Metabotropic glutamate receptor 1 (mGluR1) is a member of a large family of G-protein-coupled glutamate receptors, the physiological functions of which are largely unknown. Mice deficient in mGluR1 have severe motor coordination and spatial learning deficits. They have no gross anatomical or basic electrophysiological abnormalities in either the cerebellum or hippocampus, but they show impaired cerebellar long-term depression and hippocampal mossy fibre long-term potentiation. mGluR1-deficient mice should therefore be valuable models for studying synaptic plasticity.

In order to compare the frontal cortex of rat and macaque monkey, cortical and subcortical afferents to subdivisions of the medial frontal cortex (MFC) in the rat were analyzed with fluorescent retrograde tracers. In addition to afferent inputs common to the whole MFC, each subdivision of the MFC has a specific pattern of afferent connections. The dorsally situated precentral medial area (PrCm) was the only area to receive inputs from the somatosensory cortex. The specific pattern of afferents common to the ventrally situated prelimbic (PL) and infralimbic (IL) areas included projections from the agranular insular cortex, the entorhinal and piriform cortices, the CA1-CA2 fields of the hippocampus, the subiculum, the endopiriform nucleus, the amygdalopiriform transition, the amygdalohippocampal area, the lateral tegmentum, and the parabrachial nucleus. In all these structures, the number of retrogradely labeled cells was larger when the injection site was located in area IL. The dorsal part of the anterior cingulate area (ACd) seemed to be connectionally intermediate between the adjacent areas PrCm and PL; it receives neither the somatosensory inputs characteristic of area PrCm nor the afferents characteristic of areas PL and IL, with the exception of the afferents from the caudal part of the retrosplenial cortex. A comparison of the pattern of afferent and efferent connections of the rat MFC with the pattern of macaque prefrontal cortex suggests that PrCm and ACd areas share some properties with the macaque premotor cortex, whereas PL and IL areas may have characteristics in common with the cingulate or with medial areas 24, 25, and 32 and with orbital areas 12, 13, and 14 of macaques.

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Retinoid-related orphan receptor ␣ (ROR␣) is a member of the nuclear receptor superfamily. To study its physiological role we generated null-mutant mice by targeted insertion of a lacZ reporter gene encoding the enzyme ␤-galactosidase. In heterozygous ROR␣ ؉/؊ mice we found ␤-galactosidase activity, indicative of ROR␣ protein expression, confined to the central nervous system, skin and testis. In the central nervous system, the ROR␣ gene is expressed in cerebellar Purkinje cells, the thalamus, the suprachiasmatic nuclei, and retinal ganglion cells. In skin, ROR␣ is strongly expressed in the hair follicle, the epidermis, and the sebaceous gland. Finally, the peritubular cells of the testis and the epithelial cells of the epididymis also strongly express ROR␣. Recently, it was reported that the ataxic mouse mutant staggerer (sg͞sg) is caused by a deletion in the ROR␣ gene. The analysis of the cerebellar and the behavioral phenotype of homozygous ROR␣ ؊/؊ mice proves identity to sg͞sg mice. Although the absence of ROR␣ causes dramatic developmental effects in the cerebellum, it has no apparent morphological effect on thalamus, hypothalamus, and retina. Similarly, testis and skin of ROR␣ ؊/؊ mice display a normal phenotype. However, the pelage hair of both sg͞sg and ROR␣ ؊/؊ is significantly less dense and when shaved shows reluctance to regrow.Nuclear receptors form a structurally related superfamily of ligand-activated transcription factors (1). They are involved in several aspects of vertebrate physiology, such as development and homeostasis. Important examples are the steroid hormone receptors that regulate, in a ligand-dependent manner, specific sets of responding genes. The retinoid-related orphan nuclear receptor (ROR) ␣ (2, 3), ROR␤ (4), and ROR␥ (5) constitute a subfamily of nuclear receptors that bind to DNA both as monomers and dimers. Distribution of ROR␣ mRNA suggests that this receptor is widely expressed and functions in several organs including brain, heart, liver, lung, and testis; highest levels were found in peripheral blood leukocytes and skin (M.B.-A., unpublished data). ROR␣ exists in four splicing isoforms: ROR␣1-4. They display different N-terminal domains causing different DNA binding site preferences (3), and they display differential expression profiles: in the thalamus there is only ROR␣1 mRNA; ROR␣4 (ϭRZR␣) (2) transcripts are predominant in leukocytes and skin; ROR␣2 and ROR␣3 transcripts are exclusively detected in testis; and in the remaining tissues including the cerebellum there is a mixture of ROR␣1 and ROR␣4 transcripts (M.B.-A., unpublished results). In the central nervous system (CNS) ROR␣ mRNA localizes to the cerebellar Purkinje cells (PCs), various thalamic nuclei, and, during development, to other brain areas (6, 7). To study the physiological role of this orphan receptor we generated ROR␣ null-mutant mice by gene targeting. In the course of this work the genetic basis of the staggerer (sg) mutation in mouse was identified by positional cloning as a deletion in the R...

Cannabinoids receptors have been reported to modulate synaptic transmission in many structures of the CNS, but yet little is known about their role in the prefrontal cortex where type I cannabinoid receptor (CB-1) are expressed. In this study, we tested first the acute effects of selective agonists and antagonist of CB-1 on glutamatergic excitatory postsynaptic currents (EPSCs) in slices of rat prefrontal cortex (PFC). EPSCs were evoked in patch-clamped layer V pyramidal cells by stimulation of layer V afferents. Monosynaptic EPSCs were strongly depressed by bath application (1 microM) of the cannabinoid receptors agonists WIN55212-2 (-50.4 +/- 8.8%) and CP55940 (-42.4 +/- 10.9%). The CB-1 antagonist SR141716A reversed these effects. Unexpectedly, SR141716A alone produced a significant increase of glutamatergic synaptic transmission (+46.9 +/- 11.2%), which could be partly reversed by WIN55212-2. In the presence of strontium in the bath, the frequency but not the amplitude of asynchronous synaptic events evoked in layer V pyramidal cells by stimulating layer V afferents, was markedly decreased (-54.2 +/- 8%), indicating a presynaptic site of action of cannabinoids at these synapses. Tetanic stimulation (100 pulses at 100 Hz, 4 trains) induced in control condition, no changes (n = 7/18), long-term depression (LTD; n = 6/18), or long-term potentiation (LTP; n = 5/18) of monosynaptic EPSCs evoked by stimulation of layer V afferents. When tetanus was applied in the presence of WIN 55,212-2 or SR141716-A (1 microM) in the bath, the proportion of "nonplastic" cells were not significantly changed (n = 7/15 in both cases). For the plastic ones (n = 8 in both cases), WIN 55,212-2 strongly favored LTD (n = 7/8) at the apparent expense of LTP (n = 1/8), whereas the opposite effect was observed with SR141716-A (7/8 LTP; 1/8 LTD). These results demonstrate that cannabinoids influence glutamatergic synaptic transmission and plasticity in the PFC of rodent.

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Climbing fiber (CF)-Purkinje cell (PC) relationship were studied electrophysiologically on the cerebellum of 8 to 15 day old rats. Some animals were rendered agranular by x-irradiation from birth; some others were treated with 3-acetyl pyridine 3 days before study to selectively destroy the CF. Unitary extracellular recordings in 8-9 day old normal rats revealed that more than 50% of the PC units each exhibited either two types of all-or-none climbing fiber responses (CFR) or stepwise graded CFRs. The other PC units only presented one type of all-or-none CFR. These activities were entirely mediated via CF since they persisted at the same age in x-irradiated rats, but were absent in animals treated with 3-acetyl pyridine. Interaction experiments were performed between juxtafastigial and Inferior Olive stimulations on 49 PC units in 8-9 day old normal rats. Collisions between impulses set up in CFs were disclosed in 21 out of the 24 PCs which exhibited only one type of CFR. In the three others and in each of the 25 PCs that displayed two types of all-or-none CFRs, or CFRs graded by steps, no collision was detected. Moreover intracellular recordings of epsp's mediated via CFs in PCs of 8-9 day old normal rats revealed that they frequently fluctuated in stepwise fashion. These results demonstrate that in the immature rat more than 50% of PCs are each innervated by at least two distinct CFs; later on, the disappearance of the supernumerary synapses between CF and PC leads, as early as day 15, to the one-to-one relationship between CF and PC.