Polygenic risk for neuropsychiatric disease and vulnerability to abnormal deep grey matter development.

Neuropsychiatric disease has polygenic determinants but is often precipitated by environmental pressures, including adverse perinatal events. However, the way in which genetic vulnerability and early-life adversity interact remains obscure. We hypothesised that the extreme environmental stress of prematurity would promote neuroanatomic abnormality in individuals genetically vulnerable to psychiatric disorders. In 194 unrelated infants (104 males, 90 females), born before 33 weeks of gestation (mean gestational age 29.7 weeks), we combined Magnetic Resonance Imaging with a polygenic risk score (PRS) for five psychiatric pathologies to test the prediction that: deep grey matter abnormalities frequently seen in preterm infants are associated with increased polygenic risk for psychiatric illness. The variance explained by the PRS in the relative volumes of four deep grey matter structures (caudate nucleus, thalamus, subthalamic nucleus and lentiform nucleus) was estimated using linear regression both for the full, mixed ancestral, cohort and a subsample of European infants. Psychiatric PRS was negatively associated with lentiform volume in the full cohort (ß = -0.24, p = 8 × 10-4) and a European subsample (ß = -0.24, p = 8 × 10-3). Genetic variants associated with neuropsychiatric disease increase vulnerability to abnormal lentiform development after perinatal stress and are associated with neuroanatomic changes in the perinatal period.

Mouse subthalamic nucleus neurons with local axon collaterals.

The neuronal population of the subthalamic nucleus (STN) has the ability to prolong incoming cortical excitation. This could result from intra-STN feedback excitation. The combination of inducible genetic fate mapping techniques with in vitro targeted patch-clamp recordings, allowed identifying a new type of STN neurons that possess a highly collateralized intrinsic axon. The time window of birth dates was found to be narrow (E10.5-E14.5) with very few STN neurons born at E10.5 or E14.5. The fate mapped E11.5-12.5 STN neuronal population included 20% of neurons with profuse axonal branching inside the nucleus and a dendritic arbor that differed from that of STN neurons without local axon collaterals. They had intrinsic electrophysiological properties and in particular, the ability to generate plateau potentials, similar to that of STN neurons without local axon collaterals and more generally to that of classically described STN neurons. This suggests that a subpopulation of STN neurons forms a local glutamatergic network, which together with plateau potentials, allow amplification of hyperdirect cortical inputs and synchronization of the STN neuronal population.

Foxa1 is essential for development and functional integrity of the subthalamic nucleus.

Inactivation of transcription factor Foxa1 in mice results in neonatal mortality of unknown cause. Here, we report that ablation of Foxa1 causes impaired development and loss of the subthalamic nucleus (STN). Functional deficits in the STN have been implicated in the etiology of Huntington's and Parkinson's disease. We show that neuronal ablation by Synapsin1-Cre-mediated Foxa1 deletion is sufficient to induce hyperlocomotion in mice. Transcriptome profiling of STN neurons in conditional Foxa1 knockout mice revealed changes in gene expression reminiscent of those in neurodegenerative diseases. We identified Ppargc1a, a transcriptional co-activator that is implicated in neurodegeneration, as a Foxa1 target. These findings were substantiated by the observation of Foxa1-dependent demise of STN neurons in conditional models of Foxa1 mutant mice. Finally, we show that the spontaneous firing activity of Foxa1-deficient STN neurons is profoundly impaired. Our data reveal so far elusive roles of Foxa1 in the development and maintenance of STN function.

The subthalamic nucleus. Part I: development, cytology, topography and connections.

This monograph (Part I of two volumes) on the subthalamic nucleus (STN) accentuates the gap between experimental animal and human information concerning subthalamic development, cytology, topography and connections. The light and electron microscopical cytology focuses on the open nucleus concept and the neuronal types present in the STN. The cytochemistry encompasses enzymes, NO, glial fibrillary acidic protein (GFAP), calcium binding proteins, and receptors (dopamine, cannabinoid, opioid, glutamate, gamma-aminobutyric acid (GABA), serotonin, cholinergic, and calcium channels). The ontogeny of the subthalamic cell cord is also reviewed. The topography concerns the rat, cat, baboon and human STN. The descriptions of the connections are also given from a historical point of view. Recent tracer studies on the rat nigro-subthalamic connection revealed contralateral projections. Part II of the two volumes (volume 199) on the subthalamic nucleus (STN) starts with a systemic model of the basal ganglia to evaluate the position of the STN in the direct, indirect and hyperdirect pathways. A summary of in vitro studies is given, describing STN spontaneous activity as well as responses to depolarizing and hyperpolarizing inputs and high-frequency stimulation. STN bursting activity and the underlying ionic mechanisms are investigated. Deep brain stimulation used for symptomatic treatment of Parkinson's disease is discussed in terms of the elements that are influenced and its hypothesized mechanisms. This part of the monograph explores the pedunculopontine-subthalamic connections and summarizes attempts to mimic neurotransmitter actions of the pedunculopontine nucleus in cell cultures and high-frequency stimulation on cultured dissociated rat subthalamic neurons. STN cell models--single- and multi-compartment models and system-level models are discussed in relation to subthalamic function and dysfunction. Parts I and II are compared.

Cre fate mapping reveals lineage specific defects in neuronal migration with loss of Pitx2 function in the developing mouse hypothalamus and subthalamic nucleus.

Establishment of neuronal diversity is a central topic in developmental neurobiology. Prior studies implicated Pitx2, a paired-like homeodomain transcription factor, in mouse subthalamic nucleus neuronal development, but precise stages of neuronal differentiation affected (migration, axon outgrowth, fate specification) and underlying mechanisms were unknown. Here we report lineage tracing experiments using Pitx2(cre/+), Pitx2(cre/null), and conditional nuclear lacZ reporter mice to track embryonic Pitx2 expressing neurons. Migration of subthalamic nucleus and hypothalamic neurons was severely arrested in Pitx2(cre/null) embryos, and subclasses of subthalamic nucleus neurons identified by Lmx1b, Foxp1, and Foxp2-gene expression revealed differing sensitivities to Pitx2 dosage. Interestingly, embryonic subthalamic nucleus development was unaffected in Lmx1b null mice, suggesting that Pitx2 and Lmx1b act via independent genetic pathways. These data provide the first direct evidence for Pitx2-dependent neuronal migration in the developing hypothalamus, and demonstrate that complex transcriptional networks regulate regional specialization of distinct hypothalamic and subthalamic nucleus neurons.

Corticothalamic and thalamocortical pathfinding in the mouse: dependence on intermediate targets and guidance axis.

Recently, increasing attention has been paid to the study of intermediate targets and their relay guidance role in long-range pathfinding. In the present study, mechanisms of corticothalamic and thalamocortical pathfinding were investigated in C57BL/6 mice using in vitro DiI labeling and in vivo cholera toxin labeling. Specifically, three important intermediate targets, the subplate, ganglionic eminence, and reticular thalamic nucleus, were studied for their role in corticothalamic and thalamocortical pathfinding. The results show that the neuroepithelium of the ganglionic eminence is a source of pioneer neurons and pioneer fibers. Through radial and tangential migration, these pioneer neurons and fibers can approach the differentiating field of the ganglionic eminence, the subplate and thalamic reticular nucleus to participate in the formation of these three intermediate targets. Furthermore, the subplate, ganglionic eminence and thalamic reticular nucleus are linked by pioneer neurons and fibers to form a guidance axis. The guidance axis and the three important intermediate targets provide an ideal environment of contact guidance and chemical guidance for the corticothalamic and thalamocortical pathfinding. The concept of a "waiting time" in the subplate and the thalamic reticular nucleus is likely due to the expression of a guidance effect, so that the thalamocortical and corticothalamic projections can be deployed spatially and temporally to the subplate and thalamic reticular nucleus before these projections enter their final destinations, the neocortex and thalamus.

Identification of the anterior nucleus of the ansa lenticularis in birds as the homolog of the mammalian subthalamic nucleus.

In mammals, the subthalamic nucleus (STN) is a glutamatergic diencephalic cell group that develops in the caudal hypothalamus and migrates to a position above the cerebral peduncle. By its input from the external pallidal segment and projection to the internal pallidal segment, STN plays a critical role in basal ganglia functions. Although the basal ganglia in birds is well developed, possesses the same major neuron types as in mammals, and plays a role in movement control similar to that in mammals, it has been uncertain whether birds possess an STN. We report here evidence indicating that the so-called anterior nucleus of the ansa lenticularis (ALa) is the avian homolog of mammalian STN. First, the avian ALa too develops within the mammillary hypothalamic area and migrates to a position adjacent to the cerebral peduncle. Second, ALa specifically receives input from dorsal pallidal neurons that receive input from enkephalinergic striatal neurons, as is true of STN. Third, ALa projects back to avian dorsal pallidum, as also the case for STN in mammals. Fourth, the neurons of ALa contain glutamate, and the target neurons of ALa in dorsal pallidum possess AMPA-type glutamate receptor profiles resembling those of mammalian pallidal neurons. Fifth, unilateral lesions of ALa yield behavioral disturbances and movement asymmetries resembling those observed in mammals after STN lesions. These various findings indicate that ALa is the avian STN, and they suggest that the output circuitry of the basal ganglia for motor control is similar in birds and mammals.

Transient structures of the human fetal brain: subplate, thalamic reticular complex, ganglionic eminence.

Morphological features of the subplate, the thalamic reticular complex and the ganglionic eminence, which represent three major transient structures of the human fetal forebrain, are summarized with special reference to their functional roles. The subplate harboring various neuronal types is an outstandingly wide zone subjacent to the cortical plate in the human fetal brain. Within the subplate various cortical afferents establish synaptic contacts for a prolonged period before entering the cortical plate. Therefore, the subplate is regarded as a "waiting compartment" which is required for the formation of mature cortical connections. Next to the thalamic reticular nucleus, within the fibers of internal capsule, the perireticular nucleus is located which has been established as a distinct entity during development. Its various neuronal types express a number of different neuroactive substances. Perinatally, the perireticular nucleus is drastically reduced in size. It is involved in the guidance of corticofugal and thalamocortical fibers. The ganglionic eminence is a conspicuous proliferative area that persists throughout nearly the entire fetal period. In the human fetal brain it extends medially upon the dorsal thalamic nuclei which receive precursor cells from the ganglionic eminence. Postmitotic cells in the marginal zone of the ganglionic eminence serve as an intermediate target for growing axons. On the whole, all three structures establish transient neural circuitries that may be essential for the formation of adult projections. The characteristics of the three transient structures are particularly relevant for developmental neuropathology as these structures may be damaged in disorders that preferentially occur in preterm infants.