and paralemniscal pathways may interact with each other to regulate pattern formation and refinement in the barrel cortex.
4. CR is specifically expressed in the paralemniscal pathway, and CR deletion disrupts the unique L5a neuronal pattern, which indicates that CR may be required for the development of the paralemniscal pathway.
Our results demonstrate that L5a neurons form a unique, input-dependent serrated alignment during the development of cortical barrels and that CR may play an important role in the development of the paralemniscal pathway. Our data provide a morphological basis for studying the role of L5a pyramidal neurons in information integration within the lemniscal and paralemniscal pathways.
KeywordsCalretinin L5a pyramidal neuron Paralemniscal pathway Posterior medial nucleus Barrel cortex
In rodents, the primary somatosensory cortex (barrel cortex) integrates into the barrel- and septum-related columnar circuits and receives distinct sensory inputs via the lemniscal and the paralemniscal pathways from the whiskers ,. Via a relay of the principal sensory trigeminal nucleus (Pr5) and the contralateral ventroposteromedial nucleus (VPM), the lemniscal pathway transmits whisker-specific information exclusively to the barrel circuit and forms an input-dependent barrel pattern from the periphery to the center . Likewise, through the spinal trigeminal nucleus (Sp5i) and the contralateral posterior medial nucleus (POm), the paralemniscal pathway transmits information from multiple whiskers into both barrel and septa circuits ,,,. The main targets of POm projections are L5a neurons, although the axons also terminate at layer 4 (L4) septa and in L1. It is known that presynaptic POm axon terminals form a distinct pattern in which more axons project to the areas of L5a under septa than to the neighboring areas under barrels, and these terminals display regularly spaced triangular structures in L5A septa columns ,,,. However, whether L5a neurons are organized into unique patterns in the paralemniscal pathway, similar to those of L4 neurons in the lemniscal pathway, has not been clearly demonstrated.
In the barrel cortex, L5a is involved in both barrel and septa circuits and is considered to be an important site of information integration for the lemniscal and paralemniscal pathways ,. Electrophysiological studies show that L5a pyramidal neurons are exclusively activated by input from the POm rather than the VPM  and can form various types of intracortical synaptic connections with layer 2/3 (L2/3) neurons, L4 spiny satellite cells, and local L5a pyramidal neurons -. These studies have all indicated that L5a pyramidal neurons play key roles in barrel and septa circuits ,. However, to date, L5a pyramidal neurons are mainly distinguished by their approximate positions or by neuronal tracing, and the morphology of L5a pyramidal neurons remains poorly understood, which has prevented further clarification of the roles of L5a pyramidal neurons in the integration of information.
In this study, we found that the calcium binding protein calretinin (CR) is dynamically expressed in L5a pyramidal neurons of the barrel cortex. L5a pyramidal neurons form a unique, predominantly serrated pattern that is quite similar to the presynaptic projection pattern formed the POm in L5a. This unique alignment is dependent on sensory input, and its organization is synchronous with barrel formation during brain development. Furthermore, deletion of CR disrupts this alignment. In addition to L5a pyramidal neurons, CR is also expressed in the POm and Sp5i of the paralemniscal pathway during development, which indicates that CR may be involved in the development of the paralemniscal pathway. Our results provide an important morphological basis for studying the functions of L5a pyramidal neurons during paralemniscal pathway development and information integration.
CR is dynamically expressed in L5a pyramidal neurons of the barrel cortex
L5a pyramidal neurons form a unique serrated pattern that requires sensory input during early postnatal days for maintenance
It has been reported that the first postnatal week is critical for experience-dependent pattern formation in the barrel cortex. The afferent signal is the principal element in experience-dependent neuronal patterning ,,. It is possible that the distribution pattern of CR-positive L5a neurons may also be input-dependent. To further detect whether the distribution pattern of CR in L5a depends on sensory input, an early transection of the infraorbital nerve (ION) experiment was carried out. ION transection at P2 led to markedly reduced expression of CR in the neuropil and cell bodies of the L5a neurons by P3 (Figure4E,F). By P4, the CR-positive processes that extend to L4 had become shorter, and the septa-like pattern disappeared (Figure4G,H). At P8 and P15, few septa-like CR-positive processes were observed to extend to L4. More interestingly, the serrated distribution pattern of CR-positive L5a neurons also disappeared, and only the uniform row-like CR-positive zone remained (Figure4M,N,O). By P30, expression of CR in L5a could no longer be detected, similar to observations of the control. Taken together, our data indicate that the unique serrated alignment of CR-positive L5a pyramidal neurons is related to the paralemniscal pathway and depends on peripheral sensory input.
The alignment of L5a neurons develops synchronously with formation of the cortical barrels
Timing of the formation of the distinct serrated alignment of L5a neurons corresponds to the time window of cortical barrel formation and is input dependent, suggesting that the lemniscal and paralemniscal pathways might develop synchronously. We next compared the temporospatial development of the neuronal pattern of L5a with that of the barrels in L4 within the barrel cortex.
The serrated alignment of L5a neurons is disrupted in CR mutants
CR is also specifically expressed in the relay nucleus of the paralemniscal pathway
In rodents, the barrel cortex is a unique columnar neuronal circuit with barrel and septa columns (circuit) that receive distinct sensory information through the lemniscal and the paralemniscal pathways from the VPM and POm, respectively ,,. Information from both circuits must be integrated in the barrel cortex to mediate precise object recognition and related behavioral tasks . It has been reported that barrel dysfunction is associated with Fragile X mental retardation syndrome  and Huntingtons disease . Therefore, it is crucial to understand the mechanisms underlying the development of lemniscal and paralemniscal pathways, as well as the integration of information in the whisker-barrel cortex.
In the barrel cortex, L5a pyramidal neurons are of particular interest not only because they receive subcortical inputs exclusively from the paralemniscal pathway but also because they are involved in both the barrel and septa circuits ,,,. L5a pyramidal neurons are considered to be an important integration site of the lemniscal and paralemniscal pathways and the key output layer of the barrel cortex ,,,. However, information about L5a pyramidal neurons has remained limited.
The unique alignment of L5a pyramidal neurons may form part of the morphological basis for information integration in the barrel cortex
It is well known that the formation of peripheral-input-related neuronal patterning in the barrel cortex depends on thalamocortical afferents. Previous studies have demonstrated that the neuronal pattern in the lemniscal pathway in L4 is organized only after segregation of the presynaptic afferents ,. However, it remains unclear whether L5a neurons in the paralemniscal pathway integrate into an input-dependent distribution pattern during development that resembles the pattern of L4 neurons. Using retrograde neuronal tracing, POm axons have been shown to project mainly to L5a. Projections of the POm to L5a neurons in septa columns are denser than those to their neighbors just below the barrel columns, and POm projections form a row-like pattern with regularly spaced triangular structures, indicating that there may be a postsynaptic paralemniscal input-related neuronal pattern in L5a. In this study, using CR as a specific marker for L5a pyramidal neurons, we determined that L5a neurons are organized in a serrated alignment pattern complementary to the distribution pattern of the POm projection terminals. Furthermore, the disruption of this unique alignment after ION transection suggests that it is input dependent. Taken together, in the barrel cortex, there is an input-dependent neuronal pattern in L5a neurons of the paralemniscal pathway comparable to that formed by L4 neurons in the lemniscal pathway.
Although L5a pyramidal neurons are the main targets of the paralemniscal pathway, they also receive indirect lemniscal pathway input through monosynaptic connections between L4 barrel neurons and L5a neurons , as well as intracolumnar input from L2/3 and L5b in barrel columns ,. L5a neurons also send weak outputs to L2/3 neurons in the barrel columns ,,,,. In addition, L5a pyramidal neurons form local connections , sending outputs to intracolumn L5b cells , intercortical motor and secondary somatosensory cortices ,,, and the basal ganglia ,. Electrophysiological studies have unanimously indicated the importance of L5a pyramidal neurons as the integration site of the lemniscal and paralemniscal pathways. Feldmeyer, Roth and colleagues have reported synaptic connections between L4 spiny stellate cells and L5a pyramidal cells, and postsynaptic L5a somata are mostly located under the barrel wall and septa, suggesting the existence of a short circuit between the lemniscal and paralemniscal pathways . They also found local connections in paired L5a pyramidal neurons, mainly along the lateral border of barrel columns, and these connections appear to form vertical clusters. It is plausible that the vertical clusters may correspond to the extrusions within the serrated pattern of L5a pyramidal neurons observed in this study. Our observations have provided morphological support for connections between the barrel and septa columns. Meanwhile, more attention should be paid to the L5a neuronal intrusions into the lower part of L4 for further studies of the paralemniscal-related neuronal circuit and the integration of information in the barrel cortex.
The long processes of CR-positive L5a neurons may contribute to the composition of septa
In this study, we have shown that development of the L5a neuronal pattern parallels the segregation of VPM axons during the time window of barrel formation, indicating that the lemniscal and paralemniscal pathways may interact to regulate pattern formation and refinement of the barrel cortex.
In the somatosensory cortex, L4 is organized into cell-dense barrels and cell-sparse septa , which receive thalamocortical input from the VPM and POm, respectively ,. However, because septa are small and contain few cells, their properties remain largely unknown. In this study, from intrusions of L5a neuron alignment, we directly observed that the CR-positive neuropil extends into L4 and forms a septa-like pattern, which suggests that the dendrites of L5a pyramidal neurons may be components of the septa. Further studies are needed to understand the connections of septa with L5a pyramidal neurons and to help elucidate the function of septa and the septal circuit.
CR may be involved in development of the paralemniscal pathway and formation of the L5a neuronal alignment
The dynamic expression of CR in L5a neurons while cortical barrels are developing and the disruption of the distinct alignment of L5a pyramidal neurons in CR-null mutants indicate that CR, a critical element of calcium signaling, is involved in the development and maintenance of input-dependent patterning in L5a pyramidal neurons. Furthermore, the specific expression of CR in the paralemniscal pathway indicates that CR may also be required during development of the paralemniscal pathway and may therefore be important for its function. In this study, we were unable to evaluate the electrophysiological characteristics of CR-deficient L5a neurons. Further studies using CR mutants will be useful to elucidate the mechanisms underlying development of the paralemniscal pathway and its interaction with the lemniscal pathway in the barrel cortex.
In this study, we have shown that, as a main target of the paralemniscal pathway in the barrel cortex, CR-positive L5a pyramidal neurons form the POm projection-related neuronal pattern during early postnatal development, synchronously with lemniscal-related barrel formation. The expression of CR in the paralemniscal pathway and the changed patterning of the L5a neurons in the CR mutant indicated that CR may be important for development of the paralemniscal pathway and the barrel cortex. Our data provide an important morphological basis for studying the functions of L5a pyramidal neurons and development of the paralemniscal pathway in the barrel cortex.
The generation of GAD67-GFP knock-in mice has been previously described . The Calretinin knockout line  was purchased from Jackson Laboratory. The Fzd10-EGFP transgenic line was generated using the Frizzled10 promoter to drive the reporter gene as previously reported . Both male and female animals were used in this study. The day the vaginal plug was detected was designated as embryonic day 0.5 (E0.5). The day of birth was designated as postnatal day 0 (P0). Each group subjected to specific examination included at least 3 mice. All of the animals were bred in the animal facility at Southeast University. All of the experiments were performed according to the guidelines approved by Southeast University.
The pups were anesthetized by hypothermia at P2. Under a stereoscopic microscope, the mystacial whiskers on the left side were plucked before the operation. A small incision was made just behind the left whisker pad. The infraorbital nerve was exposed and transected with ophthalmic forceps. After hemostasis and saturation, the pups were put on a heating blanket to recover and returned to their home cages. The pups were then harvested at P3, P4, P8, P15 and P30, respectively. Each time point contained at least 5 pairs of animals.
Mice up to P4 were anesthetized by hypothermia. Mice at P8, P15, and P30 were anesthetized with sodium pentobarbital (50mg/kg body weight) via intraperitoneal injection. Each anesthetized mouse was perfused transcardially with 0.1M phosphate-buffered saline (PBS, pH7.4) followed by 4% paraformaldehyde (PFA) in 0.1M PBS under the stereoscopic microscope. The brains were removed, post-fixed for 810 hours in 4% PFA and protected with 30% sucrose in 0.1M PBS overnight at 4C. The brains were sectioned in the coronal plane using a freezing microtome (Leica). The thicknesses of the sections were 16?m (up to P4) and 25?m (P8, P15 and P30).
Immunostaining was performed according to standard protocols . Briefly, the sections were permeabilized in PBS containing 0.1% Triton X-100 (PBT) for 30min, blocked with 10% calf serum in PBT for 2h, incubated at 4C with primary antibody overnight, then incubated with the secondary antibody for 2h at room temperature (RT). Slices were then counterstained with the fluorescent nuclear stain DAPI and mounted under coverslips. The sections were washed with 0.1M PBS between the staining steps.
BrdU (Sigma-Aldrich, B5002) was dissolved in physiological saline at a concentration of 10mg/ml. Pregnant mice were given BrdU (50mg/kg, intraperitoneal injections) at E12.5, E13.5, E14.5, E15.5, and brains of the offspring were harvested at P8 for birth-dating analysis. CR immunostaining was carried out first, and sections were re-fixed with 4% PFA for 20min, then treated with 2N HCl for 15min at 42C. After HCl was washed out with PBS, immunostaining for BrdU was applied according to the standard procedure described above. At least three brains were collected from independent litters at each time point.
Primary and secondary antibodies
The following antibodies were used: rabbit polyclonal anti-CR (Chemicon, AB5054, 1:1000), mouse anti-CR (Chemicon, MAB1568, 1:1000), rat polyclonal anti-BrdU (Abcam, ab6326, 1:1000), rabbit polyclonal anti-Cux1 (Santa Cruz, sc-13024, 1:500), rat polyclonal anti-Ctip2 (Abcam, ab18465, 1:1000), rabbit polyclonal anti-Foxp2 (Abcam, ab16046, 1:1000), rabbit polyclonal anti-NeuroD2 (Abcam, ab31938, 1:100), rabbit polyclonal anti-GABA (Chemicon, AB131, 1:500), chicken anti-GFP (Invitrogen, A10262, 1:500). FITC goat anti-mouse IgG (Jackson ImmunoResearch, 115-095-146, 1:200), Alexa Fluor 555 donkey anti-mouse IgG (Invitrogen, A31570, 1:500), Alexa Fluor 633 goat anti-mouse IgG (Invitrogen, A21050, 1:500), Alexa Fluor 488/633 goat anti-rabbit IgG (Invitrogen, A11008/A21071, 1:500), Alexa Fluor 550 goat anti-rat IgG (Invitrogen, A11006, 1:500), and Alexa Fluor 488 conjugated AffiniPure donkey anti-chicken IgG (Jackson ImmunoResearch, 1:1000). DAPI was purchased from Sigma-Aldrich (D9564).
Sections were imaged under a confocal microscope (FV1000, Olympus) using the 405, 488, 559, and 633 laser channels. Pictures were captured sequentially for each channel under the 10, 20 and 40 objectives with excitation lasers and detection spectra calibrated to minimize channel crosstalk. The image format was 1024??1024pixels. Confocal image stacks were analyzed using FV10-ASW 4.1 Viewer.
In situ hybridization
Brains from P8 mice were perfused with 4% PFA, postfixed in 4% PFA overnight, and cryoprotected in 30% sucrose/DEPC-PBS at 4C. Coronal sections (25?m thick) were sliced with a Leica CM 3050S cryostat and stored at ?70C until use. For Etv1 probe preparation, total RNA was extracted from E14.5 brains. Using primers with the sequences GAG TCA CAG GCC AGT AGC ATT and ACA GCA GCG GAA GCA TTA G, we amplified Etv1 fragments that were approximately 421bp in length (23802801), and these fragments were subcloned into pBluescript SK vectors and linearized (details available upon request). In situ hybridization was performed as described previously . Pictures were captured with an OlympusBX61 microscope (Tokyo, Japan). Three brain pairs from three independent litters were examined.
Coronal sections at three comparative levels from the anterior to posterior in each brain were examined. Pictures were acquired using an Olympus FluoView FV1000 confocal microscopy with the 20 objective lens. Cell counting was performed on sections using image Pro Plus software (Media Cybernetics).
JL and CZ designed the study; JL performed immunostaining and cell counting; BL generated the Fzd10-EGFP transgenic line, XZ and BY performed in situ hybridization; BY, WG and KW performed genotyping and the birth-dating test; YY and YG performed the infraorbital nerve transection; YY and SW provided the GAD76-GFP knock-in mouse line; JL, XW and CZ analyzed the data and wrote the paper. All authors read and approved the final manuscript.
JL has been a lecturer at the Department of Anatomy and Neuroscience, Medical School at Southeast University since 1998, teaching systemic and regional anatomy. From 2000 to 2004, JL studied the pathogenesis of cerebrovascular disease and earned her M.S. Since 2008, JL has studied as a Ph.D. student in the Key Laboratory of Developmental Genes and Human Diseases, MOE, Southeast University, working on neurodevelopment and related disorders with a particular focus on the primary development and function of the barrel cortex.
Principal sensory trigeminal nucleus
The contralateral ventroposteromedial nucleus of the thalamus
The interpolar subnucleus of the spinal trigeminal nucleus
The contralateral posterior medial nucleus
Postnatal day 4
Embryonic day 12.5
Cux family transcription factor 1
Chicken ovalbumin upstream promoter transcription factor-interacting protein 2
Transcription factor neurogenic differentiation factor 2
Forkhead box protein 2
67-kDa glutamic acid decarboxylase
Green fluorescent protein
Enhanced green fluorescent protein
Ets variant 1
Parafascicular thalamic nucleus
Reticular thalamic nucleus
We thank Professor Yongchun Yu (Institutes of Brain Science, Fudan University) for his suggestions, Yiquan Wei and Li Liu for their assistance with laboratory and animal care and other members of the laboratory for their discussions. This work was supported by grant 2012AA022402 from the National High Technology Research and Development Program of China and grants 91232301 and 31171040 from the National Natural Science Foundation of China to CZ.
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