Plastic and behavioral abnormalities in experimental Huntington's disease: a crucial role for cholinergic interneurons.

Huntington's disease (HD) is a fatal hereditary neurodegenerative disease causing degeneration of striatal spiny neurons, whereas cholinergic interneurons are spared. This cell-type specific pathology produces an array of abnormalities including involuntary movements, cognitive impairments, and psychiatric disorders. Although the genetic mutation responsible for HD has been identified, little is known about the early synaptic changes occurring within the striatal circuitry at the onset of clinical symptoms. We therefore studied the synaptic plasticity of spiny neurons and cholinergic interneurons in two animal models of early HD. As a pathogenetic model, we used the chronic subcutaneous infusion of the mitochondrial toxin 3-nitropropionic acid (3-NP) in rats. This treatment caused striatal damage and impaired response flexibility in the cross-maze task as well as defective extinction of conditioned fear suggesting a perseverative behavior. In these animals, we observed a loss of depotentiation in striatal spiny neurons and a lack of long-term potentiation (LTP) in cholinergic interneurons. These abnormalities of striatal synaptic plasticity were also observed in R6/2 transgenic mice, a genetic model of HD, indicating that both genetic and phenotypic models of HD show cell-type specific alterations of LTP. We also found that in control rats, as well as in wild-type (WT) mice, depotentiation of spiny neurons was blocked by either scopolamine or hemicholinium, indicating that reversal of LTP requires activation of muscarinic receptors by endogenous acetylcholine. Our findings suggest that the defective plasticity of cholinergic interneurons could be the primary event mediating abnormal functioning of striatal circuits, and the loss of behavioral flexibility typical of early HD might largely depend on cell-type specific plastic abnormalities.

Enriched environment promotes behavioral and morphological recovery in a mouse model for the fragile X syndrome.

Fragile X syndrome, the most frequent form of hereditary mental retardation, is due to a mutation of the fragile X mental retardation 1 (FMR1) gene on the X chromosome. Like fragile X patients, FMR1-knockout (FMR1-KO) mice lack the normal fragile X mental retardation protein (FMRP) and show both cognitive alterations and an immature neuronal morphology. We reared FMR1-KO mice in a C57BL/6 background in enriched environmental conditions to examine the possibility that experience-dependent stimulation alleviates their behavioral and neuronal abnormalities. FMR1-KO mice kept in standard cages were hyperactive, displayed an altered pattern of open field exploration, and did not show habituation. Quantitative morphological analyses revealed a reduction in basal dendrite length and branching together with more immature-appearing spines along apical dendrites of layer five pyramidal neurons in the visual cortex. Enrichment largely rescued these behavioral and neuronal abnormalities while increasing alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor subunit 1 (GluR1) levels in both genotypes. Enrichment did not, however, affect FMRP levels in the WT mice. These data suggest that FMRP-independent pathways activating glutamatergic signaling are preserved in FMR1-KO mice and that they can be elicited by environmental stimulation.

Reversible inactivation of hippocampus and dorsolateral striatum in C57BL/6 and DBA/2 inbred mice failed to show interaction between memory systems in these genotypes.

C57BL/6 and DBA/2 mice with cannulae inserted bilaterally in the dorsal hippocampus or the dorsolateral striatum were released from the south arm of a cross maze and trained to find food in the east arm. Probe trials on which mice were released from the north arm were given following short or prolonged training. Prior to the probe trials, mice received intra-hippocampal or intra-striatal injections of lidocaine or saline. Results show that saline-injected C57BL/6 were fundamentally place learners whereas saline-injected DBA/2 mice did not engage any predominant system. Inactivating the hippocampus or the dorsolateral striatum in C56BL/6 mice disrupted place learning without promoting response learning. Inactivating the same brain sites in DBA/2 mice did not affect their behaviour. Thus, contrary to that observed in rats, disrupting the neural substrate of one memory system can abolish learning in that system but does not promote the use of another system in these genotypes.

Potentiation of ischemia-related behavioral alterations by electro-acupuncture in gerbils.

Gerbils subjected to global ischemia or sham-ischemia received electro-acupuncture (EA) or sham EA at points 26 Du (Renzhong) and 8 Du (Junsuo). All animals were then tested for motor activity in an open field, and for spontaneous alternation in a T maze. Results show that EA alone did not affect any behavioral parameter. Ischemia alone increased motor activity without significantly interfering with spontaneous alternation. EA in ischemic gerbils potentiated the increase of motor activity and elicited a decrease in spontaneous alternation. Thus, our data show an interaction between global ischemia and EA applied at specific acupoints which, however, consists of a potentiation rather than an alleviation of the behavioral alterations consecutive to the ischemic insult.

Enhanced procedural learning following beta-amyloid protein (1-42) infusion in the rat.

Wistar rats receiving intracerebroventricular infusion of the beta-amyloid protein (Abeta1-42) or of the inactive fragment (Abeta1-42) were subjected to the cross-maze task. According to the standard protocol, rats were released from the south arm and trained to collect food at the end of the east arm. After a 5-day training period, they were given a probe trial during which they were released from the north arm and allowed to choose either the east arm (place learning) or the west arm (response learning). Control rats showed predominant place learning whereas all rats receiving (Abeta1-42) showed response learning. These data indicate that exposure to (Abeta1-42) does not only impair cognitive responding but elicits strong procedural (motor-based) responding.

Effects of MK-801 and ethanol combinations on memory consolidation in CD1 mice: involvement of GABAergic mechanisms.

In the present research the effect of the noncompetitive N-methyl-d-aspartate receptor antagonist MK-801 and ethanol combinations on memory consolidation and the involvement of GABAergic mechanisms in this effect were investigated in CD1 mice injected intraperitoneally with the drugs immediately or 120 min after training in a one-trial inhibitory avoidance apparatus and tested for retention 24 h later. The results showed that (a) the retention performances of mice were impaired in a dose-dependent manner by immediate posttraining MK-801 (0.2 and 0.3, but not 0.1 mg/kg) and ethanol (1 and 2, but not 0.5 g/kg) administrations; (b) an otherwise ineffective dose of MK-801 (0.1 mg/kg) enhanced the deleterious effect exerted by ethanol (1 and 2 g/kg); (c) an otherwise ineffective dose of muscimol (0.5 mg/kg) enhanced, while otherwise ineffective doses of picrotoxin (0.25 mg/kg) or bicuculline (0.1 mg/kg) antagonized, this effect; and (d) no effect was observed when the treatments were carried out 120 min after training, suggesting that the effects observed following immediate posttraining administrations were due to the influence on the consolidation of memory. From these experiments it is evident that (a) MK-801 enhances ethanol's effects on memory consolidation and (b) GABAergic mechanisms are involved in this effect.

Genetic approach to variability of memory systems: analysis of place vs. response learning and fos-related expression in hippocampal and striatal areas of C57BL/6 and DBA/2 mice.

C57 and DBA mice were trained in a crossed maze to assess possible strain differences in place or response learning as a function of training duration (8 or 17 days) and extramaze cueing conditions. The first condition consisted of a diffuse visually cued environment (rich cueing). The second was the same plus an explicit visual cue marking the direction of the baited arm (rich cueing plus cue). The third was a featureless environment (poor cueing). During training, mice were released from the south arm and rewarded in the east arm. Probe trials on which mice were released from the north arm and allowed to choose either the east (place learning) or the west (response learning) arm were given either on the ninth (PT1) or the eighteenth (PT2) days. Strain x context differences in the activation of the dorsal hippocampus and the dorsolateral striatum were examined by analyzing Fos expression following each probe trial. Results first showed that C57 were essentially place-learners, whereas no learning modality was predominant in DBA, except on the PT2 run with the explicit cue available. Examination of Fos expression in C57 trained under "rich cueing" and "rich cueing plus cue" conditions revealed a strong and parallel increase of immunoreactivity in the hippocampus and dorsolateral striatum following PT1 that decreased under PT2. In that strain, the similar time-course variation of Fos expression in both areas suggests a simultaneous involvement of hippocampal- and striatal-based learning mechanisms, even if those controlled by the hippocampus were prevailing on those controlled by the dorsolateral striatum. In DBA mice, however, the absence of any preferential learning modality was associated with 1) a consistent hippocampal activation persistent across probe trials, and 2) a global superior activation of the dorsolateral striatum. Distinct patterns of Fos expression were therefore associated with every strain-specific learning modality. In each strain, however, each modality was found to be remarkably stable, whatever the training duration and the cueing conditions.

The strain-specific involvement of nucleus accumbens in latent inhibition might depend on differences in processing configural- and cue-based information between C57BL/6 and DBA mice.

Latent inhibition (LI) consists of decreased associative strength between an elemental stimulus (CS: tone) paired with an unconditioned stimulus (US: footshock) following non-reinforced pre-exposure to the tone. In view of the differences shown by C57BL/6 (C57) and DBA/2 (DBA) mice in processing elemental vs. configural stimuli, the present experiments were designed (1) to assess whether these differences were likely to interfere with the capability of each strain to show LI, and (2) to verify the extent to which lesions of the nucleus accumbens, which have been reported to enhance attention towards contextual stimuli under certain conditions, might interfere with the development of LI. C57 and DBA mice with Nacc or sham lesions were given two periods (4 or 7 days) of pre-exposure to a CS (tone) then subjected to two CS-US pairings given on a single day. On the day after, freezing to the tone was examined in each group. Results show that, following the shorter period of pre-exposure, LI developed in sham-lesioned DBA but did not in sham-lesioned C57. Nacc lesions, however, were found (1) to block LI in DBA but (2) to promote LI in C57. After the longer period of pre-exposure LI was observed in both strain and lesion conditions. In general, these results confirm that strain differences in processing the tone as a single elemental cue (DBA) or, alternatively, as a part of a contextual configural stimulus (C57) can interfere with the development of LI. In addition, they indicate that Nacc lesions, that are susceptible to increase attention to the background, might modify the salience of the tone and produce opposite effect on LI according to the strain specialisation to show elemental or configural responding.