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The term Cajal-Retzius cells (CR cells) has nowadays been used to identify an heterogeneous population of morphologically and molecularly distinct reelin-producing cell types in the marginal zone/layer I of the developmental cerebral cortex and in the immature hippocampus of different species and at different times during embryogenesis and postnatal life.

These cells were discovered by two scientists, Cajal and  Retzius, at two different times and in different species. They are originated in the developing brain in multiple sites within the neocortex and hippocampus. From there, CR cells experience migration through the marginal zone, originating the layer I of the cortex.

As these cells are involved in the correct organization of the developing brain, there are several studies implicating CR cells in neurodevelopmental disorders, especially Alzheimer’s, schizophrenia, bipolar disorder, autism, lissencephaly and temporal lobe epilepsy.

History
It all started in 1891 when the famous neuroscientist and Nobel laureate, Santiago Ramón y Cajal described slender horizontal bipolar cells he had found in an histological preparation of the developing marginal zone of lagomorphs. These cells were then considered by Gustaf Retzius as homologous to the ones he had found in the marginal zone of human fetuses around mid-gestation in 1893 and 1894. He described those cells as having large, horizontal, sometimes vertically orientated somata located at some distance from the pia,.

Later on in 1899, Cajal drew the neurons in layer I of the human fetus at term and newborn. The cells layed closer to the pia and displayed smaller, often triangular or pyriform somata, and less complex processes that lacked the ascending branchlets and had a more superficial location than the cells Retzius previously described, ,. The cells different morphologies and the fact that Cajal and Retzius used different species in different times of development led to several reviews on the definition of the Cajal-Retzius cells, , , , ,. In fact immunohistochemical studies performed at advanced developmental stages in human and macaque cortex visualize cells more similar to the cells Cajal described,. In contrast, studies of the human mid-gestation period describe cells closer to the Retzius type.

The early descriptions by Cajal and Retzius referred to the neocortex but similar cells were found since 1994 in the marginal zone of the hippocampus, , ,. Various studies then proved the Cajal-Retzius cells as being responsible for the production of reelin, ,.

In 1999 Meyer loosely defined the Cajal-Retzius cells as the family of Reln-immunoreactive neurons in the marginal zone, as so to settle a difference between the pioneer neurons, Reln-negative preplate derivatives that settle in the same area and project to the subcortical area that he had already described in 1998. He also described simpler cells with simpler morphologies in the marginal zone of rodents.

In 2005 Bielle suggested that there were distinct subpopulations of Cajal-Retzius cells in different territories of the developing cortex due to the heterogeneity of transcription factors and the discovery of new sites of origin.

However, a clear classification scheme as so far not been established.

Developmental Origin
Though still unresolved, studies show that Cajal-Retzius cells have different origins, both in the neocortex and in the hippocampus. At the neocortex they are originated in the local pallium ventricular zone, the pallial-subpallial border of the ventral pallium, a region at the septum the cortical hem and retrobulbar ventricular zone. .

It has been discovered that in mice, CR cells are generated very early in the development, appearing between 10,5 and 12,5 embryonic days. .

Cajal-Retzius cells experience tangential migration in the marginal zone, a superficial layer of the preplate in the cortical neuroepithelium that will originate the layer 1 of the cortex, and according to some studies, this migration is also dependent of the site the cell was first generated, showing a link between this site, the migration and the location of these cells.

In 2006 it was demonstrated that the subpopulation of the cortical hem is controlled by the meninges, using tissue cultures and in vivo manipulations in mice.

Subpopulations of these neurons from the septum and pallial-subpallial border express the homeodomain transcription factor Dbx1 and migrate to the medial, dorsolateral and piriform cortex and though genetically different from the other subpopulations (Dbx1 negative), all have the same morphological and electrophysiological properties, showing us that even with different origins of CR cells, they get the same characteristics.

In the hippocampus, Cajal-Retzius cells have some of the major characteristics as those in the neocortex and also have different origins, like the ventral cortical hem and dentate-fimbrial neuroepithelium. .

It is very difficult to find a CR cell in the adult cortex, because the constant number of these cells and the fact that as the brain grows, the distance between these cells increases, requiring the observation of a great number of preparations to find one of these cells.

Properties and Functions
CR cells in rodents and primates are glutamatergic (using glutamate as a transmitter), but a subpopulation of CR cells may be GABAergic(using GABA as a transmitter).

Immunohistochemical studies (detecting antigens by exploiting the principle of antibodies binding specifically to antigens in biological tissues.) show that CR cells demonstrate the expression of GABA-A and GABA-B receptors, ionotropic and metabotropic glutamate receptors , vesicular glutamate transporters , and a number of different calcium-binding proteins, such as calbindin, calretinin and parvalbumin. CR cells express several genes important in corticogenesis, such as reelin (RELN), LIS1, EMX2, and DS-CAM. In addition, CR cells selectively express p73, a member of the p53 family involved in cell death and survival.

CR cells receive an early serotonergic input, which in mice forms synaptic contacts.

In marginal zone the whole-cell patch-clamp studies (the laboratory technique in electrophysiology that allows the study of single or multiple ion channels in cells) show that CR cells have electrophysiological fingerprints. When CRN injected by a suprathreshold depolarizing current pulse, it expresses a repetitive firing mode. However, when Cajal-Ratzius cells injected by a hyperpolarizing current pulse, it expresses a hyperpolarization-activated inward current (H-current).

Using chloride-containing patch-clamp electrodes, spontaneous postsynaptic currents (sPSCs) were recorded in about 30% of the CR cells in P0-P2 rat cerebral cortex. These sPSCs decreased to about 10% at P4, indicating that CR cells became functionally disconnected during further development Kirmse and Kirischuk found that these sPSCs were reversibly blocked by bicuculline, which is a light-sensitive competitive antagonist of GABA-A receptors, suggesting activation of GABA-A receptors in these sPSCs. Moreover, the frequency and amplitude of these sPSCs are not influenced by tetrodotoxin, which inhibits the firing of action potentials in nerves, indicating that these sPSCs are independent on presynaptic action potentials.

In other regions of the immature brain and in immature neocortical pyramidal neuronsthere are prominent membrane depolarizations in CR cells caused by GABA-A and glycine receptor activation. .

A role in brain development
CR cells secrete the extracellular matrix protein reelin, which is critically involved in the control of radial neuronal migration through a signaling pathway, including the very low density lipoprotein receptor (VLDLR), the  apolipoprotein E receptor type 2 (ApoER2), and the cytoplasmic adapter protein  disabled 1 (Dab1). In early cortical development in mice, mutations of Dab1, VLDLR, and ApoER2, generate similar abnormal phenotypes, called  reeler-like phenotype. It perform several abnormal processes in brain development, such as forming an outside to inside gradient, forming cells in an oblique orientation. Therefore, CR cells control two processes: detachment from radial glia and somal translocation in the formation of cortical layers. In addition, the reeler type also manifest a poor organization of the Purkinje cell plate(PP) and the inferior olivary complex(IOC).

Neurodevelopmental Disorders
Cajal-Retzius cells are, as said before, involved in the organization of the developing brain. Problems in migration, especially those that arise from the lack of reelin production, may influence brain development and lead to disorders in brain’s normal functioning. The reeler mutant mouse was described in the 1950’s by Falconer as a naturally occurring mutant. This type of mouse exhibits some behavioral abnormalities, such as ataxia, tremor and hypotonia, which were discovered to be related to problems in neuronal migration and consequently, cytoarchitecture in the cerebellum, hippocampus and cerebral cortex, ,.

It was found later that the mutation causing these disorders was located in the RELN gene which codes for reelin, a glycoprotein secreted by Cajal-Retzius cells in the developing brain. This protein seems to act as a stop signal for migrating neurons, controlling the positioning and orientation of neurons in their layers, according to the inside-out pattern of development. When the mutation occurs, reelin expression is reduced and this signal isn’t as strong, therefore, migration of the first neurons in the brain is not done correctly,. The reeler mutant has been used, because of its characteristics, as a model for the study of neuropsychiatric disorders.

Even though Cajal-Retzius cells highly reduce its number after maturation and in adult life, in brains from Alzheimer’s disease patients their number is diminished in comparison to normal brains and their morphology is also altered, namely there is a significant reduction of their dendritic arborization, which reduces the number of synapses between these cells and other neurons. On the other hand, as Cajal-Retzius cells are important to the laminar patterning of the brain, their loss may be related to the progressive disruption of the microcolumnar ensembles of the association cortex, which may explain some symptoms of this disease.

Other diseases said to be related to Cajal-Retzius cells, especially with the production of reelin, are schizophrenia, bipolar disorder, autism, lissencephaly and temporal lobe epilepsy.

Schizophrenia is thought to be of neurodevelopmental origin, that is, there are events in our developing brain between the first and second trimester of gestation that may condition the activation of the pathological neural circuits that lead to its symptoms later in life. Actually, it has been discovered that abnormal brain lamination is one of the probable causes of schizophrenia. Furthermore, it has been show that in schizophrenic’s brains, as well as in bipolar disorder’s, the glycoprotein reelin is 50% downregulated, which is associated to abnormal DNA methylation of the RELN gene promoter. In Autism patient’s brains there are also structural abnormalities in the neocortex and levels of reelin are diminished, suggesting the involvement of CR cells in this disorder, ,.

Lissencephaly results from defective neuronal migration between the first and second trimester of gestation which causes lack of gyral and sulcal development, as well as improper lamination, giving the brain a smooth appearance. There are five genes related to lissencephaly, including LIS1, the first to be discovered, and RELN. Apparently Cajal-Retzius cells aren’t affected in case of mutation in LIS1 gene, even though the product of this gene interferes with reelin interaction with their receptors. Mutations in the RELN gene appear in the autosomal form of lissencephaly with cerebral hypoplasia, where patients show developmental delay, hypotonia, ataxia and seizures, symptoms which can be related to the reeler mutant.

In contrast to the previous referred diseases, temporal lobe epilepsy is characterized by a high number prevalence of Cajal-Retzius cells in the adult life, which supposedly causes continuous neurogenesis and migration, thus causing the seizures that characterize this disorder.