Ultracompact Multielectrode Array for Neurological Monitoring.

Patients with paralysis, spinal cord injury, or amputated limbs could benefit from using brain-machine interface technology for communication and neurorehabilitation. In this study, a 32-channel three-dimensional (3D) multielectrode probe array was developed for the neural interface system of a brain-machine interface to monitor neural activity. A novel microassembly technique involving lead transfer was used to prevent misalignment in the bonding plane during the orthogonal assembly of the 3D multielectrode probe array. Standard microassembly and biopackaging processes were utilized to implement the proposed lead transfer technique. The maximum profile of the integrated 3D neural device was set to 0.50 mm above the pia mater to reduce trauma to brain cells. Benchtop tests characterized the electrical impedance of the neural device. A characterization test revealed that the impedance of the 3D multielectrode probe array was on average approximately 0.55 MΩ at a frequency of 1 KHz. Moreover, in vitro cytotoxicity tests verified the biocompatibility of the device. Subsequently, 3D multielectrode probe arrays were implanted in rats and exhibited the capability to record local field potentials and spike signals.

Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse.

Adaptation of the nervous system to different chemical and physiologic conditions is important for the homeostasis of brain processes and for learning and remembering appropriate responses to challenges. Although processes such as tolerance and dependence to various drugs of abuse have been known for a long time, it was recently discovered that even a single pharmacologically relevant dose of various drugs of abuse induces neuroplasticity in selected neuronal populations, such as the dopamine neurons of the ventral tegmental area, which persist long after the drug has been excreted. Prolonged (self-) administration of drugs induces gene expression, neurochemical, neurophysiological, and structural changes in many brain cell populations. These region-specific changes correlate with addiction, drug intake, and conditioned drugs effects, such as cue- or stress-induced reinstatement of drug seeking. In rodents, adolescent drug exposure often causes significantly more behavioral changes later in adulthood than a corresponding exposure in adults. Clinically the most impairing and devastating effects on the brain are produced by alcohol during fetal development. In adult recreational drug users or in medicated patients, it has been difficult to find persistent functional or behavioral changes, suggesting that heavy exposure to drugs of abuse is needed for neurotoxicity and for persistent emotional and cognitive alterations. This review describes recent advances in this important area of research, which harbors the aim of translating this knowledge to better treatments for addictions and related neuropsychiatric illnesses.

Priming locus coeruleus noradrenergic modulation of medial perforant path-dentate gyrus synaptic plasticity.

Priming phenomenon, in which an earlier exposure to a stimulus or condition alters synaptic plasticity in response to a subsequent stimulus or condition, known as a challenge, is an example of metaplasticity. In this review, we make the case that the locus coeruleus noradrenergic system-medial perforant path-dentate gyrus pathway is a neural ensemble amenable to studying priming-challenge effects on synaptic plasticity. Accumulating evidence points to a tyrosine hydroxylase-dependent priming effect achieved by pharmacological (nicotine and antipsychotics) or physiological (septal theta driving) manipulations of the locus coeruleus noradrenergic system that can facilitate noradrenaline-induced synaptic plasticity in the dentate gyrus of the hippocampus. The evidence suggests the hypothesis that behavioural experiences inducing tyrosine hydroxylase expression in the locus coeruleus may be sufficient to prime this form of metaplasticity. We propose exploring this phenomenon of priming and challenge physiologically, to determine whether behavioural experiences are sufficient to prime the locus coeruleus, enabling subsequent pharmacological or behavioural challenge conditions that increase locus coeruleus firing to release sufficient noradrenaline to induce long-lasting potentiation in the dentate gyrus. Such an approach may contribute to unravelling mechanisms underlying this form of metaplasticity and its importance in stress-related mnemonic processes.

Activation of beta- and alpha-2-adrenoceptors in the basolateral amygdala has opposing effects on hippocampal-prefrontal long-term potentiation.

Noradrenaline (NA), released by the locus coeruleus (LC), plays a key role in mediating the effects of stress on memory functions. The LC provides diffuse projections to many forebrain nuclei including the hippocampus, the prefrontal cortex (PFC), and the basolateral amygdala (BLA). These three structures are intricately interlinked. The hippocampal-prefrontal (H-PFC) pathway is involved in various cognitive functions. The first aim of this study was to examine the role of BLA in H-PFC plasticity by infusion of drugs to activate and inactivate the BLA and studying the effects on H-PFC long-term potentiation (LTP) in the rat in vivo. Activation of the BLA with glutamate impaired, while inactivation with muscimol augmented, H-PFC LTP. This study also aimed to demonstrate how directly applying noradrenaline and other noradrenergic agents in the BLA can affect H-PFC LTP. Noradrenaline at 1µg/0.2µl enhanced H-PFC LTP. Stimulating alpha-2-adrenoceptors in the BLA with clonidine enhanced LTP while blocking alpha-2 adrenoceptors with idazoxan impaired it. Propranolol, a non-selective beta antagonist, enhanced H-PFC LTP while isoprenaline, a non-selective beta agonist, decreased H-PFC LTP. These results suggest that the BLA regulates H-PFC plasticity negatively and also provide a mechanism by which noradrenaline in the BLA can affect H-PFC plasticity via alpha-2 and beta adrenoceptors.

Amyloid precursor protein enhances Nav1.6 sodium channel cell surface expression.

Amyloid precursor protein (APP) is commonly associated with Alzheimer disease, but its physiological function remains unknown. Nav1.6 is a key determinant of neuronal excitability in vivo. Because mouse models of gain of function and loss of function of APP and Nav1.6 share some similar phenotypes, we hypothesized that APP might be a candidate molecule for sodium channel modulation. Here we report that APP colocalized and interacted with Nav1.6 in mouse cortical neurons. Knocking down APP decreased Nav1.6 sodium channel currents and cell surface expression. APP-induced increases in Nav1.6 cell surface expression were Go protein-dependent, enhanced by a constitutively active Go protein mutant, and blocked by a dominant negative Go protein mutant. APP also regulated JNK activity in a Go protein-dependent manner. JNK inhibition attenuated increases in cell surface expression of Nav1.6 sodium channels induced by overexpression of APP. JNK, in turn, phosphorylated APP. Nav1.6 sodium channel surface expression was increased by T668E and decreased by T668A, mutations of APP695 mimicking and preventing Thr-668 phosphorylation, respectively. Phosphorylation of APP695 at Thr-668 enhanced its interaction with Nav1.6. Therefore, we show that APP enhances Nav1.6 sodium channel cell surface expression through a Go-coupled JNK pathway.

Efficient derivation of dopaminergic neurons from SOX1⁻ floor plate cells under defined culture conditions.

BACKGROUND: Parkinson's disease (PD) is a severe neurodegenerative disease associated with loss of dopaminergic neurons. Derivation of dopaminergic neurons from human embryonic stem cells (hESCs) could provide new therapeutic options for PD therapy. Dopaminergic neurons are derived from SOX(-) floor plate (FP) cells during embryonic development in many species and in human cell culture in vitro. Early treatment with sonic hedgehog (Shh) has been reported to efficiently convert hESCs into FP lineages. METHODS: In this study, we attempted to utilize a Shh-free approach in deriving SOX1(-) FP cells from hESCs in vitro. Neuroectoderm conversion from hESCs was achieved with dual inhibition of the BMP4 (LDN193189) and TGF-ß signaling pathways (SB431542) for 24 h under defined culture conditions. RESULTS: Following a further 5 days of treatment with LDN193189 or LDN193189 + SB431542, SOX1(-) FP cells constituted 70-80 % of the entire cell population. Upon treatment with Shh and FGF8, the SOX1(-) FP cells were efficiently converted to functional Nurr1(+) and TH(+) dopaminergic cells (patterning), which constituted more than 98 % of the entire cell population. However, when the same growth factors were applied to SOX1(+) cells, only less than 4 % of the cells became Nurr1(+), indicating that patterning was effective only if SOX1 expression was down-regulated. After transplanting the Nurr1(+) and TH(+) cells into a hemiparkinsonian rat model, significant improvements were observed in amphetamine induced ipslateral rotations, apomorphine induced contra-lateral rotations and Rota rod motor tests over a duration of 8 weeks. CONCLUSIONS: Our findings thus provide a convenient approach to FP development and functional dopaminergic neuron derivation.

The duration of lithium use and biological ageing: telomere length, frailty, metabolomic age and all-cause mortality.

Lithium is an established first-line treatment for bipolar disorder. Beyond its therapeutic effect as a mood stabiliser, lithium exhibits potential anti-ageing effects. This study aimed to examine the relationship between the duration of lithium use, biological ageing and mortality. The UK Biobank is an observational study of middle-aged and older adults. We tested associations between the duration of lithium use (number of prescriptions, total duration of use and duration of the first prescription period) and telomere length, frailty, metabolomic age (MileAge) delta, pulse rate and all-cause mortality. Five hundred ninety-one individuals (mean age = 57.49 years; 55% females) had been prescribed lithium. There was no evidence that the number of prescriptions (ß = - 0.022, 95% CI - 0.081 to 0.037, p = 0.47), the total duration of use (ß = - 0.005, 95% CI - 0.023 to 0.013, p = 0.57) or the duration of the first prescription period (ß = - 0.018, 95% CI - 0.051 to 0.015, p = 0.29) correlated with telomere length. There was also no evidence that the duration of lithium use correlated with frailty or MileAge delta. However, a higher prescription count and a longer duration of use was associated with a lower pulse rate. The duration of lithium use did not predict all-cause mortality. We observed no evidence of associations between the duration of lithium use and biological ageing markers, including telomere length. Our findings suggest that the potential anti-ageing effects of lithium do not differ by the duration of use.

Mechanisms of biased agonism by Gαi/o-biased stapled peptide agonists of the relaxin-3 receptor.

The neuropeptide relaxin-3 is composed of an A chain and a B chain held together by disulfide bonds, and it modulates functions such as anxiety and food intake by binding to and activating its cognate receptor RXFP3, mainly through the B chain. Biased ligands of RXFP3 would help to determine the molecular mechanisms underlying the activation of G proteins and ß-arrestins downstream of RXFP3 that lead to such diverse functions. We showed that the i, i+4 stapled relaxin-3 B chains, 14s18 and d(1-7)14s18, were Gαi/o-biased agonists of RXFP3. These peptides did not induce recruitment of ß-arrestin1/2 to RXFP3 by GPCR kinases (GRKs), in contrast to relaxin-3, which enabled the GRK2/3-mediated recruitment of ß-arrestin1/2 to RXFP3. Relaxin-3 and the previously reported peptide 4 (an i, i+4 stapled relaxin-3 B chain) did not exhibit biased signaling. The staple linker of peptide 4 and parts of both the A chain and B chain of relaxin-3 interacted with extracellular loop 3 (ECL3) of RXFP3, moving it away from the binding pocket, suggesting that unbiased ligands promote a more open conformation of RXFP3. These findings highlight roles for the A chain and the N-terminal residues of the B chain of relaxin-3 in inducing conformational changes in RXFP3, which will help in designing selective biased ligands with improved therapeutic efficacy.

Investigating the role of the relaxin-3/RXFP3 system in neuropsychiatric disorders and metabolic phenotypes: A candidate gene approach.

The relaxin-3/RXFP3 system has been implicated in the modulation of depressive- and anxiety-like behaviour in the animal literature; however, there is a lack of human studies investigating this signalling system. We seek to bridge this gap by leveraging the large UK Biobank study to retrospectively assess genetic risk variants linked with this neuropeptidergic system. Specifically, we conducted a candidate gene study in the UK Biobank to test for potential associations between a set of functional, candidate single nucleotide polymorphisms (SNPs) pertinent to relaxin-3 signalling, determined using in silico tools, and several outcomes, including depression, atypical depression, anxiety and metabolic syndrome. For each outcome, we used several rigorously defined phenotypes, culminating in subsample sizes ranging from 85,881 to 386,769 participants. Across all outcomes, there were no associations between any candidate SNP and any outcome phenotype, following corrections for multiple testing burden. Regression models comprising several SNPs per relevant candidate gene as exploratory variables further exhibited no prediction of outcome. Our findings corroborate conclusions from previous literature about the limitations of candidate gene approaches, even when based on firm biological hypotheses, in the domain of genetic research for neuropsychiatric disorders.

Elevated Soluble TNF-Receptor 1 in the Serum of Predementia Subjects with Cerebral Small Vessel Disease.

Tumor necrosis factor-receptor 1 (TNF-R1)-mediated signaling is critical to the regulation of inflammatory responses. TNF-R1 can be proteolytically released into systemic blood circulation in a soluble form (sTNF-R1), where it binds to circulating TNF and functions to attenuate TNF-mediated inflammation. Increases of peripheral sTNF-R1 have been reported in both Alzheimer's disease (AD) dementia and vascular dementia (VaD). However, the status of sTNF-R1 in predementia subjects (cognitive impairment, no dementia, CIND) is unknown, and putative associations with cerebral small vessel disease (CSVD), as well as with longitudinal changes in cognitive functions are unclear. We measured baseline serum sTNF-R1 in a longitudinally assessed cohort of 93 controls and 103 CIND, along with neuropsychological evaluations and neuroimaging assessments. Serum sTNF-R1 levels were increased in CIND compared with controls (p < 0.001). Higher baseline sTNF-R1 levels were specifically associated with lacunar infarcts (rate ratio = 6.91, 95% CI 3.19-14.96, p < 0.001), as well as lower rates of cognitive decline in the CIND subgroup. Our data suggest that sTNF-R1 interacts with vascular cognitive impairment in a complex manner at predementia stages, with elevated levels associated with more severe CSVD at baseline, but which may subsequently be protective against cognitive decline.

Progesterone impairs human ether-a-go-go-related gene (HERG) trafficking by disruption of intracellular cholesterol homeostasis.

The prolongation of QT intervals in both mothers and fetuses during the later period of pregnancy implies that higher levels of progesterone may regulate the function of the human ether-a-go-go-related gene (HERG) potassium channel, a key ion channel responsible for controlling the length of QT intervals. Here, we studied the effect of progesterone on the expression, trafficking, and function of HERG channels and the underlying mechanism. Treatment with progesterone for 24 h decreased the abundance of the fully glycosylated form of the HERG channel in rat neonatal cardiac myocytes and HERG-HEK293 cells, a cell line stably expressing HERG channels. Progesterone also concentration-dependently decreased HERG current density, but had no effect on voltage-gated L-type Ca(2+) and K(+) channels. Immunofluorescence microscopy and Western blot analysis show that progesterone preferentially decreased HERG channel protein abundance in the plasma membrane, induced protein accumulation in the dilated endoplasmic reticulum (ER), and increased the protein expression of C/EBP homologous protein, a hallmark of ER stress. Application of 2-hydroxypropyl-ß-cyclodextrin (a sterol-binding agent) or overexpression of Rab9 rescued the progesterone-induced HERG trafficking defect and ER stress. Disruption of intracellular cholesterol homeostasis with simvastatin, imipramine, or exogenous application of cholesterol mimicked the effect of progesterone on HERG channel trafficking. Progesterone may impair HERG channel folding in the ER and/or block its trafficking to the Golgi complex by disrupting intracellular cholesterol homeostasis. Our findings may reveal a novel molecular mechanism to explain the QT prolongation and high risk of developing arrhythmias during late pregnancy.

Test, rinse, repeat: A review of carryover effects in rodent behavioral assays.

Behavioral phenotyping has been gaining prominence due to the increased use of transgenic animal models of neurological disorders. Repeated testing in the same cohort of animals can reduce the overall number of animals used and is desired especially when animal numbers are difficult to obtain as well as for studies involving within-subject design such as drug treatments or aging. This review aims to provide researchers with a comprehensive overview of the carryover effects when subjecting the same set of animals to the same behavioral test. We have focused on three behavioral domains of testing: anxiety, cognition and depression. Based on a review of the literature and our own experiences as a neurobehavioral core facility, we have found that manipulating inter-test interval, environmental contextual cues and stimuli can mitigate the carryover effects to a large extent, although there are certain tests that still show strong residual effects. In addition, the effects of strain on carryover effects from repeated testing are also discussed in this review.

Shared signaling pathways in Alzheimer's and metabolic disease may point to new treatment approaches.

'A peculiar severe disease process of the cerebral cortex' are the exact words used by A. Alzheimer in 1906 to describe a patient's increasingly severe condition of memory loss, changes in personality, and sleep disturbance. A century later, this 'peculiar' disease has become widely known as Alzheimer's disease (AD), the world's most common neurodegenerative disease, affecting more than 35 million people globally. At the same time, its pathology remains unclear and no successful treatment exists. Several theories for AD etiology have emerged throughout the past century. In this review, we focus on the metabolic mechanisms that are similar between AD and metabolic diseases, based on the results from genome-wide association studies. We discuss signaling pathways involved in both types of disease and look into new optogenetic methods to study the in vivo mechanisms of AD.

Locus coeruleus stimulation and noradrenergic modulation of hippocampo-prefrontal cortex long-term potentiation.

Stimulation of the subiculum/CA1 of the hippocampal formation evokes monosynaptic field potentials in the prefrontal cortex (PFC). High-frequency stimulation of the hippocampus (HPC) can induce long-term potentiation (LTP) in this hippocampo-prefrontal cortical (hippo-PFC) pathway. Previous studies have shown that dopamine and serotonin modulate hippo-PFC LTP. Here, we investigated whether the locus coeruleus (LC) and noradrenaline (NA) can modulate LTP in the rat hippo-PFC pathway. Stimulation of the LC in combination with stimulation of the HPC increased hippo-PFC LTP. Infusion of lidocaine into the LC reduced hippo-PFC LTP. Administration of the noradrenaline reuptake inhibitor, nisoxetine or the alpha2 adrenoceptor antagonist, idazoxan prior to high-frequency stimulation of the HPC enhanced hippo-LTP. In contrast, administration of clonidine, an alpha2 adrenoceptor agonist, impaired hippo-PFC LTP. Partial noradrenergic (NAergic) lesioning with DSP-4 also impaired hippo-PFC LTP. In conclusion, the LC and NAergic mechanisms modulate hippo-PFC LTP.

Microgel iron oxide nanoparticles for tracking human fetal mesenchymal stem cells through magnetic resonance imaging.

Stem cell transplantation for regenerative medicine has made significant progress in various injury models, with the development of modalities to track stem cell fate and migration post-transplantation being currently pursued rigorously. Magnetic resonance imaging (MRI) allows serial high-resolution in vivo detection of transplanted stem cells labeled with iron oxide particles, but has been hampered by low labeling efficiencies. Here, we describe the use of microgel iron oxide (MGIO) particles of diameters spanning 100-750 nm for labeling human fetal mesenchymal stem cells (hfMSCs) for MRI tracking. We found that MGIO particle uptake by hfMSCs was size dependent, with 600-nm MGIO (M600) particles demonstrating three- to sixfold higher iron loading than the clinical particle ferucarbotran (33-263 versus 9.6-42.0 pg iron/hfMSC; p < .001). Cell labeling with either M600 particles or ferucarbotran did not affect either cellular proliferation or tri-lineage differentiation into osteoblasts, adipocytes, and chondrocytes, despite differences in gene expression on a genome-wide microarray analysis. Cell tracking in a rat photothrombotic stroke model using a clinical 1.5-T MRI scanner demonstrated the migration of labeled hfMSCs from the contralateral cortex to the stroke injury, with M600 particles achieving a five- to sevenfold higher sensitivity for MRI detection than ferucarbotran (p < .05). However, model-related cellular necrosis and acute inflammation limited the survival of hfMSCs beyond 5-12 days. The use of M600 particles allowed high detection sensitivity with low cellular toxicity to be achieved through a simple incubation protocol, and may thus be useful for cellular tracking using standard clinical MRI scanners.

Effect of voluntary running on adult hippocampal neurogenesis in cholinergic lesioned mice.

BACKGROUND: Cholinergic neuronal dysfunction of the basal forebrain is observed in patients with Alzheimer's disease and dementia, and has been linked to decreased neurogenesis in the hippocampus, a region involved in learning and memory. Running is a robust inducer of adult hippocampal neurogenesis. This study aims to address the effect of running on hippocampal neurogenesis in lesioned mice, where septohippocampal cholinergic neurones have been selectively eliminated in the medial septum and diagonal band of Broca of the basal forebrain by infusion of mu-p75-saporin immunotoxin. RESULTS: Running increased the number of newborn cells in the dentate gyrus of the hippocampus in cholinergic denervated mice compared to non-lesioned mice 24 hours after injection of bromodeoxyuridine (BrdU). Although similar levels of surviving cells were present in cholinergic depleted animals and their respective controls four weeks after injection of BrdU, the majority of progenitors that proliferate in response to the initial period of running were not able to survive beyond one month without cholinergic input. Despite this, the running-induced increase in the number of surviving neurones was not affected by cholinergic depletion. CONCLUSION: The lesion paradigm used here models aspects of the cholinergic deficits associated with Alzheimer's Disease and aging. We showed that running still increased the number of newborn cells in the adult hippocampal dentate gyrus in this model of neurodegenerative disease.

Morphological and functional characterization of predifferentiation of myelinating glia-like cells from human bone marrow stromal cells through activation of F3/Notch signaling in mouse retina.

Recently, we have demonstrated that F3/contactin and NB-3 are trans-acting extracellular ligands of Notch that promote differentiation of neural stem cells and oligodendrocyte precursor cells into mature oligodendrocytes (OLs). Here, we demonstrate that human bone marrow stromal cells (hBMSCs) can be induced to differentiate into cells with myelinating glial cell characteristics in mouse retina after predifferentiation in vitro. Isolated CD90(+) hBMSCs treated with beta-mercaptoethanol for 1 day and retinoic acid for 3 days in culture changed into myelinating glia-like cells (MGLCs). More cells expressed NG2, an early OL marker, after treatment, but expression of O4, a mature OL marker, was negligible. Subsequently, the population of O4(+) cells was significantly increased after the MGLCs were predifferentiated in culture in the presence of either F3/contactin or multiple factors, including forskolin, basic fibroblast growth factor, platelet-derived growth factor, and heregulin, in vitro for another 3 days. Notably, 2 months after transplantation into mouse retina, the predifferentiated cells changed morphologically into cells resembling mature MGLCs and expressing O4 and myelin basic protein, two mature myelinating glial cell markers. The cells sent out processes to contact and wrap axons, an event that normally occurs during early stages of myelination, in the retina. The results suggest that CD90(+) hBMSCs are capable of morphological and functional differentiation into MGLCs in vivo through predifferentiation by triggering F3/Notch signaling in vitro.

Role of phospholipase A(2) in prepulse inhibition of the auditory startle reflex in rats.

High levels of calcium-independent phospholipase A(2) (iPLA(2)) are present in the striatum and cerebral cortex [W.Y. Ong, J.F. Yeo, S.F. Ling, A.A. Farooqui, Distribution of calcium-independent phospholipase A(2) (iPLA(2)) in monkey brain, J. Neurocytol. 34 (2005) 447-458], and several clinical investigations have suggested a possible role of altered iPLA(2) activity in neurodegenerative and psychiatric disorders. The present study was carried out to elucidate a possible effect of PLA(2) on prepulse inhibition (PPI) of the acoustic startle reflex. Rats that received intraperitoneal injection of the non-specific PLA(2) inhibitor, quinacrine, showed significantly decreased PPI at 76, 80, and 84dB, compared to saline injected controls. In addition, rats that received intrastriatal injection of antisense oligonucleotide to iPLA(2) showed significant reduction in PPI at prepulse intensities of 76 and 84dB compared to scrambled sense injected controls. Together, these findings point to a role of PLA(2) in PPI of the auditory startle reflex and sensorimotor gating.

Effects of haloperidol on cognitive function and behavioural flexibility in the IntelliCage social home cage environment.

This study examined the effects of chronic administration of haloperidol in female C57BL/6 mice. As patients with schizophrenia often show perseverant behaviours and lack of behavioural flexibility, it is important to know whether the effect of haloperidol makes these traits worse. This study, therefore, was designed to evaluate the effects of haloperidol on the learning performance of mice using an automated home cage environment, the IntelliCage. Behavioural shuttling in the IntelliCage enabled us to assess learning in tasks including place discrimination learning and reversal place learning. In reversal place learning, spatial patterns of rewarded and non-rewarded places that mice had learned to discriminate were reversed, and the adaptability of mice to change the previously acquired place learning was measured. Haloperidol (1 mg/kg/day) reduced locomotor activity and water intake. Haloperidol impaired the cognitive flexibility of mice during reversal place learning rewarded by access to water but enhanced the rapid acquisition of behavioural flexibility when airpuff punishment was applied.

The chakragati mouse shows deficits in prepulse inhibition of acoustic startle and latent inhibition.

The chakragati (ckr) mouse, which was serendipitously created as a result of a transgenic insertional mutation, has been proposed as a model of aspects of schizophrenia. The mice exhibit circling, hyperactivity, reduced social interactions, and enlarged lateral ventricles, which parallel aspects of the pathophysiology of schizophrenia. Deficits in sensorimotor gating and processing of the relevance of stimuli are core features of schizophrenia, which underlie many of the symptoms presented. Measures of prepulse inhibition (PPI) and latent inhibition (LI) can assess sensorimotor gating and processing of relevance in both humans and animal models. We investigated PPI of acoustic startle and LI of aversive conditioning in wild-type, heterozygous, and ckr mice. The ckr mice, which are homozygous for the transgene insertion, but not heterozygous littermates, showed impaired PPI in the absence of any difference in acoustic startle amplitude and showed deficits in LI of conditioning of a light stimulus to footshock, measured as suppression of licking for water in water-restricted mice. Together with the previous evidence for hyperactivity, reduced social interactions, and enlarged lateral ventricles, these data lend further support to the suggestion that the ckr mouse has utility as an animal model of aspects of schizophrenia.