Behavioral performance of tfm mice supports the beneficial role of androgen receptors in spatial learning and memory

In adulthood, androgens and androgen receptors might contribute to the sexually dimorphic performance in spatial learning and memory, but their roles seem complex. To study the potential role of androgen receptors in spatial learning and memory, we tested adult 6-8-month-old mutant mice with a naturally occurring defect in the androgen receptor gene (testicular feminization mutant or tfm) and C57Bl/6J wild-type mice. Because the trait is X-linked, only tfm males are completely androgen insensitive while female tfm mice are heterozygous, carrying one wild-type and one tfm copy of the androgen receptor. Here we show that female tfm carrier mice outperform tfm male mice in the water maze, while there are no gender differences in water maze performance in wild-type mice. In tfm mice, there were no gender differences in measures of anxiety in the open field or plus maze or sensorimotor function, indicating that potential differences in these measures did not contribute to the differences observed in the water maze. There were no differences in tfm and wild-type female and male mice in emotional learning and memory in the passive avoidance test. These findings support a beneficial role for androgen receptors in spatial learning and memory.     

The dopamine D1 but not D3 receptor plays a fundamental role in spatial working memory and BDNF expression in prefrontal cortex of mice

Although dopamine within the prefrontal cortex has been implicated in working memory, how different dopamine receptor subtypes contribute to this process need to be further characterized. Previous studies have suggest the importance of dopamine receptors signaling in regulating the brain-derived neurotrophic factor (BDNF) function that is associated with synaptic plasticity underlying normal memory formation. Changes in BDNF expression through the dopamine receptors within the prefrontal cortex may accompany and mediate the spatial working memory. To test the possibility, dopamine D1 and D3 receptor mutant mice were tested in Morris water maze for spatial working memory. We found that trial-dependent, matching-to-sample, learning of the platform location, an index of short-term spatial working memory in mice, was significantly impaired in D1 receptor knockout mice compared to wild-type mice, and regular performance of D3 receptor mutants was observed in the similar working memory task. BDNF protein was significantly decreased in prefrontal cortex, though not in hippocampus, of the D1 receptor knockout mice, whereas no changes were found in both prefrontal cortex and hippocampus of D3 receptor knockout mice. These data suggest that dopamine D1 but not D3 receptors are critical for prefrontal cortex BDNF expression which may be related to spatial working memory processes.     

Corticosteroid Receptor Antagonists are Amnestic for Passive Avoidance Learning in Day-old Chicks

Glucocorticoids can modulate behavioural processes and neural plasticity. They are released during learning situations and can trigger neural actions through binding to brain receptors. We hypothesized that a glucocorticoid action could play a critical role in the mechanisms involved in long-term memory formation. In order to test this hypothesis, chicks were trained on a passive avoidance learning task and given bilateral intracerebral injections of selective mineralocorticoid (RU-28318) or glucocorticoid (RU-38486) receptor antagonists. The results showed that both antagonists alter information processing when injected prior to the training session. Possible state-dependent effects were discharged. Further experiments evaluating possible effects of the antagonists on concomitant aspects of the learning situation (such as novelty reaction and pecking pattern) indicated that, as opposed to the glucocorticoid receptor antagonist, the mineralocorticoid antagonist altered the birds' reactivity to non-specific aspects of the training task. These results suggest that the two types of intracellular corticosteroid receptors could be mediating different aspects of the information processing and storage involved in avoidance learning. In addition, this study points out that passive avoidance learning in the chick could be a good model to investigate the biochemical mechanisms involved in corticosteroid actions on learning-induced neural plasticity     

Effects of environmental enrichment on exploration, anxiety, and memory in female TgCRND8 Alzheimer mice

After we could recently demonstrate a beneficial effect of environmental enrichment on AD-like brain pathology in female TgCRND8 mice [Ambrée O, Leimer U, Herring A, G?rtz N, Sachser N, Heneka MT, et al. Reduction of amyloid angiopathy and Abeta plaque burden after enriched housing in TgCRND8 mice: involvement of multiple pathways. Am J Pathol 2006;169:544-52] the present study focuses on the behavioural effects of environmental enrichment with special emphasis on learning and memory performance in this AD model. In the first experiment spontaneous exploration, locomotor activity and anxiety-related behaviour were assessed as the performance in learning tasks can be biased substantially by exploratory behavioural traits. In the second experiment spatial memory in the Barnes maze test and object recognition memory were examined. Regarding exploratory behaviour transgenic mice from standard housing condition were statistically indistinguishable from wild-type controls. Enrichment had comparable effects in both genotypes indicated by higher levels of exploration and locomotor activity. In transgenic mice the elevated plus-maze revealed less anxiety-related behaviour due to enrichment in contrast to wild-type mice that statistically did not differ in anxiety-related behaviour. Concerning learning and memory performance, cognitive deficits of standard housed transgenic mice could be demonstrated in both learning tasks. Surprisingly, in both housing conditions a significantly higher number of transgenic mice refused to explore any objects compared to wild-type mice. Furthermore, the Barnes maze test revealed deficits of the transgenic mice in spatial memory compared to wild-type mice whereas no effect of environmental enrichment was detectable. Thus environmental enrichment increased exploratory behaviour and decreased anxiety-related behaviour but could not clearly ameliorate deficits in learning and memory performance of TgCRND8 mice.     

Continuous blockade of brain glucocorticoid receptors facilitates spatial learning and memory in rats

Previously, a corticosterone surge associated with a learning task was shown to facilitate cognitive processes through brain glucocorticoid receptors (GR) while chronic overexposure to this stress hormone impaired cognition. In the present study we tested the hypothesis that opposing effects on learning and memory might also occur after either phasic or continuous blockade of brain GR by intracerebroventricular (i.c.v.) administration of the GR antagonist RU38486 (aGR). We used a Morris water maze procedure to assess spatial learning and memory abilities in male Wistar rats. The effect of phasic brain GR blockade was studied following daily pretraining administration of 10 and 100 ng/μL aGR i.c.v. on 3 consecutive days. This repetitive aGR treatment impaired spatial learning and memory dose-dependently in comparison with vehicle controls. For continuous brain GR blockade, animals received an i.c.v. infusion of aGR (10 and 100 ng/0.5 μL per h or vehicle) over 10 days. Infusion of 100 ng aGR per hour resulted in a long-lasting facilitation of spatial performance. The 10 ng aGR infusion also caused initially a facilitating effect, which was, however, transient and performance became impaired during retest. Possible anxiolytic properties of the drugs were excluded in view of the animals' behaviour in the elevated plus maze. Both doses of aGR infusion reduced the number of mineralocorticoid receptors in the hippocampus, but only the high dose of aGR resulted in a significant reduction of available GR sites. In conclusion, continuous administration of GR antagonist improves cognitive function, while phasic blockade of brain GR function causes a cognitive deficit.     

Loss of forebrain cholinergic neurons and impairment in spatial learning and memory in LHX7-deficient mice

The identification of the genetic determinants specifying neuronal networks in the mammalian brain is crucial for the understanding of the molecular and cellular mechanisms that ultimately control cognitive functions. Here we have generated a targeted allele of the LIM-homeodomain-encoding gene Lhx7 by replacing exons 3-5 with a LacZ reporter. In heterozygous animals, which are healthy, fertile and have no apparent cellular deficit in the forebrain, b-galactosidase activity reproduces the pattern of expression of the wild-type Lhx7 locus. However, homozygous mutant mice show severe deficits in forebrain cholinergic neurons (FCNs), while other classes of forebrain neurons appear unaffected. Using the LacZ reporter as a marker, we show that in LHX7-deficient mice FCN progenitors survive but fail to generate cholinergic interneurons in the striatum and cholinergic projection neurons in the basal forebrain. Analysis of behaviour in a series of spatial and non-spatial learning and memory tasks revealed that FCN ablation in Lhx7 mutants is associated with severe deficits in spatial but only mild impairment of non-spatial learning and memory. In addition, we found no deficit in long-term potentiation in mutant animals, suggesting that FCNs modulate hippocampal function independently of its capacity to store information. Overall our experiments demonstrate that Lhx7 expression is required for the specification or differentiation of cholinergic forebrain neurons involved in the processing of spatial information.     

Long-term monitoring of hippocampus-dependent behavior in naturalistic settings: mutant mice lacking neurotrophin receptor TrkB in the forebrain show spatial learning but impaired behavioral flexibility

Previous behavioral studies (Minichiello et al., Neuron 1999;24:401-414) showed that mice deficient for the TrkB receptor in the forebrain were unable to learn a swimming navigation task with an invisible platform and were severely impaired in finding a visible platform in the same setup. Likewise, additional behavioral deficits suggested a malfunction of the hippocampus and proximally connected forebrain structures. In order to discriminate whether the behavioral impairment was caused either by deficits in spatial memory and learning, or alternatively by loss of behavioral flexibility, 8 trkB mutant, 13 wild-type, and 22 heterozygous mice were implanted with transponders and released for 21 days into a large outdoor pen (10 x 10 m). The enclosure contained 2 shelters and 8 computer-controlled feeder boxes, delivering food portions for every mouse only during their first visit. Every third day, mice received food ad libitum inside the shelters. All mice learned to patrol the boxes correctly within a few days. However, significant differences emerged during those days with free food available. Wild-type mice remained inside the shelters, while all homozygous mutants continued to patrol the boxes in their habitual way, the heterozygous mutants showing intermediate scores. These and previous data suggest that one of the natural functions of the mouse hippocampus is to comediate behavioral flexibility, and that TrkB receptors might play an essential role in maintaining the neuronal short-term plasticity necessary for this capacity.     

The Effect of Corticosterone on Reactivity to Spatial Novelty is Mediated by Central Mineralocorticosteroid Receptors

Corticosterone, secreted by the adrenal glands, binds to central mineralocorticoid receptors with high affinity and to glucocorticoid receptors with a tenfold lower affinity. In previous studies we have shown that the selective activation of either mineralocorticoid receptors or glucocorticoid receptors exerts distinctly different behavioural effects. In this study we examined in particular the mineralocorticoid receptor-mediated effect of corticosterone on the control of the behavioural response of male Wistar rats to spatial novelty. This analysis was based on our observation that in adrenal-intact rats the presence of an object in the centre of an open field alters the time spent and distance walked in the centre compared to the peripheral area, i.e. the pattern of reactive locomotor activity is changed. Using this paradigm we found that 1 day after removal of the adrenals the rats increased their behavioural reactivity towards the object. Treatment of adrenalectomized rats with a low dose of corticosterone (50 μg/kg s.c.) 1 h prior to testing restored the behavioural reactivity to the level of sham-operated, intact rats. Surprisingly, a high dose of corticosterone (1000 μg/kg s.c.) also increased the rat's reactivity towards the object. The same high dose of corticosterone given to adrenal-intact rats also increased behavioural reactivity. Pretreatment of these rats with an intracerebroventricular injection of the selective mineralocorticoid receptor antagonist RU28318 (100 ng/μl) prevented the corticosterone-induced increase in behavioural reactivity, while the blockade of glucocorticoid receptors with the antagonist RU38486 (100 ng/μl) was not effective. Administration of the mineralocorticoid receptor antagonist without corticosterone to adrenal-intact rats also increased behavioural reactivity, but this increase did not reach statistical significance. General locomotor activity was not affected by either treatment. In conclusion, we found a U-shaped relationship between the pattern of behavioural reactivity in a novel environment and the circulating plasma corticosterone level. The response to spatial novelty appeared to be sensitive with respect to the activation and blockade of central, presumably hippocampal mineralocorticoid receptors.     

Mild deficits in mice lacking pituitary adenylate cyclase-activating polypeptide receptor type 1 (PAC1) performing on memory tasks

Pituitary adenylate cyclase-activating polypeptide (PACAP) and its receptor subtype 1 (PAC1) have been suggested to play a role in the modulation of learning and memory. However, behavioral evidence for altered mnemonic function due to altered PAC1 activity is missing. Therefore, the role of PAC1 in learning and memory was studied in mouse mutants lacking this receptor (PAC1 knock-out mice), tested in water maze two-choice spatial discrimination, one-trial contextual and cued fear conditioning, and multiple-session contextual discrimination. Water maze spatial discrimination was unaffected in PAC1 mutants, while a mild deficit was observed in multiple session contextual discrimination in PAC1 knock-out mice. Furthermore, PAC1 knock-out mice were able to learn the association between context and shock in one-trial contextual conditioning, but showed faster return to baseline than wild-type mice. Thus, the effects of PAC1 knock-out on modulating performance in these tasks were subtle and suggest that PAC1 only plays a limited role in learning and memory.     

Disrupted allocentric but preserved egocentric spatial learning in transgenic mice with impaired glucocorticoid receptor function

Spatial and non-spatial learning of mice with an incorporated antisense RNA complementary to a fragment of cDNA coding for the glucocorticoid receptor (GR) were evaluated in allocentric and egocentric radial maze and water maze tasks, and in spontaneous object recognition and sensorimotor learning paradigms. Mice with impaired GR function did not acquire two maze paradigms based on allocentric spatial navigation, radial maze non-matching to position and water maze spatial discrimination learning. Comparison of performance in spaced and massed trials indicated that this may be due to a general inability to store information into allocentric reference memory or in retrieval processes. However, both groups of animals learned the rules of an egocentric radial maze task at similar rates and there was no difference in their ability to recognise objects once animals had equal opportunity to explore the sample objects. Sensorimotor performance was impaired in transgenic animals, but it is suggested that this is due to non-specific factors rather than to disrupted sensorimotor learning per se. These results are consistent with a disruption of hippocampal function. Histological examination of the hippocampus revealed no obvious structural abnormalities in transgenic animals. Therefore, the data suggest that functional underactivity of GRs at the level of the hippocampus induces a deficit in allocentric navigation while sparing egocentric navigation and object recognition.     

Impaired water maze learning performance in mu-opioid receptor knockout mice

Previous study has demonstrated that the lack of mu-opioid receptor decreased LTP in the dentate gyrus of the hippocampus, suggesting the possibility that the lack of mu-opioid receptor may accompany a change in learning and memory. However, no behavioral study has been undertaken to correlate LTP deficits with spatial memory impairment in mu-opioid receptor knockout mice. Therefore, the present study investigated the hypothesis that mu-opioid receptors contribute to learning and memory by using the Morris water maze, and comparing responses in wild type and mu-opioid receptor gene knockout mice. Our results indicated that mu-opioid receptor knockout mice showed a significant spatial memory impairment compared to wild type in the Morris water maze. This result suggests that the expression of mu-opioid receptor plays an important role in spatial learning and memory examined by Morris water maze.     

Wheel-running in a transgenic mouse model of Alzheimer's disease: protection or symptom?

Several studies on both humans and animals reveal benefits of physical exercise on brain function and health. A previous study on TgCRND8 mice, a transgenic model of Alzheimer's disease, reported beneficial effects of premorbid onset of long-term access to a running wheel on spatial learning and plaque deposition. Our study investigated the effects of access to a running wheel after the onset of Abeta pathology on behavioural, endocrinological, and neuropathological parameters. From day 80 of age, the time when Abeta deposition becomes apparent, TgCRND8 and wildtype mice were kept with or without running wheel. Home cage behaviour was analysed and cognitive abilities regarding object recognition memory and spatial learning in the Barnes maze were assessed. Our results show that, in comparison to Wt mice, Tg mice were characterised by impaired object recognition memory and spatial learning, increased glucocorticoid levels, hyperactivity in the home cage and high levels of stereotypic behaviour. Access to a running wheel had no effects on cognitive or neuropathological parameters, but reduced the amount of stereotypic behaviour in transgenics significantly. Furthermore, wheel-running was inversely correlated with stereotypic behaviour, suggesting that wheel-running may have stereotypic qualities. In addition, wheel-running positively correlated with plaque burden. Thus, in a phase when plaques are already present in the brain, it may be symptomatic of brain pathology, rather than protective. Whether or not access to a running wheel has beneficial effects on Alzheimer-like pathology and symptoms may therefore strongly depend on the exact time when the wheel is provided during development of the disease.     

Metabotropic glutamate receptor 1 blockade impairs acquisition and retention in a spatial Water maze task

Metabotropic glutamate receptors, including the mGlu1 receptor, have received considerable attention as potential targets for anxiolytic, antidepressant, antipsychotic and antinociceptive drugs. mGlu1 receptors have also been suggested to play a role in the modulation of cognitive processes, but knowledge is still very limited. In the present study the effects of the selective mGlu1 receptor antagonist 3,4-dihydro-2H-pyrano[2,3]beta-quinolin-7-yl)(cis-4-methoxycyclohexyl)methanone (JNJ16259685, 0.63-10 mg/kg s.c.) on more or less spatially demanding learning and spatial memory (retention and re-acquisition) were investigated in mice performing in a water maze. Selective mGlu1 receptor blockade with JNJ16259685 impaired spatial acquisition processes, irrespective of spatial load, as well as spatial re-acquisition, already at the lowest dose tested (0.63 mg/kg). In contrast, effects on spatial retention performance were relatively mild in mice that had learned to locate the position of the escape platform prior to treatment. Thigmotaxic behaviour and locomotor activity appeared to be unaffected by JNJ16259685. These data suggest that blockade of the mGlu1 receptor primarily affects learning of new information, but leaves retention of spatial information relatively unaffected. Blockade of the mGlu5 receptor with MPEP also impaired spatial learning, although only at the highest dose tested (10 mg/kg). An ex vivo receptor occupancy study in rats revealed that MPEP occupied central mGlu5 receptors with an ED(50) of 2.0 mg/kg one hour after subcutaneous administration. This is 50-150 times higher than the ED(50) reported for JNJ16259685 at central mGlu1 receptors and suggests that one reason why the two compounds cause cognitive effects at different doses might be due to differences in central mGlu receptor occupancy, rather than fundamentally different roles of mGlu1 and mGlu5 receptors in the modulation of cognitive function.     

SR 141716A prevents delta 9-tetrahydrocannabinol-induced spatial learning deficit in a Morris-type water maze in mice

This study reports a series of spatial discrimination procedures in a Morris-type maze to investigate the effects of delta9-tetrahydrocannabinol (delta9-THC) on different phases of learning and memory in mice. Adult male mice were given training trails to find the submerged platform at a fixed location in the water maze adapted for mice. In additional experiments, mice were trained with the repeated acquisition procedure to test the working memory. Results indicate that delta9-THC (8 mg/kg i.p.) 30 min pretest impaired specifically the acquisition of spatial learning and the performance of mice in the working memory task, while consolidation and retrieval of a previously learned task were not affected. There was no evidence of motoric difficulty, as the number of quadrant line crossings was not decreased and no visible sign of sensorimotor disturbance was observed during swimming. Pretreatment with SR 141716A (1 mg/kg i.p.), a CB1 cannabinoid receptor antagonist, significantly prevented the learning deficits in the water maze. These findings show that delta9-THC impairs spatial discrimination learning in a selective way in the water maze in mice and that these deficits may be mediated by cannabinoid receptors.     

Impaired learning and memory and altered hippocampal neurodevelopment resulting from interleukin-2 gene deletion.

Interleukin-2 (IL-2), the protypical T cell growth factor and immunoregulatory cytokine produced by lymphocytes, has been implicated as a brain neurotrophic factor and neuromodulator. The consequences of the absence of endogenous IL-2 on brain development and function were unknown. Brain IL-2 receptors are enriched in the hippocampal formation, an area critical for the acquisition and consolidation of spatial learning and memory. Thus, we tested the hypothesis that mice lacking IL-2 would exhibit alterations in hippocampal-dependent learning and neurodevelopment. Compared with C57BL/6-IL-2+/+ wild-type mice, we observed that C57BL/6-IL-2-/- gene knockout mice had markedly impaired spatial learning and memory in the Morris water maze. No significant deficits in parameters of learning and memory performance were found in severe combined immunodeficient (SCID) mice (C57BL/6scid), however, suggesting that the impaired spatial learning and memory exhibited by IL-2 knockout mice is not attributable to generalized immunodeficiency resulting from the absence of endogenous IL-2. Examination of other domains of behavioral performance showed that the IL-2 knockout and wildtype mice did not differ in measures of fearfulness or locomotor activity in an elevated plus maze, or in reflexive startle responses to auditory stimuli--although prepulse inhibition of acoustic startle (PPI) was increased significantly in IL-2 knockout mice. The spatial learning and memory impairment in IL-2 knockout mice was accompanied by reductions in hippocampal infrapyramidal mossy neuronal fiber length, a factor shown previously to correlate positively with spatial learning ability. These findings indicate that, in addition to being a pivotal cytokine in immune regulation, IL-2 may play a role in the development and regulation of brain neurons involved in spatial learning and memory.     

Impaired spatial working memory but spared spatial reference memory following functional loss of NMDA receptors in the dentate gyrus

Novel spatially restricted genetic manipulations can be used to assess contributions made by synaptic plasticity to learning and memory, not just selectively within the hippocampus, but even within specific hippocampal subfields. Here we generated genetically modified mice (NR1(deltaDG) mice) exhibiting complete loss of the NR1 subunit of the N-methyl-D-aspartate receptor specifically in the granule cells of the dentate gyrus. There was no evidence of any reduction in NR1 subunit levels in any of the other hippocampal subfields, or elsewhere in the brain. NR1(deltaDG) mice displayed severely impaired long-term potentiation (LTP) in both medial and lateral perforant path inputs to the dentate gyrus, whereas LTP was unchanged in CA3-to-CA1 cell synapses in hippocampal slices. Behavioural assessment of NR1(deltaDG) mice revealed a spatial working memory impairment on a three-from-six radial arm maze task despite normal hippocampus-dependent spatial reference memory acquisition and performance of the same task. This behavioural phenotype resembles that of NR1(deltaCA3) mice but differs from that of NR1(deltaCA1) mice which do show a spatial reference memory deficit, consistent with the idea of subfield-specific contributions to hippocampal information processing. Furthermore, this pattern of selective functional loss and sparing is the same as previously observed with the global GluR-A L-alpha-amino-3-hydroxy-5-methyl-4-isoxazelopropionate receptor subunit knockout, a mutation which blocks the expression of hippocampal LTP. The present results show that dissociations between spatial working memory and spatial reference memory can be induced by disrupting synaptic plasticity specifically and exclusively within the dentate gyrus subfield of the hippocampal formation.     

Spontaneous alternation and spatial learning in Dab1scm (scrambler) mutant mice

Homozygous Dab1scm mutants with cell ectopias in cerebellar cortex, hippocampus, and neocortex were compared with non-ataxic heterozygous and wild-type controls in spontaneous alternation and Morris water maze tests. Although there were no group differences in alternation rates, wild-type and heterozygote groups alternated above chance levels, whereas homozygous Dab1scm mutants did not. In the Morris water maze, Dab1scm mutants were impaired in both hidden and visible platform subtests. The deficits in spontaneous alternation and water maze measures reproduce the phenotype previously described in Reln(rl-Orl) mutants, attributed to disturbance of the same molecular pathway involving reelin.     

Increased Intermale Aggression and Neuroendocrine Response in Mice Deficient for the Neural Cell Adhesion Molecule (NCAM)

Mice deficient for the neural cell adhesion molecule (NCAM) show morphological and behavioural abnormalities in the adult form, including a reduced size of the olfactory bulb, reduced exploratory behaviour, and deficits in spatial learning. Here we report increased aggressive behaviour of both homozygous (NCAM -/–) and heterozygous (NCAM +/–) male mutant mice towards an unfamiliar male intruding into their home cage. While plasma testosterone concentrations did not differ between genotypes before or after behavioural testing, corticosterone levels were higher in mutant residents than in wild-type (NCAM +/+) residents 30 min after encountering the intruder. Levels of c-fos mRNA, analysed to monitor neuronal activation, were similar in primary output structures of the olfactory bulb in NCAM-deficient and NCAM +/+ mice, but were increased in brain areas of the limbic system in both NCAM –/– and NCAM +/– mutant mice after the behavioural test. These results indicate that abnormalities in social behaviour correlate with enhanced neuronal activity in limbic brain areas and result in increased social stress in NCAM-deficient mice.     

Characteristics of behavioral abnormalities in alpha1d-adrenoceptors deficient mice

To investigate the functional role of alpha1d-adrenergic receptor (alpha1d-AR) in the CNS, we have generated mutant mice lacking the alpha1d-AR using a gene targeting approach and examined in detail the effects of alpha1d-AR knockout mice on motor function, sensory function, and learning and memory. alpha1d-AR knockout mice showed better motor coordination at the highest rotating speed of the rotarod performance and stronger muscle tone using the traction meter, but their locomotor activity and swimming ability in the water maze were not affected. In the water maze requiring reference memory, alpha1d-AR knockout mice showed normal spatial learning. In the Y-maze task requiring working memory or attention, alpha1d-AR knockout mice displayed an impaired spontaneous alternation performance. The alpha1d-AR knockout mice tended to display lower levels of acoustic startle responses than the wild-type group at lower pulse intensities, although the acoustic prepulse inhibition was not impaired in the alpha1d-AR knockout mice. Furthermore, the NMDA receptor antagonist, MK-801-induced deficits of acoustic prepulse inhibition were not observed in the alpha1d-AR knockout mice. These results clearly demonstrate that the alpha1d-AR receptor plays an important role in the process of auditory sensory function, attention or working memory rather than reference memory, and the sensorimotor gating deficits induced by the NMDA receptor antagonist.