Department of Psychiatry and Department of Neurology and Neuroscience, Weill Medical College of Cornell University, Box 244, Room 929A Lasdon, 1300 York Ave., New York, NY 10021, USA
Address correspondence to Stewart A. Anderson, Department of Psychiatry, Department of Neurology and Neuroscience, Weill Medical College of Cornell University, Box 244, Room 929A Lasdon, 1300 York Ave., New York, NY 10021, USA. Email: SAA2007{at}med.cornell.edu.
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Abstract |
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Introduction |
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Although the distinct functions of interneuron subtypes are just beginning to be unraveled, both neurological and psychiatric diseases have been linked to abnormalities in interneuron function. Some forms of epilepsy may be related to abnormal number or function of chandelier cells (DeFelipe, 1999). Neuropeptide Y (NPY), expressed by subgroups of interneurons in the hippocampus and neocortex, has been linked to both anti-seizure and anxiolytic effects (Baraban, 2002
; Heilig and Thorsell, 2002
). Chandelier cell dysfunction has also been implicated schizophrenia (Woo et al., 1998
; Volk et al., 2002
), and other interneuron abnormalities have been described in bipolar disorder (Benes and Berretta, 2001
). Unfortunately, these studies cannot easily distinguish whether the interneuron defects are a cause rather than an effect of the disease.
Despite the relevance to cortical function and dysfunction, little is known about the generation of cortical interneuron diversity. Part of the difficulty may be due to fact that, at first glance, organizing this diversity appears rather forbidding. It has been known for some time that immunochemically detected parvalbumin, somatostatin, and calretinin is present in largely non-overlapping subgroups of interneurons in rodent neocortex (Rogers, 1992; Kubota et al., 1994
). These subgroups together comprise >80% of cortical interneurons (Gonchar and Burkhalter, 1997
), but the importance of these subgroups in terms of understanding the development of interneuron diversity is complicated by the fact that they cut across morphologically defined subtypes. For example, parvalbumin, present in
50% of interneurons in the neocortex of adult rats, is expressed in both Chandelier cells and in some basket cells. On the other hand, some physiological and connectivity characteristics appear to also separate into these same subgroups. Thus, RT-PCR analysis of interneurons characterized as fast spiking, regular spiking or irregular-spiking reveals expression of either parvalbumin, somatostatin or calretinin, respectively (Cauli et al., 2000
). Similar findings have also been reported using immunohistochemical methods after electrophysiological recordings (Kawaguchi and Kubota, 1997
). Connectivity also appears to distinguish between these neurochemically defined subgroups, as calretinin- and VIP-expressing cells appear to have a greater propensity for innervating other interneurons in both cortex and hippocampus (Gulyas et al., 1996
; Defelipe et al., 1999
; Gonchar and Burkhalter, 1999
). As shall be discussed below, the calretinin-expressing subgroup, as opposed to those expressing parvalbumin or somatostatin, also appear to differ in terms of their origins.
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Sources of Cortical Interneurons |
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The fact that many cortical interneurons derive from the subcortical telencephalon suggests two general possibilities for the generation of interneuron diversity. First, interneuron diversity could be established in proliferative zone(s) where they originate. This scenario appears to be the case for other subtypes of neurons, including those in the spinal cord (Jessell, 2000) retina (Livesey and Cepko, 2001
), and projection neurons of the cerebral cortex (McConnell, 1995
). Alternatively (or in addition), interneuron subtypes could be differentiated from multipotential GABAergic proto-interneurons by the actions of local cues within the cerebral cortex (Mione et al., 1994
).
Clearly, the proper differentiation of interneurons depends upon factors within the cortex (Gotz and Bolz, 1994). Some of these include activity (Antonopoulos et al., 1992
; Obst et al., 1998
), neurotrophins such as BDNF (Marty et al., 1997
; Huang et al., 1999
) and cytokines such as leukemia inhibitory factor (LIF) (Wahle et al., 2000
). The specificity for these effects on any particular subtype of interneuron has not been well established, although differences in exposure or sensitivity to LIF may explain transient versus permanent expression of NPY in parvalbumin or somatostatin expressing subgroups, respectively (Wahle et al., 2000
). Further exploration of epigenetic factors in the differentiation of interneurons are likely to find additional subtype specific influences, but the concept that important steps in the generation of interneuron diversity occur at the cells origin is supported by recent evidence that spatial and/or temporal differences exist in the genesis of interneuron subtypes (Table 1
).
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Temporal Differences in the Generation of Interneuron Subtypes |
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Spatial Differences in the Generation of Interneuron Subtypes |
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Similar results were recently found by focally injecting tritiated thymidine into the ventrallateral wall of the lateral ventricle, or into the neocortical proliferative zone, in neonatal ferrets (Anderson et al., 2002). At this age the pups are still generating neurons destined for the superficial cortical layers, so that the fate of cells born within the cortical or subcortical proliferative zones could be assessed at 6 weeks of age. Some of the subcortically labeled cells gave rise to cortical interneurons expressing parvalbumin or somatostatin, but not calretinin. The cortical injections gave rise to pyramidal neurons, and very small number of apparently GABA-expressing cells, but virtually no neurons expressing somatostatin, parvalbumin or calretinin.
Further evidence that interneuron subtypes may have distinct sources comes from the analysis of mice lacking the homeobox transcription factor Nkx2.1. In these mutants, which die at birth, the normal MGE has been replaced by tissue with a lateral ganglionic eminence (LGE)-like character (Sussel et al., 1999). The early (pre-E14.5), MGE to cortex migration appears to be absent in these animals (Anderson et al., 2001
), and the animals lack 50% of cortical GABA-expressing cells at E18.5 (Sussel et al., 1999
). Interestingly, later (E14.5E16.5) subcortical to cortex migration, which in wild-type mice appears to contain cells born in both the MGE and LGE, appears to be intact (Anderson et al., 2001
). At these stages the Nkx2.1 mutants lack markers of MGE-derived cells, including Lhx6 and Lhx7. However, although only half of the cortical GABAergic neurons are missing in these mutants, they appear to be missing all of those that express NPY and NOS (Anderson et al., 2001
).
Consistent with the findings in tissue sections, primary cultures of cortical cells from E18.5 Nkx2.1 mutants also lack NPY and NOS, and somatostatin expressing cells after 2 weeks in vitro. However, preliminary results suggest that calretinin expressing bipolar neurons do grow out of these mutant cultures (Q. Xu and S.A. Anderson, in preparation). These results further support the notion that somatostatin-expressing multipolar interneurons derive from the MGE, whereas the calretinin-expressing bipolar interneurons do not.
Another mutant in which calretinin-expressing cortical interneurons are differentially affected relative to other subtypes is the flathead rat (Sarkisian et al., 1999, 2001
). These animals harbor a recessive mutation in the gene encoding Citron-K (Sarkisian et al., 2002
). Neural progenitors in the telencephali of homozygous mutants display cytokinetic abnormalities and apoptosis that particularly affects the ganglionic eminences. In the cortex, interneurons appear to be affected more than projection neurons, but calretinin-expressing interneurons are spared relative to those that express parvalbumin. Although the cause of this difference is unclear, the results again are consistent with the hypothesis that interneuron subtypes are molecularly distinct at the progenitor stage.
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Potential Origins of Calretinin-expressing Interneurons |
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Another subcortical source of distinct subtypes of cortical interneurons may lie within the caudal telencephalon. An interneuron migration from ventral to dorsal telencephalon that runs in a caudal-dorsal direction has recently been described in chick (Anderson et al., 1997b; Cobos et al., 2001
). In rodents, the caudal ganglionic eminence (CGE) gives rise to neuronal migrations that are distinct from those of the LGE or MGE, and also gives rise to cortical interneurons (Nery et al., 2002
). It is not clear whether the CGE gives rise to particular subclasses of cortical interneurons.
Alternatively, calretinin expressing bipolar interneurons could originate from the cortex itself. Recent evidence from explant cultures of human embryos suggests that a substantial number of cortical interneurons arise from the cortical SVZ (Letinic et al., 2002). This may represent a species difference between rodents and humans, although several lines of evidence suggest that the late gestation or early postnatal cortical SVZ of rodents could conceivably give rise to interneurons. First, mice lacking both transcription factors Dlx1 and Dlx2, which also lack migration from the ganglionic eminences into the cortex in explant cultures, nonetheless have only a 75% reduction of cortical GABA-expressing cells at birth (Anderson et al., 1997b
, 2001
). It remains unclear whether this belies the presence of a leaky phenotype with regard to subcortical to cortical migration, migration of interneurons from a subcortical area other than the ganglionic eminences, or the generation of interneurons in the Dlx1/2 mutant cortex itself. In support of the leaky hypothesis, a few cells expressing Lhx6, a lim-homeodomain transcription factor that is expressed in cells migrating from the MGE to the cortex (Grigoriou et al., 1998
; Sussel et al., 1999
), are present in tissue sections from the Dlx1/2 mutant cortex (Anderson et al., 2001
).
Another, perhaps stronger line of evidence supporting a cortical source of calretinin expressing interneurons comes from cortical cultures prepared from E14 to E16 rats. These cultures give rise to calretinin expressing interneurons that proliferate in response to Fgf2 and that appear to be distinct from CajalRetzius cells (Pappas and Parnavelas, 1998). Interestingly, this effect did not occur for calbindin-expressing interneurons, which label a different subpopulation in postnatal cortex (Defelipe et al., 1999
). Moreover, calbindin labels apparent interneuron precursors migrating from the ganglionic eminences (Anderson et al., 1997a
), and thus may be restricted to a subcortically derived interneuron subgroup. The implication is that cortical precursors in the rodent, perhaps later in gestation, could generate the calretinin-expressing interneurons.
Studies whose results weigh against this possibility include the recent finding that injections of the S-phase marker [3H]thymidine into the cortical proliferative zone in the neonatal ferret, whose neocortex is at a similar developmentally age as the E15 mouse, do not label calretinin-expressing interneurons in vivo (Anderson et al., 2002). However, this age may be too early for labeling these cells. Another relevant study is that of the cortical phenotype of the Fgf2 mutant (Raballo et al., 2000
). These animals live into adulthood but have a dramatic reduction in projection neuron production in the rostral and lateral cortex with a corresponding increase in proportion of GABA-expressing cells (Korada et al., 2002
). Calbindin and parvalbumin expressing interneuron subtypes were also increased in proportion, although an affect on calretinin expressing subtypes was not reported.
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Virtually All Cortical Interneurons Appear to Express Dlx Genes |
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The most plausible interpretation of this result is that, in rodents, nearly all cortical interneurons derive from Dlx-expressing proliferative zones of the ventral telencephalon. But there is another possibility. After E14.5 in the mouse, many Dlx-expressing cells appear to migrate from the subcortical SVZ directly into the SVZ of the neocortex. Some of these cells express the postmitotic neuronal marker Tuj1, and, at E16.5, are not proliferating based on their lack of labeling with antibodies against proliferating cell nuclear antigen (PCNA) (Anderson et al., 2001). Slice transplant experiments of E14.5 GE, pulsed with BrdU for 4 h before fixation at 2 days in vitro (DIV), also found that GE cells did not proliferate after migration into the cortex (Polleux et al., 2002
).
Surprisingly, although DLX1 expressing cells in the cortical SVZ were negative for PCNA at E16.5, at P0 many of them colabel with PCNA and thus appear to be proliferating (Anderson et al., 2001). So what might be the source of proliferating Dlx-expressing cells in the neonatal cortical SVZ? One possibility, as has been proposed to be the case in humans (Letinic et al., 2002
), is that Mash1 expression in a minority of cortical progenitors induces Dlx genes. Another possibility is that, as occurs in the RMS, cells fated to be interneurons may be able to migrate while maintaining the capacity to proliferate. A logical source of this migration would be the MGE or LGE.
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Migratory Cells from the Ganglionic Eminences Do Not Appear to Proliferate in the Cortical SVZ In Vitro |
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To determine whether the mitogenic properties of Fgf2 may be necessary for the proliferation of migratory GFP-expressing cells 10 ng/ml of Fgf2 was added to the medium. Again, migration of GFP-labeled GE cells into the cortical PZ was robust, as was proliferation in the cortical PZ. However, the percentage of GFP expressing cells that incorporated BrdU within the cortical proliferative zone remained extremely small (E15.5 + 2DIV, 4/734; E17.5 + 2DIV, 0/560, E18.5 + 2DIV, 0/518).
To confirm that DLX1-expressing cells do proliferate in these slices, we tested DLX1 and BrdU double labeling in the cortical PZ of the non-transplanted hemisphere. In the cortical proliferative zone of sections of E17.5 + 2DIV there were 54 DLX1/BrdU co-labeled cells out of 416 that expressed Dlx1 (13%, data not shown). This percentage is consistent with the previous, unquantified finding that roughly half of DLX1 expressing cells in the cortical SVZ of tissue sections prepared at P0 also express PCNA (Anderson et al., 2001), a marker that is expressed throughout the cell cycle and shortly beyond.
These findings are consistent with a previous report that used similar methods at earlier time points (Polleux et al., 2002). They suggest that some proliferative, DLX expressing cells in the cortical SVZ of rodents derive from truly cortical, pallial progenitors, as has been proposed to occur in humans (Letinic et al., 2002
). However, their interpretation must be tempered by the many limitations of explant cultures, and by the possibility that proliferating DLX-expressing cells could migrate into the cortical SVZ from Dlx expressing regions other than the ganglionic eminences, such as the RMS. Regardless of the initially pallial or pallidal origin of the mitotic Dlx expressing cell in the cortical SVZ, it would be interesting to determine whether they selectively give rise to calretinin-expressing interneuron subtypes. Indeed, they might not give rise to neurons at all, as Dlx genes also appear to be expressed in progenitors of cortical oligodendrocytes (He et al., 2001
; Marshall and Goldman, 2002
) and astrocytes (Marshall and Goldman, 2002
).
In summary, although the issue is far from settled, converging lines of evidence suggest that spatial and temporal origins distinguish between major neurochemically and morphologically defined interneuron subtypes. Specifically, parvalbumin (Pv) expressing Chandelier cells (and probably also Pv-expressing basket cells), as well as somatostatin expressing interneurons, appear to derive from the MGE. Small, bipolar, calretinin expressing interneurons appear not to derive from the MGE, and some evidence suggests that they may undergo their final mitosis within the perinatal SVZ of the cortex itself. In relation to a recent report that the majority of interneurons in humans derive from the cortical SVZ (Letinic et al., 2002), it is interesting to note that in the cortex of humans and other primates a far higher percentage of interneurons express calretinin than in rodents (Conde et al., 1994
; Gabbot and Bacon, 1996; Gabbot et al., 1997; Gonchar and Burkhalter, 1997
; Kawaguchi and Kubota, 1997
).
The presence of spatial and temporal differences in the origins of distinct interneuron subtypes does not constitute proof that differences in factors present at these origins accounts for later phenotypic differences. Differential influences encountered during migration, or based upon the timing or location of their entry into the cortical plate, may also direct the initial expression of sub-phenotypes. Still, identification of the sources of interneuron subtypes will be a crucial step for studies of the factors that may determine their fate. Gaining knowledge of these factors should have important therapeutic benefits by shedding light on potential mechanisms of diseases that involve interneuron deficits. In addition, the directed use of factors that dictate the fates of interneuron subtypes could be useful for therapeutic cell replacement strategies for diseases such as epilepsy.
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Acknowledgments |
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