Jean-Francois Pare

The thalamostriatal system: a highly specific network of the basal ganglia circuitry

Although the existence of thalamostriatal projections has long been known, the role(s) of this system in the basal ganglia circuitry remains poorly characterized. The intralaminar and ventral motor nuclei are the main sources of thalamic inputs to the striatum. This review emphasizes the high degree of anatomical and functional specificity of basal ganglia-thalamostriatal projections and discusses various aspects of the synaptic connectivity and neurochemical features that differentiate this glutamate system from the corticostriatal network. It also discusses the importance of thalamostriatal projections from the caudal intralaminar nuclei in the process of attentional orientation. A major task of future studies is to characterize the role(s) of corticostriatal and thalamostriatal pathways in regulating basal ganglia activity in normal and pathological conditions.

Glutamate-dependent neuroglial calcium signaling differs between young and adult brain

The Adult Astrocyte Is Different The concept of the tripartite synapse, whereby astrocytes actively modulate the communication between the pre- and postsynaptic site, is widely accepted. The release of gliotransmitters has been linked to release of Ca2÷ from intracellular stores via the activation of astrocytic metabotropic glutamate receptor 5 (mGluR5) by glutamate spillover from synapses. However, nearly all studies on the tripartite synapse have used brain tissue collected from young individuals. Many receptors undergo changes in expression level during development. Sun et al. (p. 197; see the Perspective by Grosche and Reichenbach) applied genomic analysis, electron microscopy, and calcium imaging in slices and in vivo to assess the presence and the functionality of mGluR5 and mGluR3 receptors during postnatal development in human and mouse astrocytes. Astrocytic expression of mGluR5 was lost by the third postnatal week in mice and was not present in human cortical astrocytes, which calls into question the viability of the tripartite synapse model for adult synapses. The expression of metabotropic glutamate receptors in brain astrocytes is down-regulated in early postnatal development. [Also see Perspective by Grosche and Reichenbach] An extensive literature shows that astrocytes exhibit metabotropic glutamate receptor 5 (mGluR5)–dependent increases in cytosolic calcium ions (Ca2+) in response to glutamatergic transmission and, in turn, modulate neuronal activity by their Ca2+-dependent release of gliotransmitters. These findings, based on studies of young rodents, have led to the concept of the tripartite synapse, in which astrocytes actively participate in neurotransmission. Using genomic analysis, immunoelectron microscopy, and two-photon microscopy of astrocytic Ca2+ signaling in vivo, we found that astrocytic expression of mGluR5 is developmentally regulated and is undetectable after postnatal week 3. In contrast, mGluR3, whose activation inhibits adenylate cyclase but not calcium signaling, was expressed in astrocytes at all developmental stages. Neuroglial signaling in the adult brain may therefore occur in a manner fundamentally distinct from that exhibited during development.

Differential innervation of parvalbumin-immunoreactive interneurons of the basolateral amygdaloid complex by cortical and intrinsic inputs

In the basolateral (BL) amygdaloid complex, the excitability of projection cells is regulated by intrinsic inhibitory interneurons using γ‐aminobutyric acid (GABA) as a transmitter. A subset of these cells are labeled in a Golgi‐like manner by Parvalbumin (PV) immunohistochemistry. Recently, we have shown that the overwhelming majority of axon terminals contacting these PV‐immunoreactive neurons form asymmetric synapses. The present study was undertaken to identify the source(s) of these inputs. Since previous work had revealed that thalamic axons form very few synapses on BL interneurons (<1%), we focused on cortical and intra‐amygdaloid inputs. Iontophoretic injections of the anterograde tracers Phaseolus vulgaris‐leucoagglutinin or biotinylated dextran amine were performed in various cortical fields in cats (perirhinal, entorhinal, pre/infralimbic cortices) and monkeys (orbitofrontal region) or in the BL amygdaloid nucleus in cats. These injections resulted in a large number of anterogradely labeled terminals forming asymmetric synapses in the BL complex. Following cortical injections, numerous anterogradely labeled terminals were found in the vicinity of PV‐immunoreactive interneurons in the BL amygdala. However, only ≈1% of these terminals formed synaptic contacts with PV‐immunoreactive profiles. In contrast, as many as 11% of the terminals contributed by the intranuclear axon collaterals of BL projection cells established synapses with PV‐immunoreactive elements. Since the axon terminals of PV‐immunoreactive interneurons are enriched in GABA and they exclusively form symmetric synapses, these results suggest that PV‐immunoreactive interneurons are predominantly involved in feedback inhibition in the BL amygdaloid complex. J. Comp. Neurol. 416:496–508, 2000.

Intra-amygdaloid projections of the basolateral and basomedial nuclei in the cat: Phaseolus vulgaris-leucoagglutinin anterograde tracing at the light and electron microscopic level

The amygdaloid complex plays an essential role in auditory fear conditioning of the Pavlovian type. The available evidence suggests that the lateral nucleus is the input station of the amygdala for auditory conditioned stimuli, whereas the central medial nucleus is the output for conditioned fear responses. However, the intrinsic pathway transmitting auditory information about the conditioned stimulus from the lateral to the central medial nuclei is unknown as there are no direct projections between these nuclei. The present study was undertaken to determine if the main intra-amygdaloid targets of the lateral nucleus, namely the basomedial and basolateral nuclei, project to the central medial nucleus. To this end, iontophoretic injections of the anterograde tracer Phaseolus vulgaris-leucoagglutinin were performed in these nuclei. To rule out the possibility that the anterograde labeling reflected passing fibers merging with the major fiber bundles that course in and around the central medial nucleus, labeled terminals and varicosities were observed in the electron microscope. It was determined that the basolateral and basomedial nuclei have partially overlapping intraamygdaloid targets. They both project to the central medial nucleus, nucleus of the lateral olfactory tract and peri-amygdaloid cortex, but have limited projections to each other. Small Phaseolus vulgaris-leucoagglutinin injections in both nuclei gave rise to prominent intranuclear projections but only the basomedial nucleus was found to project to the lateral and anterior cortical nuclei. At the electron microscopic level, all labeled axon terminals and varicosities formed asymmetric synapses (n = 245) with dendritic spines (83%) or with dendritic shafts (17%). This is the first unambiguous demonstration that the basolateral and basomedial nuclei project to the central medial nucleus. Since these nuclei constitute the main intra-amygdaloid targets of the lateral nucleus, they represent likely candidates for the transmission of auditory conditioned stimuli to the central medial nucleus in auditory fear conditioning.

The thalamostriatal systems: anatomical and functional organization in normal and parkinsonian states.

Although we have gained significant knowledge in the anatomy and microcircuitry of the thalamostriatal system over the last decades, the exact function(s) of these complex networks remain(s) poorly understood. It is now clear that the thalamostriatal system is not a unique entity, but consists of multiple neural systems that originate from a wide variety of thalamic nuclei and terminate in functionally segregated striatal territories. The primary source of thalamostriatal projections is the caudal intralaminar nuclear group which, in primates, comprises the centromedian and parafascicular nuclei (CM/Pf). These two nuclei provide massive, functionally organized glutamatergic inputs to the whole striatal complex. There are several anatomical and physiological features that distinguish this system from other thalamostriatal projections. Although all glutamatergic thalamostriatal neurons express vGluT2 and release glutamate as neurotransmitter, CM/Pf neurons target preferentially the dendritic shafts of striatal projection neurons, whereas all other thalamic inputs are almost exclusively confined to the head of dendritic spines. This anatomic arrangement suggests that transmission of input from sources other than CM/Pf to the striatal neurons is likely regulated by dopaminergic afferents in the same manner as cortical inputs, while the CM/Pf axo-dendritic synapses do not display any particular relationships with dopaminergic terminals. A better understanding of the role of these systems in the functional circuitry of the basal ganglia relies on future research of the physiology and pathophysiology of these networks in normal and pathological basal ganglia conditions. Although much remains to be known about the role of these systems, recent electrophysiological studies from awake monkeys have provided convincing evidence that the CM/Pf-striatal system is the entrance for attention-related stimuli to the basal ganglia circuits. However, the processing and transmission of this information likely involves intrinsic GABAergic and cholinergic striatal networks, thereby setting the stage for complex physiological responses of striatal output neurons to CM/Pf activation. Finally, another exciting development that will surely generate significant interest towards the thalamostriatal systems in years to come is the possibility that CM/Pf may be a potential surgical target for movement disorders, most particularly Tourette syndrome and Parkinsons disease. Although the available clinical evidence is encouraging, these procedures remain empirical at this stage because of the limited understanding of the thalamostriatal systems.

Nigral and pallidal inputs to functionally segregated thalamostriatal neurons in the centromedian/parafascicular intralaminar nuclear complex in monkey

In primates, thalamostriatal projections from the centromedian (CM) and parafascicular (Pf) nuclei are strong and organized according to a strict pattern of functional connectivity with various regions of the striatal complex. In turn, the CM/Pf complex receives a substantial innervation from the internal globus pallidus (GPi). In this study, we demonstrate that the substantia nigra pars reticulata (SNr) also provides a massive input to Pf in monkeys. These pallidothalamic and nigrothalamic projections provide routes whereby information can flow in functional loops between the basal ganglia and the intralaminar nuclear group. To understand better the anatomical organization and the degree of functional specificity of these loops, we combined retrograde and anterograde labeling methods from functionally defined regions of the striatum and GPi/SNr to determine the relationships between thalamostriatal neurons and basal ganglia afferents. Together with previous studies, our data suggest the existence of tightly connected functional circuits between the basal ganglia and the CM/Pf in primates: 1) A “sensorimotor” circuit links together the medial two‐thirds of CM, the postcommissural putamen, and the ventrolateral part of the caudal GPi; 2) a “limbic” circuit involves the rostral one‐third of Pf, the ventral striatum, and the rostromedial pole of GPi; and 3) an “associative”circuit exists between the caudal two‐thirds of Pf, the caudate nucleus, and the SNr. An additional “associative” circuit that involves the caudate‐receiving territory of GPi (dorsal one‐third), the dorsolateral Pf (Pfdl), and the precommissural putamen was also disclosed. In conclusion, findings of this study provide additional evidence for the high degree of functional specificity of the thalamostriatal system through which CM/Pf may provide attention‐specific sensory information important for conditional responses to the primate striatum. J. Comp. Neurol. 447:286–299, 2002.

Ionotropic and metabotropic GABA and glutamate receptors in primate basal ganglia.

The functions of glutamate and GABA in the CNS are mediated by ionotropic and metabotropic, G protein-coupled, receptors. Both receptor families are widely expressed in basal ganglia structures in primates and nonprimates. The recent development of highly specific antibodies and/or cDNA probes allowed the better characterization of the cellular localization of various GABA and glutamate receptor subtypes in the primate basal ganglia. Furthermore, the use of high resolution immunogold techniques at the electron microscopic level led to major breakthroughs in our understanding of the subsynaptic and subcellular localization of these receptors in primates. In this review, we will provide a detailed account of the current knowledge of the localization of these receptors in the basal ganglia of humans and monkeys.

Ultrastructural evidence for pre‐ and postsynaptic localization of Cav1.2 L‐type Ca2+ channels in the rat hippocampus

In the hippocampal formation, Cav1.2 (L‐type) voltage‐gated Ca2+ channels mediate Ca2+ signals that can trigger long‐term alterations in synaptic efficacy underlying learning and memory. Immunocytochemical studies indicate that Cav1.2 channels are localized mainly in the soma and proximal dendrites of hippocampal pyramidal neurons, but electrophysiological data suggest a broader distribution of these channels. To define the subcellular substrates underlying Cav1.2 Ca2+ signals, we analyzed the localization of Cav1.2 in the hippocampal formation by using antibodies against the pore‐forming α1‐subunit of Cav1.2 (α11.2). By light microscopy, α11.2‐like immunoreactivity (α11.2‐IR) was detected in pyramidal cell soma and dendritic fields of areas CA1–CA3 and in granule cell soma and fibers in the dentate gyrus. At the electron microscopic level, α11.2‐IR was localized in dendrites, but also in axons, axon terminals, and glial processes in all hippocampal subfields. Plasmalemmal immunogold particles representing α11.2‐IR were more significant for small‐ than large‐caliber dendrites and were largely associated with extrasynaptic regions in dendritic spines and axon terminals. These findings provide the first detailed ultrastructural analysis of Cav1.2 localization in the brain and support functionally diverse roles of these channels in the hippocampal formation. J. Comp. Neurol. 506:569–583, 2008.

Cat intraamygdaloid inhibitory network: Ultrastructural organization of parvalbumin‐immunoreactive elements

Projection neurons of the basolateral (BL) amygdaloid complex are regulated by an intrinsic inhibitory network. To improve our understanding of this inhibitory circuit, we studied the synaptology of parvalbumin‐immunopositive (PV+) elements as this calcium‐binding protein is localized in a subpopulation of γ‐aminobutyric acid (GABA)‐ergic interneurons.

The schizophrenia susceptibility factor dysbindin and its associated complex sort cargoes from cell bodies to the synapse

A novel vesicle transport mechanism is described that requires dysbindin-associated complexes for cargo targeting from neuronal cell bodies to neurites and nerve terminals. The results suggest that mistargeting of specific vesicular cargoes may underlie, in part, the molecular pathogenesis of schizophrenia.