New insights into cortical interneurons development and classification: contribution of developmental studies

The concerted development of GABAergic interneurons and glutamatergic neurons is a key feature in the construction of the cerebral cortex. In contrast with glutamatergic neurons, GABAergic interneurons are heterogeneous differing by their axonal and dendritic morphologies, biochemical markers, connectivity, and physiology. Furthermore, interneurons have recently been shown to be generated in a variety of telencephalic structures (the ganglionic eminences, the entopeduncular and preoptic areas and the cortex). This review describes the origin, specification and differentiation of interneurons. These recent developmental studies may help to clarify the classification of mature interneurons. In particular recent studies, including our own, provide compelling evidences that most interneurons are specify after their last division in their region of origin before migration. The roles of target tissues in determining the final physiological properties of interneurons are also discussed.     

Neurons on the move: migration and lamination of cortical interneurons

The modulation of cortical activity by GABAergic interneurons is required for normal brain function and is achieved through the immense level of heterogeneity within this neuronal population. Cortical interneurons share a common origin in the ventral telencephalon, yet during the maturation process diverse subtypes are generated that form the characteristic laminar arrangement observed in the adult brain. The long distance tangential and short-range radial migration into the cortical plate is regulated by a combination of intrinsic and extrinsic signalling mechanisms, and a great deal of progress has been made to understand these developmental events. In this review, we will summarize current findings regarding the molecular control of subtype specification and provide a detailed account of the migratory cues influencing interneuron migration and lamination. Furthermore, a dysfunctional GABAergic system is associated with a number of neurological and psychiatric conditions, and some of these may have a developmental aetiology with alterations in interneuron generation and migration. We will discuss the notion of additional sources of interneuron progenitors found in human and non-human primates and illustrate how the disruption of early developmental events can instigate a loss in GABAergic function.     

Excitatory projection neuron subtypes control the distribution of local inhibitory interneurons in the cerebral cortex

In the mammalian cerebral cortex, the developmental events governing the integration of excitatory projection neurons and inhibitory interneurons into balanced local circuitry are poorly understood. We report that different subtypes of projection neurons uniquely and differentially determine the laminar distribution of cortical interneurons. We find that in Fezf2?/? cortex, the exclusive absence of subcerebral projection neurons and their replacement by callosal projection neurons cause distinctly abnormal lamination of interneurons and altered GABAergic inhibition. In addition, experimental generation of either corticofugal neurons or callosal neurons below the cortex is sufficient to recruit cortical interneurons to these ectopic locations. Strikingly, the identity of the projection neurons generated, rather than strictly their birthdate, determines the specific types of interneurons recruited. These data demonstrate that in the neocortex individual populations of projection neurons cell-extrinsically control the laminar fate of interneurons and the assembly of local inhibitory circuitry.     

PROX1: A Lineage Tracer for Cortical Interneurons Originating in the Lateral/Caudal Ganglionic Eminence and Preoptic Area

The homeobox-encoding gene Prox1 and its Drosophila homologue prospero are key regulators of cell fate-specification. In the developing rodent cortex a sparse population of cells thought to correspond to late-generated cortical pyramidal neuron precursors expresses PROX1. Using a series of transgenic mice that mark cell lineages in the subcortical telencephalon and, more specifically, different populations of cortical interneurons, we demonstrate that neurons expressing PROX1 do not represent pyramidal neurons or their precursors but are instead subsets of cortical interneurons. These correspond to interneurons originating in the lateral/caudal ganglionic eminence (LGE/CGE) and a small number of preoptic area (POA)-derived neurons. Expression within the cortex can be detected from late embryonic stages onwards when cortical interneurons are still migrating. There is persistent expression in postmitotic cells in the mature brain mainly in the outer cortical layers. PROX1^+ve interneurons express neurochemical markers such as calretinin, neuropeptide Y, reelin and vasoactive intestinal peptide, all of which are enriched in LGE/CGE- and some POA-derived cells. Unlike in the cortex, in the striatum PROX1 marks nearly all interneurons regardless of their origin. Weak expression of PROX1 can also be detected in oligodendrocyte lineage cells throughout the forebrain. Our data show that PROX1 can be used as a genetic lineage tracer of nearly all LGE/CGE- and subsets POA-derived cortical interneurons at all developmental and postnatal stages in vivo.     

Postembryonic changes in circadian photo-responsiveness rhythms of optic lobe interneurons in the cricket Gryllus bimaculatus

The photo-responsiveness of 2 groups of interneurons responding to light in the protocerebrum was investigated at 2 developmental stages, the last instar nymphs and adults, in the cricket Gryllus bimaculatus. The cricket is diurnally active during the nymphal stage but becomes nocturnal as an adult. In both adults and nymphs, light-induced responses of optic lobe light-responding interneurons that conduct light information from the optic medulla to the lobula and the cerebral lobe showed a circadian rhythm peaking during the subjective night. Amplitudes of the rhythms were not significantly different between adults and nymphs, but adults showed more stable day and night states than did nymphs. The medulla bilateral neurons that interconnect the bilateral medulla areas of the optic lobe also showed circadian rhythms in their light-induced responses in both adults and nymphs. The rhythm had a clear peak and a trough in adults, and its amplitude was significantly greater than that of nymphs. These results suggest that the 2 classes of interneurons are differentially controlled by the circadian clock. The difference might be related to their functional roles in the animal's circadian behavioral organization.     

Parallel motor pathways from thoracic interneurons of the ventral giant interneuron system of the cockroach, Periplaneta americana

The data described here complete the principal components of the cockroach wind-mediated escape circuit from cercal afferents to leg motor neurons. It was previously known that the cercal afferents excite ventral giant interneurons which then conduct information on wind stimuli to thoracic ganglia. The ventral giant interneurons connect to a large population of interneurons in the thoracic ganglia which, in turn, are capable of exciting motor neurons that control leg movements. Thoracic interneurons that receive constant short latency inputs from ventral giant interneurons have been referred to as type A thoracic interneurons (TIAs). In this paper, we demonstrate that the motor response of TIAs occurs in adjacent ganglia as well as in the ganglion of origin for the TIA. We then describe the pathway from TIAs to motor neurons in both ganglia. Our observations reveal complex interactions between thoracic interneurons and leg motor neurons. Two parallel pathways exist. TIAs excite leg motor neurons directly and via local interneurons. Latency and amplitude of post-synaptic potentials (PSPs) in motor neurons and local interneurons either in the ganglion of origin or in adjacent ganglia are all similar. However, the sign of the responses recorded in local interneurons (LI) and motor neurons varies according to the TIA subpopulation based on the location of their cell bodies. One group, the dorsal posterior group, (DPGs) has dorsal cell bodies, whereas the other group, the ventral median cells, (VMC) has ventral cell bodies. All DPG interneurons either excited postsynaptic cells or failed to show any connection at all. In contrast, all VMC interneurons either inhibited postsynaptic cells or failed to show any connection. It appears that the TIAs utilize directional wind information from the ventral giant interneurons to make a decision on the optimal direction of escape. The output connections, which project not only to cells within the ganglion of origin but also to adjacent ganglia and perhaps beyond, could allow this decision to be made throughout the thoracic ganglia as a single unit. However, nothing in these connections indicates a mechanism for making appropriate coordinated leg movements. Because each pair of legs plays a unique role in the turn, this coordination should be controlled by circuits dedicated to each leg. We suggest that this is accomplished by local interneurons between TIAs and leg motor neurons.     

Genetic code correlations: Amino acids and their anticodon nucleotides

Summary The data here show direct correlations between both the hydrophobicity and the hydrophilicity of the homocodonic amino acids and their anticodon nucleotides. While the differences between properties of uracil and cytosine derivatives are small, further data show that uracil has an affinity for charged species. Although these data suggest that molecular relationships between amino acids and anticodons were responsible for the origin of the code, it is not clear what the mechanism of the origin might have been.     

Changes in TRPC channel expression during postnatal development of cerebellar neurons

In the brain, classical (canonical) transient receptor potential (TRPC) channels are thought to be involved in different aspects of neuronal development. We investigated the developmental expression profile of TRPC channels in rat cerebellum during the first 6 weeks after birth. TRPC3 expression is significantly up-regulated whereas TRPC4 and TRPC6 expression are significantly down-regulated over this period of time. TRPC3 expression is mainly found on Purkinje cells and their dendrites, suggesting that the increase in TRPC3 expression reflects development of the dendritic tree of Purkinje cells. TRPC4 expression was restricted to granule and their precursor cells. TRPC6 expression is found on Purkinje cell bodies, on mature granule cells in the internal granule cell layer (but not their precursors) and interneurons in the molecular layer. The decrease in TRPC4 expression suggests that it is required for proper granule cell development whereas the decrease in TRPC6 expression is presumably correlated with interneuron development. Moreover, we demonstrate the presence of functional TRPC channels on Purkinje cell dendrites that are activated following stimulation of metabotropic glutamate receptors. Our results reveal cell-specific expression patterns for different TRPC proteins and suggest that developmental changes in TRPC protein expression may be required for proper postnatal cerebellar development.     

Parallel motor pathways from thoracic interneurons of the ventral giant interneurons system of the cockroach,Periplaneta americana

The data described here complete the principal components of the cockroach wind-mediated escape circuit form cercal afferents to leg motor neurons. It was previously known that the cercal afferents excite ventral giant interneurons which then conduct information on wind stimuli to thoracic ganglia. The ventral giant interneurons connect to a large population of interneurons in the thoracic ganglia which, in turn, are capable of exciting motor neurons that control leg movements. Thoracic interneurons that receive constant short latency inputs from ventral giant interneurons have been referred to as type A thoracic interneurons (TI_As). In this paper, we demonstrate that the motor response of TI_As occurs in adjacent ganglia as well as in the ganglion of origin for the TI_A. We then describe the pathway from TI_As to motor neurons in both ganglia. Our observations reveal complex interactions between thoracic interneurons and leg motor neurons. Two parallel pathways exist. TI_As excite leg motor neurons directly and via local interneurons. Latency and amplitude of post-synaptic potentials (PSPs) in motor neurons and local interneurons either in the ganglion of origin or in adjacent ganglia are all similar. However, the sign of the responses recorded in local interneurons (LI) and motor neurons varies according to the TI_A subpopulation based on the location of their cell bodies. One group, the dorsal posterior group, (DPGs) has dorsal cell bodies, whereas the other group, the ventral median cells, (VMC) has ventral cell bodies. All DPG interneurons either excited postsynaptic cells or failed to show any connection at all. In contrast, all VMC interneurons either inhibited postsynaptic cells or failed to show any connection. It appears that the TI_As utilize directional wind information from the ventral giant interneurons to make a decision on the optimal direction of escape. The output connections, which project not only to cells within the ganglion of origin but also to adjacent ganglia and perhaps beyond, could allow this decision to be made throughout the thoracic ganglia as a single unit. However, nothing in these connections indicates a mechanism for making appropriate coordinated leg movements. Because each pair of legs plays a unique role in the turn, this coordination should be controlled by circuits didicated to each leg. We suggest that this is accomplished by local interneurons between TI_As and leg motor neurons.     

Genetic Analysis of Size-Scaling Patterns in the Mouse Mandible

The relationship between multidimensional form of the adult mouse mandible and body size is examined from an ontogenetic perspective. The origin and ontogeny of phenotypic correlations are described in terms of genetic and environmental covariance patterns between adult skeletal morphology and growth in body weight. Different ontogenetic patterns are observed in the genetic correlations, and these can be related to the developmental as well as the functional aspects of mandibular form. The quantitative genetic aspects of craniomandibular growth and morphogenesis are explored, together with an examination of the impact of ontogenetic changes in the genetic variance-covariance structure on morphogenetic integration and evolution by selection.     

A spatial bias for the origins of interneuron subgroups within the medial ganglionic eminence

Although it is well established that the ventral telencephalon is the primary source of GABAergic cortical interneurons in rodents, little is known about the specification of specific interneuron subtypes. It is also unclear whether the potential to achieve a given fate is established at their place of origin or by signals received during their migration to or during their maturation within the cerebral cortex. Using both in vivo and in vitro transplantation techniques, we find that two major interneuron subgroups have largely distinct origins within the MGE. Somatostatin (SST)-expressing interneurons are primarily generated within the dorsal MGE, while parvalbumin (PV)-expressing interneurons primarily originate from the ventral MGE. In addition, we show that significant heterogeneity exists between gene expression patterns in the dorsal and ventral MGE. These results suggest that, like the spinal cord, neuronal fate determination in the ventral telencephalon is largely the result of spatially segregated, molecularly distinct microdomains arranged on the dorsal-ventral axis.     

Phenotypic integration and plastic correlations in Phlox drummondii (Polemoniaceae)

Clones from two populations of Phlox drummondii were grown in three different nutrient environments to determine the extent to which the overall level and pattern of correlation among traits within an environment changes across environments. With one exception, the level of phenotypic correlation in both populations was the same across environments. Plants from Lexington, Texas exhibited a significantly lower level of phenotypic correlation when grown at a high nutrient concentration. The two populations did not differ from one another in their levels of phenotypic correlation when compared within environments. The pattern of correlation was homogenous both within populations across environments and among populations within environments. Tests of a priori hypotheses regarding the associations among functionally or developmentally related traits suggest that the correlations among traits are higher in traits that share a common function or developmental origin. We also compared the level and pattern of plasticity correlations among populations for three different components of the plastic response. We found that the level and pattern of plastic correlation for the average, linear, and nonlinear components of the plastic response did not differ among the two populations. With only one exception, the relationships among the plastic responses of different traits fit our model of functional and developmental integration. The results from our analyses of phenotypic and plastic correlations support the hypothesis that plastic correlations determine the extent to which phenotypic correlations are environment-dependent.