Peripubertal viral-like challenge and social isolation mediate overlapping but distinct effects on behaviour and brain interferon regulatory factor 7 expression in the adult Wistar rat.

A range of adverse, early life environmental influences such as viral infection and social deprivation are thought to increase risk of psychiatric illness later in life. Here, we used peripheral administration of the viral infection mimic polyriboinosinic-polyribocytidylic acid (polyI:C) to compare the consequences of peripubertal infection and isolation rearing. Isolation rearing induced deficits in sensorimotor gating and recognition memory while no changes in social interaction or spatial learning were observed. PolyI:C injection during the peripubertal period markedly increased expression of interferon-stimulated genes (Ifit2, Prkr, Mx2 and Irf7) in the hippocampal dentate gyrus demonstrating that peripheral administration of the viral mimic in the adolescent animal does have direct effects in the brain. Peripubertal infection mimicry induced a similar but later emerging behavioural deficit in prepulse inhibition implying the existence of a peripubertal window of opportunity for viral-mediated cytokine increases to impact brain development and function. PolyI:C treatment also impaired novel object recognition but did not alter spatial reference memory or social interaction. Combining the polyI:C challenge with social isolation did not exacerbate the behavioural deficits seen with isolation rearing alone. Using Irf7 as a marker, peripubertal viral infection mimicry, isolation rearing and a combination of both were all seen to produce a long-lasting molecular imprint on the interferon-associated signalling pathway in the principal neuron population of the hippocampal dentate gyrus. The data suggest that the sensitivity of brain structure and function to disruption by viral infection extends into the peripubertal period. Moreover, augmented interferon signalling in hippocampus may represent a common molecular imprint of environmental insults associated with neuropsychiatric illnesses like schizophrenia.

Temporal proteomic profile of memory consolidation in the rat hippocampal dentate gyrus.

Information storage in the brain depends on the ability of neurons to alter synaptic connectivity within key circuitries such as the hippocampus. Memory-associated synaptic plasticity is mediated by a temporal cascade of de novo protein synthesis and altered protein processing. Here, we have used two-dimensional difference in gel electrophoresis (2-D DIGE) to investigate memory-specific protein changes in the hippocampal dentate gyrus at increasing times following spatial learning. We identified 42 proteins that were significantly regulated in the first 24 h of spatial memory consolidation. Two distinct waves of protein expression regulation were evident, at 3 and 12 h post-learning and this is in agreement with studies employing inhibitors of global translation. Functional classification of the memory-associated proteins revealed that the majority of regulated proteins contributed either to cellular structure or cellular metabolism. For example, actins, tubulins and intermediate filament proteins, core proteins of the three major cytoskeletal components, were dynamically regulated at times that suggest a role in memory-associated synaptic reorganization. Increased proteasome-mediated protein degradation was evident in the early post-training period including the down-regulation of phosphoprotein enriched in astrocytes 15 kDa, a key inhibitor of extracellular signal-regulated kinase signaling. Some of the most substantial protein expression changes were observed for secreted carrier proteins including transthyretin and serum albumin at 6-12 h post-learning, regulations that could serve an important role in increasing the supply of retinoic acid and thyroid hormone, key synaptic plasticity-promoting signals in the adult brain. Together these observations provide further insight into protein level regulations occurring in the hippocampus during spatial memory consolidation.

AAV-mediated chronic over-expression of SNAP-25 in adult rat dorsal hippocampus impairs memory-associated synaptic plasticity.

Long-term memory is formed by alterations in glutamate-dependent excitatory synaptic transmission, which is in turn regulated by synaptosomal protein of 25 kDa (SNAP-25), a key component of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor complex essential for exocytosis of neurotransmitter-filled synaptic vesicles. Both reduced and excessive SNAP-25 activity has been implicated in various disease states that involve cognitive dysfunctions such as attention deficit hyperactivity disorder, schizophrenia and Alzheimer's disease. Here, we over-express SNAP-25 in the adult rat dorsal hippocampus by infusion of a recombinant adeno-associated virus vector, to evaluate the consequence of late adolescent-adult dysfunction of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor protein in the absence of developmental disruption. We report a specific and significant increase in the levels of extracellular glutamate detectable by microdialysis and a reduction in paired-pulse facilitation in the hippocampus. In addition, SNAP-25 over-expression produced cognitive deficits, delaying acquisition of a spatial map in the water maze and impairing contextual fear conditioning, both tasks known to be dorsal hippocampal dependent. The high background transmission state and pre-synaptic dysfunction likely result in interference with requisite synapse selection during spatial and fear memory consolidation. Together these studies provide the first evidence that excess SNAP-25 activity, restricted to the adult period, is sufficient to mediate significant deficits in the memory formation process.

Temporal dysregulation of cortical gene expression in the isolation reared Wistar rat.

The critical sequence of molecular, neurotransmission and synaptic disruptions that underpin the emergence of psychiatric disorders like schizophrenia remain to be established with progress only likely using animal models that capture key features of such disorders. We have related the emergence of behavioural, neurochemical and synapse ultrastructure deficits to transcriptional dysregulation in the medial prefrontal cortex of Wistar rats reared in isolation. Isolation reared animals developed sensorimotor deficits at postnatal day 60 which persisted into adulthood. Analysis of gene expression prior to the emergence of the sensorimotor deficits revealed a significant disruption in transcriptional control, notably of immediate early and interferon-associated genes. At postnatal day 60 many gene transcripts relating particularly to GABA transmission and synapse structure, for example Gabra4, Nsf, Syn2 and Dlgh1, transiently increased expression. A subsequent decrease in genes such as Gria2 and Dlgh2 at postnatal day 80 suggested deficits in glutamatergic transmission and synapse integrity, respectively. Microdialysis studies revealed decreased extracellular glutamate suggesting a state of hypofrontality while ultrastructural analysis showed total and perforated synapse complement in layer III to be significantly reduced in the prefrontal cortex of postnatal day 80 isolated animals. These studies provide a molecular framework to understand the developmental emergence of the structural and behavioural characteristics that may in part define psychiatric illness.

Learning-associated regulation of polysialylated neural cell adhesion molecule expression in the rat prefrontal cortex is region-, cell type- and paradigm-specific.

The prefrontal cortex (PFC) is an interconnected set of cortical areas that function in the synthesis of a diverse range of information and production of complex behaviour. It is now clear that these frontal structures, through bidirectional excitatory communication with the hippocampal formation, also play a substantial role in long-term memory consolidation. In the hippocampus, morphological synaptic plasticity, supported by regulation of neural cell adhesion molecule (NCAM) polysialylation status, is crucial to information storage. The recent description of polysialylated neurons in the various fields of the medial PFC suggests these structures to possess a similar capacity for synaptic plasticity. Here, using double-labelling immunohistochemistry with glutamic acid decarboxylase 67, we report that the nature of NCAM polysialic acid-positive neurons in the PFC is region-specific, with a high proportion (30-50%) of a gamma-aminobutyric acid (GABA)ergic phenotype in the more ventral infralimbic, orbitofrontal and insular cortices compared with just 10% in the dorsal structures of the cingulate, prelimbic and frontal cortices. Moreover, spatial learning was accompanied by activations in polysialylation expression in ventral PFC structures, while avoidance conditioning involved downregulation of this plasticity marker that was restricted to the dorsomedial PFC--the cingulate and prelimbic cortices. Thus, in contrast to other structures integrated functionally with the hippocampus, memory-associated plasticity mobilized in the PFC is region-, cell type- and task-specific.

The selective 5-HT6 receptor antagonists SB-271046 and SB-399885 potentiate NCAM PSA immunolabeling of dentate granule cells, but not neurogenesis, in the hippocampal formation of mature Wistar rats.

While there is now substantial evidence that 5-HT(6) antagonism leads to significantly improved cognitive ability, the mechanism(s) and/or pathway(s) involved are poorly understood. We have evaluated the consequence of chronic administration of the 5-HT(6) receptor antagonists SB-271046 and SB-399885 on neural cell adhesion molecule polysialylation state (NCAM PSA), a neuroplastic mechanism necessary for memory consolidation. Quantitative analysis of NCAM PSA immunopositive neurons in the dentate gyrus of drug-treated animals revealed a dose-dependent increase in polysialylated cell frequency following treatment with both SB-271046 and SB-399885. These effects could not be attributed to increased neurogenesis, as no difference in the rate of bromodeoxyuridine incorporation was apparent between the control and drug-treated groups. A substantial increase in the frequency of polysialylated cells in layer II of the entorhinal and perirhinal cortices was also observed, brain regions not previously associated with neurogenesis. Chronic treatment with SB-271046 or SB-399885 also significantly increased the activation of dentate polysialylation that is specific to learning. This effect does not occur with other cognition-enhancing drugs, such as tacrine, and this action potentially differentiates 5-HT(6) receptor antagonism as an unique neuroplastic mechanism for cognitive processes which may slow or reverse age/neurodegenerative related memory deficits.

Structurally novel histamine H3 receptor antagonists GSK207040 and GSK334429 improve scopolamine-induced memory impairment and capsaicin-induced secondary allodynia in rats.

GSK207040 (5-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-2-pyrazinecarboxamide) and GSK334429 (1-(1-methylethyl)-4-({1-[6-(trifluoromethyl)-3-pyridinyl]-4-piperidinyl}carbonyl)hexahydro-1H-1,4-diazepine) are novel and selective non-imidazole histamine H(3) receptor antagonists from distinct chemical series with high affinity for human (pK(i)=9.67+/-0.06 and 9.49+/-0.09, respectively) and rat (pK(i)=9.08+/-0.16 and 9.12+/-0.14, respectively) H(3) receptors expressed in cerebral cortex. At the human recombinant H(3) receptor, GSK207040 and GSK334429 were potent functional antagonists (pA(2)=9.26+/-0.04 and 8.84+/-0.04, respectively versus H(3) agonist-induced changes in cAMP) and exhibited inverse agonist properties (pIC(50)=9.20+/-0.36 and 8.59+/-0.04 versus basal GTPgammaS binding). Following oral administration, GSK207040 and GSK334429 potently inhibited cortical ex vivo [(3)H]-R-alpha-methylhistamine binding (ED(50)=0.03 and 0.35 mg/kg, respectively). Functional antagonism of central H(3) receptors was demonstrated by blockade of R-alpha-methylhistamine-induced dipsogenia in rats (ID(50)=0.02 and 0.11 mg/kg p.o. for GSK207040 and GSK334429, respectively). In more pathophysiologically relevant pharmacodynamic models, GSK207040 (0.1, 0.3, 1 and 3mg/kg p.o.) and GSK334429 (0.3, 1 and 3mg/kg p.o.) significantly reversed amnesia induced by the cholinergic antagonist scopolamine in a passive avoidance paradigm. In addition, GSK207040 (0.1, 0.3 and 1mg/kg p.o.) and GSK334429 (3 and 10mg/kg p.o.) significantly reversed capsaicin-induced reductions in paw withdrawal threshold, suggesting for the first time that blockade of H(3) receptors may be able to reduce tactile allodynia. Novel H(3) receptor antagonists such as GSK207040 and GSK334429 may therefore have therapeutic potential not only in dementia but also in neuropathic pain.

Chronic exposure of rats to cognition enhancing drugs produces a neuroplastic response identical to that obtained by complex environment rearing.

Recent data suggest that Alzheimer's patients who discontinue treatment with cholinesterase inhibitors have a significantly delayed cognitive decline as compared to patients receiving placebo. Such observations suggest cholinesterase inhibitors to provide a disease-modifying effect as well as symptomatic relief and, moreover, that this benefit remains after drug withdrawal. Consistent with this suggestion, we now demonstrate that chronic administration of tacrine, nefiracetam, and deprenyl, drugs that augment cholinergic function, increases the basal frequency of dentate polysialylated neurons in a manner similar to the enhanced neuroplasticity achieved through complex environment rearing. While both drug-treated and complex environment reared animals continue to exhibit memory-associated activation of hippocampal polysialylated neurons, the magnitude is significantly reduced suggesting that such interventions induce a more robust memory pathway that can acquire and consolidate new information more efficiently. This hypothesis is supported by our findings of improved learning behavior and enhanced resistance to cholinergic deficits seen following either intervention. Furthermore, the level of enhancement of basal neuroplastic status achieved by either drug or environmental intervention correlates directly with improved spatial learning ability. As a combination of both interventions failed to further increase basal polysialylated cell frequency, complex environment rearing and chronic drug regimens most likely enhanced cognitive performance by the same mechanism(s). These findings suggest that improved memory-associated synaptic plasticity may be the fundamental mechanism underlying the disease modifying action of drugs such as cholinesterase inhibitors. Moreover, the molecular and cellular events underpinning neuroplastic responses are identified as novel targets in the search for interventive drug strategies for the treatment of neurodegenerative and neuropsychiatric disorders.

SB-399885 is a potent, selective 5-HT6 receptor antagonist with cognitive enhancing properties in aged rat water maze and novel object recognition models.

SB-399885 (N-[3,5-dichloro-2-(methoxy)phenyl]-4-(methoxy)-3-(1-piperazinyl)benzenesulfonamide) has high affinity for human recombinant and native 5-HT(6) receptors, with pK(i) values 9.11+/-0.03 and 9.02+/-0.05, respectively and is a potent competitive antagonist (pA(2) 7.85+/-0.04). It displays over 200-fold selectivity for the 5-HT(6) receptor over all other receptors, ion channels and enzymes tested to date. SB-399885 inhibited ex vivo [(125)I]SB-258585 (4-Iodo-N-[4-methoxy-3-(4-methyl-piperazin-1-yl)-phenyl]-benzenesulfonamide) binding with an ED(50) of 2.0+/-0.24 mg/kg p.o. in rats. It had a minimum effective dose of 1 mg/kg p.o. in a rat maximal electroshock seizure threshold test and a long duration of action, overall demonstrating an excellent pharmacokinetic-pharmacodynamic correlation. Repeated administration of this agent (10 mg/kg p.o., b.i.d. for 7 days) significantly reversed a scopolamine-induced deficit (0.5 mg/kg i.p.) in a rat novel object recognition paradigm. Moreover, in aged rats (22 months old) SB-399885 (10 mg/kg p.o., b.i.d. for 7 days) fully reversed the age-dependent deficit in water maze spatial learning compared to vehicle-treated age-matched controls and significantly improved recall of the task measured by increases in the searching of the target quadrant on post-training days 1, 3 and 7. In vivo microdialysis in the rat medial prefrontal cortex demonstrated that acute SB-399885 (10 mg/kg p.o.) significantly increased extracellular acetylcholine levels. These data demonstrate that SB-399885 is a potent, selective, brain penetrant, orally active 5-HT(6) receptor antagonist with cognitive enhancing properties that are likely to be mediated by enhancements of cholinergic function. These studies provide further support for the potential therapeutic utility of 5-HT(6) receptor antagonists in disorders characterised by cognitive deficits such as Alzheimer's disease and schizophrenia.

Modulation of hippocampal NCAM polysialylation and spatial memory consolidation by fear conditioning.

BACKGROUND: Cell adhesion molecule function is involved in hippocampal synaptic plasticity and associated with memory consolidation. At the infragranular zone of the dentate gyrus, neurons expressing the polysialylated form of the neural cell adhesion molecule (NCAM PSA) transiently increase their frequency 12 hours after training in different tasks. METHODS: Using immunohistochemical procedures, we investigated NCAM polysialylation following training in a contextual fear conditioning paradigm that employed increasing shock intensities to separately model stressful and traumatic experiences in adult male Wistar rats. RESULTS: Fear conditioning with a stressful.4-mA stimulus resulted in an increased frequency of dentate polysialylated neurons, the magnitude of which was indistinguishable from that observed following water maze training. By contrast, training with a traumatic 1-mA stimulus resulted in a significant decrease in the frequency of polysialylated neurons at the 12 hours posttraining time. Whereas sequential training in the water maze paradigm followed by fear conditioning resulted in potentiated consolidation of spatial information when conditioning involved a.4-mA stimulus, amnesia for spatial learning occurred when conditioning was performed with a 1-mA stimulus. CONCLUSIONS: These results suggest traumatic fear conditioning suppresses NCAM-PSA-mediated plasticity and the concomitant inability to store the trace of recently acquired information.

Pentyl-4-yn-valproic acid reverses age-associated memory impairment in the Wistar rat.

Pentyl-4-yn-valproic acid (VPA), a cognition-enhancing agent whose mode of action has been attributed to cell adhesion molecule-mediated neuritogenesis, has been shown to enhance hippocampus-dependent spatial learning. Here, we investigated its potential to reverse age-related memory impairment that relates mainly to declarative memory. Aged spatial learning deficits in the water maze paradigm were demonstrated by swim angle analysis, the angle between axes of start-to-platform and start-to-animal position, and latency to reach a submerged platform. Chronic pentyl-4-yn-VPA administration mediated a significant improvement in both search strategy and latency to find the submerged platform in aged animals. Pentyl-4-yn-VPA also facilitated task recall in aged animals as evidenced by increased time in the target quadrant during a probe trial 3 days following the final training session. The action of pentyl-4-yn-VPA on platform latency, search strategy and task recall suggests that this agent may have great benefit in the treatment of age-dependent cognitive decline.

The 5-HT(6) receptor antagonist SB-271046 reverses scopolamine-disrupted consolidation of a passive avoidance task and ameliorates spatial task deficits in aged rats.

The highly potent and selective 5-HT(6) receptor antagonist SB-271046 [5-chloro-N-(4-methoxy-3-piperazin-1-yl-phenyl)-3-methyl-2-benzothiophenesulfonamide] has previously been demonstrated to improve retention significantly in a spatial water maze paradigm in adult rats. However, SB-271046 did not have any effect on task acquisition. As these apparently contradictory findings may be reconciled by a prime influence of SB-271046 on memory consolidation, the ability of this compound to reverse the discrete temporal action of a cholinergic antagonist in the 6-h period following passive avoidance training was investigated. SB-271046, given orally, by gavage, 30 min prior to training Wistar rats in a step-through, light-dark passive avoidance task, was found to reverse significantly the amnesia produced by administering scopolamine (0.8 mg/kg, intraperitoneal) in the 6-h post-training period. The effect was dose-dependent over a range of 3-20 mg/kg. Further, we investigated the cognition-enhancing effects of chronic SB-271046 administration (10 or 20 mg/kg/day; 40 days) on the acquisition and consolidation of a water maze spatial learning task in a population of 20-month-old Wistar rats with age-related learning deficits. Drug treatment progressively and significantly decreased platform swim angle and escape latencies over the five sequential trials on four consecutive daily sessions compared to vehicle-treated controls. SB-271046 also improved task recall as measured by significant increases in the searching of the target quadrant on post-training days 1 and 3, when the animals would have been substantially drug-free. This significant improvement of task recall suggests SB-271046, in addition to inducing symptomatic cognition-enhancing actions, also attenuates age-related decline in neural function.

Valproate activates phosphodiesterase-mediated cAMP degradation: relevance to C6 glioma G1 phase progression.

Forskolin, a diterpene activator of adenylate cyclase, stimulates the production of cyclic adenosine monophosphate (cAMP) in a wide variety of cell types. In C6 glioma, used in this study, the anticonvulsant agent valproic acid (VPA) inhibited forskolin-stimulated cAMP accumulation in intact cells in a concentration-dependent manner. Kinetic studies indicated this valproate effect not to be mediated by direct inhibition of adenylate cyclase activity. The valproate-induced inhibition of cAMP accumulation was partially reversed by the phosphodiesterase (PDE) inhibitor isobutylmethyl xanthine (IBMX). Degradation of cAMP over time was more rapid in valproate-treated cells than in controls, and this effect was also reversed by IBMX. In synchronised C6 glioma, phosphodiesterase type IV (PDE4A1) expression was selectively upregulated during the G1 phase, in tandem with temporal biphasic peaks of cAMP. However, the expression of PDE4 isoforms was not affected by a 48-h exposure to valproate. These findings suggest inhibition of forskolin-stimulated cAMP levels in C6 glioma by valproate to be mediated by increased activation of PDE in the G1 phase. Since the degree of cell cycle arrest induced by valproate is intimately associated with its teratogenic potency, it appears that PDE-mediated inhibition of cAMP may contribute to the molecular mechanisms of valproate-induced teratogenicity.

Pentyl-4-yn-VPA, a histone deacetylase inhibitor, ameliorates deficits in social behavior and cognition in a rodent model of autism spectrum disorders.

In utero exposure of rodents to valproic acid (VPA) has been proposed to induce an adult phenotype with behavioural characteristics reminiscent of those observed in autism spectrum disorder (ASD). Our previous studies have demonstrated the social cognition deficits observed in this model, a major core symptom of ASD, to be ameliorated following chronic administration of histone deacetylase (HDAC) inhibitors. Using this model, we now demonstrate pentyl-4-yn-VPA, an analogue of valproate and HDAC inhibitor, to significantly ameliorate deficits in social cognition as measured using the social approach avoidance paradigm as an indicator of social reciprocity and spatial learning to interrogate dorsal stream cognitive processing. The effects obtained with pentyl-4-yn-VPA were found to be similar to those obtained with SAHA, a pan-specific HDAC inhibitor. Histones isolated from the cerebellar cortex and immunoblotted with antibodies recognising lysine-specific modification revealed SAHA and pentyl-4-yn-VPA to enhance the acetylation status of H4K8. Additionally, the action of pentyl-4-yn-VPA, could be differentiated from that of SAHA by its ability to decrease H3K9 acetylation and enhance H3K14 acetylation. The histone modifications mediated by pentyl-4-yn-VPA are suggested to act cooperatively through differential acetylation of the promoter and transcription regions of active genes.

Captodiamine, a putative antidepressant, enhances hypothalamic BDNF expression in vivo by synergistic 5-HT2c receptor antagonism and sigma-1 receptor agonism.

The putative antidepressant captodiamine is a 5-HT2c receptor antagonist and agonist at sigma-1 and D3 dopamine receptors, exerts an anti-immobility action in the forced swim paradigm, and enhances dopamine turnover in the frontal cortex. Captodiamine has also been found to ameliorate stress-induced anhedonia, reduce the associated elevations of hypothalamic corticotrophin-releasing factor (CRF) and restore the reductions in hypothalamic BDNF expression. Here we demonstrate chronic administration of captodiamine to have no significant effect on hypothalamic CRF expression through sigma-1 receptor agonism; however, both sigma-1 receptor agonism or 5-HT2c receptor antagonism were necessary to enhance BDNF expression. Regulation of BDNF expression by captodiamine was associated with increased phosphorylation of transcription factor CREB and mediated through sigma-1 receptor agonism but blocked by 5-HT2c receptor antagonism. The existence of two separate signalling pathways was confirmed by immunolocalisation of each receptor to distinct cell populations in the paraventricular nucleus of the hypothalamus. Increased BDNF induced by captodiamine was also associated with enhanced expression of synapsin, but not PSD-95, suggesting induction of long-term structural plasticity between hypothalamic synapses. These unique features of captodiamine may contribute to its ability to ameliorate stress-induced anhedonia as the hypothalamus plays a prominent role in regulating HPA axis activity.

Alzheimer brain-derived amyloid ß-protein impairs synaptic remodeling and memory consolidation.

Aggregation of the amyloid ß-protein (Aß) is believed to play a central role in initiating the molecular cascade that culminates in Alzheimer-type dementia (AD), a disease which in its early stage is characterized by synaptic loss and impairment of episodic memory. Here we show that intracerebroventricular injection of Aß-containing water-soluble extracts of AD brain inhibits consolidation of the memory of avoidance learning in the rat and that this effect is highly dependent on the interval between learning and administration. When injected at 1 hour post training extracts from 2 different AD brains significantly impaired recall tested at 48 hours. Ultrastructural examination of hippocampi from animals perfused after 48 hours revealed that Aß-mediated impairment of avoidance memory was associated with lower density of synapses and altered synaptic structure in the dentate gyrus and CA1 fields. These behavioral and ultrastructural data suggest that human brain-derived Aß impairs formation of long-term memory by compromising the structural plasticity essential for consolidation and that Aß targets processes initiated very early in the consolidation pathway.

Class I histone deacetylase inhibition ameliorates social cognition and cell adhesion molecule plasticity deficits in a rodent model of autism spectrum disorder.

In utero exposure of rodents to valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, has been proposed to induce an adult phenotype with behavioural characteristics reminiscent of those observed in autism spectrum disorder (ASD). We have evaluated the face validity of this model in terms of social cognition deficits which are a major core symptom of ASD. We employed the social approach avoidance paradigm as a measure of social reciprocity, detection of biological motion that is crucial to social interactions, and spatial learning as an indicator of dorsal stream processing of social cognition and found each parameter to be significantly impaired in Wistar rats with prior in utero exposure to VPA. We found no significant change in the expression of neural cell adhesion molecule polysialylation state (NCAM PSA), a measure of construct validity, but a complete inability to increase its glycosylation state which is necessary to mount the neuroplastic response associated with effective spatial learning. Finally, in all cases, we found chronic HDAC inhibition, with either pan-specific or HDAC1-3 isoform-specific inhibitors, to significantly ameliorate deficits in both social cognition and its associated neuroplastic response. We conclude that in utero exposure to VPA provides a robust animal model for the social cognitive deficits of ASD and a potential screen for the development of novel therapeutics for this condition.

Aß oligomers inhibit synapse remodelling necessary for memory consolidation.

Extensive research has implicated the amyloid-ß protein (Aß) in the aetiology of Alzheimer's disease (AD). This protein has been shown to produce memory deficits when injected into rodent brain and in mouse models of AD Aß production is associated with impaired learning and/or recall. Here we examined the effects of cell-derived SDS-stable 7PA2-derived soluble Aß oligomers on consolidation of avoidance learning. At 0, 3, 6, 9 or 12h after training, animals received an intracerebroventricular injection of Aß-containing or control media and recall was tested at 24 and 48 h. Immediately after 48 h recall animals were transcardially perfused and the brain removed for sectioning and EM analysis. Rats receiving injections of Aß at 6 or 9h post-training showed a significant impairment in memory consolidation at 48 h. Importantly, impaired animals injected at 9h had significantly fewer synapses in the dentate gyrus. These data suggest that Aß low-n oligomers target specific temporal facets of consolidation-associated synaptic remodelling whereby loss of functional synapses results in impaired consolidation.

Reduced reelin protein synthesis in ventral hippocampus of isolation reared Wistar rats accompanies impaired avoidance conditioning.

Given that suppressed reelin protein synthesis is associated with cognitive dysfunction in both rodents and humans, we examined the ontogeny of these deficits in rats reared in isolation as a basis for understanding developmental emergence of neuropsychiatric illness. Isolation rearing exerted minimal effects on spatial learning other than to inhibit the transient learning improvement observed in social reared rats at postnatal day 60. By contrast, at postnatal day 80, animals reared in isolation were significantly impaired in an avoidance conditioning paradigm, a deficit that correlated with suppressed reelin synthesis restricted to the ventral aspect of the dentate gyrus. These findings suggest that environmental factors alone can impair forms of cognitive development with relevant region-specific dysfunctional plasticity.

H3 receptor antagonism enhances NCAM PSA-mediated plasticity and improves memory consolidation in odor discrimination and delayed match-to-position paradigms.

To further understand the procognitive actions of GSK189254, a histamine H(3) receptor antagonist, we determined its influence on the modulation of hippocampal neural cell adhesion molecule (NCAM) polysialylation (PSA) state, a necessary neuroplastic mechanism for learning and memory consolidation. A 4-day treatment with GSK189254 significantly increased basal expression of dentate polysialylated cells in rats with the maximal effect being observed at 0.03-0.3 mg/kg. At the optimal dose (0.3 mg/kg), GSK189254 enhanced water maze learning and the associated transient increase in NCAM-polysialylated cells. The increase in dentate polysialylated cell frequency induced by GSK189254 was not attributable to enhanced neurogenesis, although it did induce a small, but significant, increase in the survival of these newborn cells. GSK189254 (0.3 mg/kg) was without effect on polysialylated cell frequency in the entorhinal and perirhinal cortex, but significantly increased the diffuse PSA staining observed in the anterior, ventromedial, and dorsomedial aspects of the hypothalamus. Consistent with its ability to enhance the learning-associated, post-training increases in NCAM PSA state, GSK189254 (0.3 mg/kg) reversed the amnesia induced by scopolamine given in the 6-h post-training period after training in an odor discrimination paradigm. Moreover, GSK189254 significantly improved the performance accuracy of a delayed match-to-position paradigm, a task dependent on the prefrontal cortex and degree of cortical arousal, the latter may be related to enhanced NCAM PSA-associated plasticity in the hypothalamus. The procognitive actions of H3 antagonism combined with increased NCAM PSA expression may exert a disease-modifying action in conditions harboring fundamental deficits in NCAM-mediated neuroplasticity, such as schizophrenia and Alzheimer's disease.