The specific functions of dopamine D 2 receptor-positive (D 2 R) striatopallidal neurons remain poorly understood. Using a genetic mouse model, we found that ablation of D 2 R neurons in the entire striatum induced hyperlocomotion, whereas ablation in the ventral striatum increased amphetamine conditioned place preference. Thus D 2 R striatopallidal neurons limit both locomotion and, unexpectedly, drug reinforcement.The striatum is critically involved in motor and motivational functions 1,2 . The dorsal striatum, caudate-putamen, is primarily implicated in motor control and the learning of habits and skills, whereas the ventral striatum, the nucleus accumbens (NAc), is essential for motivation and drug reinforcement 1,3 . Striatal dysfunction has been demonstrated in movement disorders, including Parkinson's and Huntington's disease, and in psychiatric disorders, such as schizophrenia and drug addiction 4 .The GABA medium-sized spiny neurons (MSNs, about 95% of striatal neurons), which are targets of the cerebral cortex and the midbrain dopaminergic neurons, form two pathways 5 . The dopamine D 1 receptor-positive (D 1 R) striatonigral MSNs project to the medial globus pallidus and substantia nigra pars reticulata (direct pathway) and coexpress dopamine D 1 receptors and substance P, whereas D 2 R striatopallidal MSNs project to the lateral globus pallidus (indirect pathway) and coexpress dopamine D 2 receptor, adenosine A 2A receptor (A 2A R) and enkephalin (Enk). The specific role of the two efferent pathways in motor and motivational control remains poorly understood. D 1 R striatonigral and D 2 R striatopallidal neurons, which are intermingled and morphologically indistinguishable, cannot be functionally dissociated with techniques such as chemical lesions or surgery and the currently available tools for selective targeting of these populations are unsatisfactory. The Drd1a-and Drd2-egfp transgenic mice obtained by BAC transgenesis 6 have recently shed some light on the role of MSN subpopulations or genes in striatal pathophysiology [7][8][9][10] . In regards to their role in motivation and drug addiction, current studies are focused mostly on the D 1 R striatonigral neurons 2 .To assess the role of D 2 R striatopallidal neurons, we selectively ablated these cells in adult mice by Cre-mediated expression of a diphtheria toxin receptor (DTR) and diphtheria toxin injection 11 (Supplementary Methods online). All animal procedures were approved by the Université Libre de Bruxelles School of Medicine Ethical Committee. We generated mice expressing Cre recombinase under the control of the Adora2a (A 2A R) promoter (Adora2a-cre mice, Supplementary Fig. 1 online) by BAC transgenesis. A 2A R was chosen because it is expressed more in D 2 R neurons than in any other brain area 12 and, in contrast to D 2 R, A 2A R is supposed to not be expressed in striatal cholinergic interneurons and mesostriatal dopaminergic cells. In Adora2a-cre mice mated with a Rosa26-LacZ reporter strain, b-galactosidase staining was only found ...
Calcium-binding proteins such as calretinin are abundantly expressed in distinctive patterns in the CNS, but their physiological function remains poorly understood. Calretinin is expressed in cerebellar granule cells, which provide the major excitatory input to Purkinje cells through parallel fibers. Calretinin-deficient mice exhibit dramatic alterations in motor coordination and Purkinje cell firing recorded in vivo through unknown mechanisms. In the present study, we used patch-clamp recording techniques in acute slice preparation to investigate the effect of a null mutation of the calretinin gene on the intrinsic electroresponsiveness of cerebellar granule cells at a mature developmental stage. Calretinin-deficient granule cells exhibit faster action potentials and generate repetitive spike discharge showing an enhanced frequency increase with injected currents. These alterations disappear when 0.15 mm of the exogenous fast-calcium buffer BAPTA is infused in the cytosol to restore the calcium-buffering capacity. A proposed mathematical model demonstrates that the observed alterations of granule cell excitability can be explained by a decreased cytosolic calcium-buffering capacity resulting from the absence of calretinin. This result suggests that calcium-binding proteins modulate intrinsic neuronal excitability and may therefore play a role in information processing in the CNS.
In cerebellum and other brain regions, neuronal cell death because of ethanol consumption by the mother is thought to be the leading cause of neurological deficits in the offspring. However, little is known about how surviving cells function. We studied cerebellar Purkinje cells in vivo and in vitro to determine whether function of these cells was altered after prenatal ethanol exposure. We observed that Purkinje cells that were prenatally exposed to ethanol presented decreased voltage-gated calcium currents because of a decreased expression of the ␥-isoform of protein kinase C. Longterm depression at the parallel fiber-Purkinje cell synapse in the cerebellum was converted into long-term potentiation. This likely explains the dramatic increase in Purkinje cell firing and the rapid oscillations of local field potential observed in alert fetal alcohol syndrome mice. Our data strongly suggest that reversal of longterm synaptic plasticity and increased firing rates of Purkinje cells in vivo are major contributors to the ataxia and motor learning deficits observed in fetal alcohol syndrome. Our results show that calcium-related neuronal dysfunction is central to the pathogenesis of the neurological manifestations of fetal alcohol syndrome and suggest new methods for treatment of this disorder.calcium ͉ cerebellum ͉ protein kinase ͉ long-term depression ͉ motor learning F etal alcohol syndrome (FAS) is the leading cause of intellectual disability in the Western world with a prevalence of 1 to 1.5 cases per 1,000 live births (1) and a lifetime cost of care of approximately $1.4 million per case. This cost is mainly because of ethanol toxicity in the developing central nervous system, causing intellectual disability, deficits in learning, and fine-motor dysfunction (2).The cerebellum is one of the main targets of in utero ethanol toxicity (3). Within the cerebellum, Purkinje cells (PCs) are highly sensitive to ethanol. PCs constitute the sole output of the cerebellar cortex and thus have a central functional role in integration. All animal models of FAS display a reduction in the number of PCs by Ϸ20% (4), and various authors have proposed that neuronal loss is the only cause of cerebellar deficits in FAS. One study conducted on adult anesthetized rats with FAS led to the conclusion that PCs that survive ethanol administration function normally (5). Thomas et al. (6) found a correlation between total PCs number and motor performance. These experimental data led to the assumption that surviving PCs function normally and that motor coordination impairment in FAS results only from a quantitative defect of PCs. This is crucially important from a therapeutic point of view because very few options exist to replace dead neurons. Many studies have therefore focused on different ways to decrease PC loss in FAS (7,8). However, different models of ataxia that result from PC death per se (pcd mice, SV4 mice, T147 transgenic mice) have demonstrated that considerable neuropathology can occur without the manifestation of a neurologic...
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