High frequency stimulation of the subthalamic nucleus impacts adult neurogenesis in a rat model of Parkinson's disease

APP.V717I and Tau.P301L transgenic mice develop Alzheimer's disease pathology comprising important aspects of human disease including increased levels of amyloid peptides, cognitive and motor impairment, amyloid plaques and neurofibrillary tangles. The combined model, APP.V717I × Tau.P301L bigenic mice (biAT mice) exhibit aggravated amyloid and tau pathology with severe cognitive and behavioral defects. In the present study, we investigated early changes in synaptic function in the CA1 and CA3 regions of acute hippocampal slices of young APP.V717I, Tau.P301L and biAT transgenic animals. We have used planar multi-electrode arrays (MEA) and improved methods for simultaneous multi-site recordings from two hippocampal sub-regions. In the CA1 region, long-term potentiation (LTP) was severely impaired in all transgenic animals when compared with age-matched wild-type controls, while basal synaptic transmission and paired-pulse facilitation were minimally affected. In the CA3 region, LTP was normal in Tau.P301L and APP.V717I but clearly impaired in biAT mice. Surprisingly, frequency facilitation in CA3 was significantly enhanced in Tau.P301L mice, while not affected in APP.V717I mice and depressed in biAT mice. The findings demonstrate important synaptic changes that differ considerably in the hippocampal sub-regions already at young age, well before the typical amyloid or tau pathology is evident.     

Deficit in hippocampal long-term potentiation in monosodium glutamate-treated rats

Rats subjected to monosodium glutamate (MSG) administration during the neonatal period present chronic neuroendocrine dysfunction associated with marked cognitive deficits. Long-term potentiation (LTP) in the hippocampus provides a model suited for the study of mammalian brain plasticity and memory formation. In the present work, we used the LTP protocol to investigate the synaptic plasticity in the hippocampal CA1 area of adult rats subjected to MSG treatment during the first 10 days of life. Synaptic transmission in CA1 area was analyzed using extracellular field recordings in response to Schaffer's collateral fiber stimulation in hippocampal slices. Animals injected with MSG exhibited a dramatic decrement of LTP field excitatory postsynaptic potentials (fEPSPs) compared to control group. Analysis of percent enhancement of fEPSP slope at 2 min after high frequency stimulation (HFS) increased by 189.3 +/- 33.2% in slices from control rats and 129.45 +/- 18.5% (p < 0.01) in slices from MSG-treated rats. Additionally, MSG-treated animals failed to maintain or consolidate LTP as revealed by a significant reduction in fEPSP slope enhancement over time after HFS. The mean fEPSP slope, 60 min after HFS, was 154.28 +/- 21% of the average baseline slope in control slices versus only 124.4 +/- 15% in MSG-treated rats (p < 0.01). At 90 min after HFS, slices from controls reached a potentiation of 44.5 +/- 2.9%, whereas the MSG group displayed an overall response enhancement of 17.65 +/- 2.7% of basal levels (p < 0.01). These findings indicate that MSG-treated rats display a chronic impairment of CA1 synaptic plasticity.     

Possible relationship between the stress‐induced synaptic response and metaplasticity in the hippocampal CA1 field of freely moving rats

Hippocampal long‐term potentiation (LTP) is suppressed not only by stress paradigms but also by low frequency stimulation (LFS) prior to LTP‐inducing high frequency stimulation (HFS; tetanus), termed metaplasticity. These synaptic responses are dependent on N‐methyl‐D ‐aspartate receptors, leading to speculations about the possible relationship between metaplasticity and stress‐induced LTP impairment. However, the functional significance of metaplasticity has been unclear. The present study elucidated the electrophysiological and neurochemical profiles of metaplasticity in the hippocampal CA1 field, with a focus on the synaptic response induced by the emotional stress, contextual fear conditioning (CFC). The population spike amplitude in the CA1 field was decreased during exposure to CFC, and LTP induction was suppressed after CFC in conscious rats. The synaptic response induced by CFC was mimicked by LFS, i.e., LFS impaired the synaptic transmission and subsequent LTP. Plasma corticosterone levels were increased by both CFC and LFS. Extracellular levels of γ‐aminobutyric acid (GABA), but not glutamate, in the hippocampus increased during exposure to CFC or LFS. Furthermore, electrical stimulation of the medial prefrontal cortex (mPFC), which caused decreases in freezing behavior during exposure to CFC, counteracted the LTP impairment induced by LFS. These findings suggest that metaplasticity in the rat hippocampal CA1 field is related to the neural basis of stress experience‐dependent fear memory, and that hippocampal synaptic response associated stress‐related processes is under mPFC regulation. Synapse 63:549‐556, 2009. © 2009 Wiley‐Liss, Inc.     

Deficits in cognitive function and hippocampal plasticity in GM2/GD2 synthase knockout mice

In this study, we used GM2/GD2 synthase knockout (GM2/GD2^?/?) mice to examine the influence of deficiency in ganglioside “a‐pathway” and “b‐pathway” on cognitive performances and hippocampal synaptic plasticity. Eight‐week‐old GM2/GD2^?/? male mice showed a longer escape‐latency in Morris water maze test and a shorter latency in step‐down inhibitory avoidance task than wild‐type (WT) mice. Schaffer collateral‐CA1 synapses in the hippocampal slices from GM2/GD2^?/? mice showed an increase in the slope of EPSPs with reduced paired‐pulse facilitation, indicating an enhancement of their presynaptic glutamate release. In GM2/GD2^?/? mice, NMDA receptor (NMDAr)‐dependent LTP could not be induced by high‐frequency (100–200 Hz) tetanus or θ‐burst conditioning stimulation (CS), whereas NMDAr‐independent LTP was induced by medium‐frequency CS (20–50 Hz). The application of mono‐sialoganglioside GM1 in the slice from GM2/GD2^?/? mice, to specifically recover the a‐pathway, prevented the increased presynaptic glutamate release and 20 Hz‐LTP induction, whereas it could not rescue the impaired NMDAr‐dependent LTP. These findings suggest that b‐pathway deficiency impairs cognitive function probably through suppression of NMDAr‐dependent LTP, while a‐pathway deficiency may facilitate NMDAr‐independent LTP through enhancing presynaptic glutamate release. As both of the NMDAr‐independent LTP and increased presynaptic glutamate release were sensitive to the blockade of L‐type voltage‐gated Ca²⁺ channels (L‐VGCC), a‐pathway deficiency may affect presynaptic L‐VGCC. © 2013 Wiley Periodicals, Inc.     

Differential contributions of microglial and neuronal IKKβ to synaptic plasticity and associative learning in alert behaving mice

Microglia are CNS resident immune cells and a rich source of neuroactive mediators, but their contribution to physiological brain processes such as synaptic plasticity, learning, and memory is not fully understood. In this study, we used mice with partial depletion of IκB kinase β, the main activating kinase in the inducible NF‐κB pathway, selectively in myeloid lineage cells (mIKKβKO) or excitatory neurons (nIKKβKO) to measure synaptic strength at hippocampal Schaffer collaterals during long‐term potentiation (LTP) and instrumental conditioning in alert behaving individuals. Resting microglial cells in mIKKβKO mice showed less Iba1‐immunoreactivity, and brain IL‐1β mRNA levels were selectively reduced compared with controls. Measurement of field excitatory postsynaptic potentials (fEPSPs) evoked by stimulation of the CA3‐CA1 synapse in mIKKβKO mice showed higher facilitation in response to paired pulses and enhanced LTP following high frequency stimulation. In contrast, nIKKβKO mice showed normal basic synaptic transmission and LTP induction but impairments in late LTP. To understand the consequences of such impairments in synaptic plasticity for learning and memory, we measured CA1 fEPSPs in behaving mice during instrumental conditioning. IKKβ was not necessary in either microglia or neurons for mice to learn lever‐pressing (appetitive behavior) to obtain food (consummatory behavior) but was required in both for modification of their hippocampus‐dependent appetitive, not consummatory behavior. Our results show that microglia, through IKKβ and therefore NF‐κB activity, regulate hippocampal synaptic plasticity and that both microglia and neurons, through IKKβ, are necessary for animals to modify hippocampus‐driven behavior during associative learning. GLIA 2015;63:549–566     

Short‐term exposure to enriched environment rescues chronic stress‐induced impaired hippocampal synaptic plasticity,anxiety, and memory deficits

Exposure to prolonged stress results in structural and functional alterations in the hippocampus including reduced long‐term potentiation (LTP), neurogenesis, spatial learning and working memory impairments, and enhanced anxiety‐like behavior. On the other hand, enriched environment (EE) has beneficial effects on hippocampal structure and function, such as improved memory, increased hippocampal neurogenesis, and progressive synaptic plasticity. It is unclear whether exposure to short‐term EE for 10 days can overcome restraint stress–induced cognitive deficits and impaired hippocampal plasticity. Consequently, the present study explored the beneficial effects of short‐term EE on chronic stress–induced impaired LTP, working memory, and anxiety‐like behavior. Male Wistar rats were subjected to chronic restraint stress (6 hr/day) over a period of 21 days, and then they were exposed to EE (6 hr/day) for 10 days. Restraint stress reduced hippocampal CA1‐LTP, increased anxiety‐like symptoms in elevated plus maze, and impaired working memory in T‐maze task. Remarkably, EE facilitated hippocampal LTP, improved working memory performance, and completely overcame the effect of chronic stress on anxiety behavior. In conclusion, exposure to EE can bring out positive effects on synaptic plasticity in the hippocampus and thereby elicit its beneficial effects on cognitive functions. © 2016 Wiley Periodicals, Inc.     

Melatonin protects against amyloid‐β‐induced impairments of hippocampal LTP and spatial learning in rats

Alzheimer's disease (AD), the most prevalent neurodegenerative disease in the elderly, leads to progressive loss of memory and cognitive deficits. Amyloid‐β protein (Aβ) in the brain is thought to be the main cause of memory loss in AD. Melatonin, an indole hormone secreted by the pineal gland, has been reported to produce neuroprotective effects. We examined whether melatonin could protect Aβ‐induced impairments of hippocampal synaptic plasticity, neuronal cooperative activity, and learning and memory. Rats received bilateral intrahippocampal injection of Aβ1‐42 or Aβ31‐35 followed by intraperitoneal application of melatonin for 10 days, and the effects of chronic melatonin treatment on in vivo hippocampal long‐term potentiation (LTP) and theta rhythm and Morris water maze performance were examined. We showed that intrahippocampal injection of Aβ1‐42 or Aβ31‐35 impaired hippocampal LTP in vivo, while chronic melatonin treatment reversed Aβ1‐42‐ or Aβ31‐35‐induced impairments in LTP induction. Intrahippocampal injection of Aβ31‐35 impaired spatial learning and decreased the power of theta rhythm in the CA1 region induced by tail pinch, and these synaptic, circuit, and learning deficits were rescued by chronic melatonin treatment. These results provide evidence for the neuroprotective action of melatonin against Aβ insults and suggest a strategy for alleviating cognition deficits of AD. Synapse 67:626–636, 2013 . © 2013 Wiley Periodicals, Inc.     

Inactivation of ATRX in forebrain excitatory neurons affects hippocampal synaptic plasticity

α‐Thalassemia X‐linked intellectual disability (ATR‐X) syndrome is a neurodevelopmental disorder caused by mutations in the ATRX gene that encodes a SNF2‐type chromatin‐remodeling protein. The ATRX protein regulates chromatin structure and gene expression in the developing mouse brain and early inactivation leads to DNA replication stress, extensive cell death, and microcephaly. However, the outcome of Atrx loss of function postnatally in neurons is less well understood. We recently reported that conditional inactivation of Atrx in postnatal forebrain excitatory neurons (ATRX‐cKO) causes deficits in long‐term hippocampus‐dependent spatial memory. Thus, we hypothesized that ATRX‐cKO mice will display impaired hippocampal synaptic transmission and plasticity. In the present study, evoked field potentials and current source density analysis were recorded from a multichannel electrode in male, urethane‐anesthetized mice. Three major excitatory synapses, the Schaffer collaterals to basal dendrites and proximal apical dendrites, and the temporoammonic path to distal apical dendrites on hippocampal CA1 pyramidal cells were assessed by their baseline synaptic transmission, including paired‐pulse facilitation (PPF) at 50‐ms interpulse interval, and by their long‐term potentiation (LTP) induced by theta‐frequency burst stimulation. Baseline single‐pulse excitatory response at each synapse did not differ between ATRX‐cKO and control mice, but baseline PPF was reduced at the CA1 basal dendritic synapse in ATRX‐cKO mice. While basal dendritic LTP of the first‐pulse excitatory response was not affected in ATRX‐cKO mice, proximal and distal apical dendritic LTP were marginally and significantly reduced, respectively. These results suggest that ATRX is required in excitatory neurons of the forebrain to achieve normal hippocampal LTP and PPF at the CA1 apical and basal dendritic synapses, respectively. Such alterations in hippocampal synaptic transmission and plasticity could explain the long‐term spatial memory deficits in ATRX‐cKO mice and provide insight into the physiological mechanisms underlying intellectual disability in ATR‐X syndrome patients.     

Requirement of appropriate glutamate concentrations in the synaptic cleft for hippocampal LTP induction

Although glutamate transporters maintain low extracellular levels of the excitatory neurotransmitter glutamate in the nervous system, little is known about their roles in synaptic plasticity. Here, using knockout mice lacking GLT-1, that is the most abundant glial subtype of glutamate transporters, we showed that long-term potentiation (LTP) induced by tetanic stimulation in mutant mice was impaired in the hippocampal CA1 region. When tetanic stimulation was applied in the presence of low concentrations of an N-methyl-D-aspartate (NMDA) receptor antagonist, the impairment was overcome. Consistent with these results, the increased glutamate in the synaptic cleft of mutant mice preferentially activated NMDA receptors. Furthermore, analyses of mutant mice revealed that the magnitude of NMDA receptor-dependent transient synaptic potentiation during low-frequency stimulation depended on the concentration of glutamate in the synaptic cleft. These findings suggest that GLT-1 plays critical roles in LTP induction, as well as in short-term potentiation, through regulation of extracellular levels of glutamate, which enables appropriate NMDA receptor activation.     

Abnormal glutamate homeostasis and impaired synaptic plasticity and learning in a mouse model of tuberous sclerosis complex

Mice with inactivation of the Tuberous sclerosis complex-1 (Tsc1) gene in glia (Tsc1 GFAP CKO mice) have deficient astrocyte glutamate transporters and develop seizures, suggesting that abnormal glutamate homeostasis contributes to neurological abnormalities in these mice. We examined the hypothesis that Tsc1 GFAP CKO mice have elevated extracellular brain glutamate levels that may cause neuronal death, abnormal glutamatergic synaptic function, and associated impairments in behavioral learning. In vivo microdialysis documented elevated glutamate levels in hippocampi of Tsc1 GFAP CKO mice and several cell death assays demonstrated neuronal death in hippocampus and neocortex. Impairment of long-term potentiation (LTP) with tetanic stimulation was observed in hippocampal slices from Tsc1 GFAP CKO mice and was reversed by low concentrations of NMDA antagonist, indicating that excessive synaptic glutamate directly inhibited LTP. Finally, Tsc1 GFAP CKO mice exhibited deficits in two hippocampal-dependent learning paradigms. These results suggest that abnormal glutamate homeostasis predisposes to excitotoxic cell death, impaired synaptic plasticity and learning deficits in Tsc1 GFAP CKO mice.     

Acute Exposure to the Mitochondrial Complex I Toxin Rotenone Impairs Synaptic Long‐Term Potentiation in Rat Hippocampal Slices

Aims: To evaluate the acute effects of the mitochondrial complex I inhibitor rotenone on rat hippocampal synaptic plasticity. Methods: Electrophysiological field potential recordings were used to measure basal synaptic transmission and synaptic plasticity in rat coronal hippocampal slices. Synaptic long‐term potentiation (LTP) was induced by high‐frequency stimulation (100 Hz, 1 second × 3 at an interval of 20 seconds). In addition, mitochondrial complex I function was measured using MitoSOX imaging in mitochondrial preparations. Results: Acute exposure of hippocampal slices to 50 nM rotenone for 1 h did not alter basal CA3–CA1 synaptic transmission though 500 nM rotenone significantly reduced basal synaptic transmission. However, 50 nM rotenone significantly impaired LTP and this rotenone's effect was prevented by co‐application of rotenone plus the ketones acetoacetate and β‐hydroxybutyrate (1 mM each). Finally, we measured mitochondrial function using MitoSOX imaging in mitochondrial preparations and found that 50 nM rotenone partially reduced mitochondrial function whereas 500 nM rotenone completely eliminated mitochondrial function. Conclusions: Our findings suggest that mitochondrial activity driven by complex I is a sensitive modulator of synaptic plasticity in the hippocampus. Acute exposure of the hippocampus to rotenone eliminates complex I function and in turn impairs LTP.     

Cytoarchitectural,behavioural and neurophysiological dysfunctions in the BCNU‐treated rat model of cortical dysplasia

Cortical dysplasias (CDs) include a spectrum of cerebral lesions resulting from cortical development abnormalities during embryogenesis that lead to cognitive disabilities and epilepsy. The experimental model of CD obtained by means of in utero administration of BCNU (1‐3‐bis‐chloroethyl‐nitrosurea) to pregnant rats on embryonic day 15 mimics the histopathological abnormalities observed in many patients. The aim of this study was to investigate the behavioural, electrophysiological and anatomical profile of BCNU‐treated rats in order to determine whether cortical and hippocampal lesions can directly lead to cognitive dysfunction. The BCNU‐treated rats showed impaired short‐term working memory but intact long‐term aversive memory, whereas their spontaneous motor activity and anxiety‐like response were normal. The histopathological and immunohistochemical analyses, made after behavioural tests, revealed the disrupted integrity of neuronal populations and connecting fibres in hippocampus and prefrontal and entorhinal cortices, which are involved in memory processes. An electrophysiological evaluation of the CA1 region of in vitro hippocampal slices indicated a decrease in the efficiency of excitatory synaptic transmission and impaired paired pulse facilitation, but enhanced long‐term potentiation (LTP) associated with hyperexcitability in BCNU‐treated rats compared with controls. The enhanced LTP, associated with hyperexcitability, may indicate a pathological distortion of long‐term plasticity. These findings suggest that prenatal developmental insults at the time of peak cortical neurogenesis can induce anatomical abnormalities associated with severe impairment of spatial working memory in adult BCNU‐treated rats and may help to clarify the pathophysiological mechanisms of cognitive dysfunction that is often associated with epilepsy in patients with CD.     

Age‐related synaptic dysfunction in Tg2576 mice starts as a failure in early long‐term potentiation which develops into a full abolishment of late long‐term potentiation

Tg2576 mice are widely used to study amyloid‐dependent synaptic dysfunction related to Alzheimer's disease. However, conflicting data have been reported for these mice with regard to basal transmission as well as the in vitro correlate of memory, long‐term potentiation (LTP). Some studies show clear impairments, whereas others report no deficiency. The present study uses hippocampal slices from 3‐, 10‐, and 15‐month‐old wild‐type (WT) and Tg2576 mice to evaluate synaptic function in each group, including experiments to investigate basal synaptic transmission, short‐ and long‐term plasticity by inducing paired‐pulse facilitation, and both early and late LTP. We show that synaptic function remains intact in hippocampal slices from Tg2576 mice at 3 months of age. However, both early and late LTP decline progressively during aging in these mice. This deterioration of synaptic plasticity starts affecting early LTP, ultimately leading to the abolishment of both forms of LTP in 15‐month‐old animals. In comparison, WT littermates display normal synaptic parameters during aging. Additional pharmacological investigation into the involvement of NMDA receptors and L‐type voltage‐gated calcium channels in LTP suggests a distinct mechanism of induction among age groups, demonstrating that both early and late LTP are differentially affected by these channels in Tg2576 mice during aging. © 2015 Wiley Periodicals, Inc.     

The selective noradrenergic reuptake inhibitor reboxetine restores spatial learning deficits,biochemical changes,and hippocampal synaptic plasticity in an animal model of depression

Depression is a major psychiatric illness that is associated with cognitive dysfunctions. The underlying mechanism of depression‐associated memory impairment is unclear. Previously, we showed altered hippocampal synaptic plasticity in an animal model of depression. Although several antidepressants are beneficial in the treatment of depression, very little is known about the effects of these drugs on depression‐associated learning and memory deficits. Prolonged antidepressant treatment might contribute to neuroplastic changes required for clinical outcomes. Accordingly, we evaluated the effect of chronic reboxetine (a selective noradrenergic reuptake inhibitor) treatment on depression‐induced reduced hippocampal synaptic plasticity, neurotransmitter levels, and spatial learning and memory impairments. Depression was induced in male Wistar rats by the administration of clomipramine from postnatal days 8 to 21, and these rats were treated with reboxetine in adulthood. The neonatal clomipramine administration resulted in impaired hippocampal long‐term potentiation (LTP), decreased hippocampal cholinergic activity and monoamine levels, and poor performance in a partially baited eight‐arm radial maze task. Chronic reboxetine treatment restored the hippocampal LTP, acetylcholinesterase activity, and levels of biogenic amines and ameliorated spatial learning and memory deficits in the depressed state. Thus, restoration of hippocampal synaptic plasticity might be a cellular mechanism underlying the beneficial effect of reboxetine in depression‐associated cognitive deficits. This study furthers the existing understanding of the effects of antidepressants on learning, memory, and synaptic plasticity and could ultimately assist in the development of better therapeutic strategies to treat depression and associated cognitive impairments. © 2014 Wiley Periodicals, Inc.     

Decreased purinergic inhibition of synaptic activity in a mouse model of Niemann‐Pick disease type C

Niemann‐Pick disease type C (NPC) is a progressive neurodegenerative disorder characterized by accumulation of free cholesterol in lysosomes, mainly due to a mutation in the NPC1 gene. The pathophysiological basis of the neural disorders in NPC, however, is not well understood. We found that the hippocampal field excitatory postsynaptic potential (fEPSP) was enhanced in NPC1 mutant mice. A1‐receptor antagonist or adenosine degrading enzyme enhanced the fEPSP in both types of mice, but had a much weaker effect in the mutant mice, suggesting less tonic inhibition of synaptic transmission by endogenous adenosine in the mutant. Further evidence showed impaired hippocampal long term potentiation (LTP) in mutant mice. Supplement of A1 agonist N6‐Cyclopentyladenosine (CPA) partially rescued the impaired LTP in mutant mice. Moreover, adenosine release from hippocampal slices was significantly decreased in the mutant. The enhanced excitatory synaptic transmission and the decreased synaptic plasticity due to the decreased adenosine release in NPC brain may partially contribute to the neural disorders of NPC disease, such as seizures, neurodegeneration, and dementia. © 2010 Wiley‐Liss, Inc.     

Regional- and age-dependent reduction in trkB receptor expression in the hippocampus is associated with altered spine morphologies.

BACKGROUND: Changes in densities and in the morphology of dendritic spines in the hippocampus are linked to hippocampal long-term potentiation (LTP), spatial learning, and depression. Decreased brain-derived neurotrophic factor (BDNF) levels seem to contribute to depression. Through its receptor trkB, BDNF is also involved in hippocampal LTP and hippocampus-dependent learning. Conditionally gene-targeted mice in which the ablation of trkB is restricted to the forebrain and occurs only during postnatal development display impaired learning and LTP. METHODS: To examine whether there is a link among impaired hippocampal synaptic plasticity, altered spines, and trkB receptors, we performed a quantitative analysis of spine densities and spine length in the hippocampal area CA1 and the dentate gyrus in conditional mutant mice (trkB(lox/lox)CaMKII-CRE mice). TrkB protein and mRNA levels were assayed using Western blot and in situ hybridization analysis. RESULTS: Fifteen-week-old mutant mice exhibit specific reductions in spine densities and a significant increase in spine length of apical and basal dendrites in area CA1. These alterations correlate with a time- and region-specific reduction in full-length trkB mRNA in the hippocampus. CONCLUSIONS: TrkB functions in structural remodeling of hippocampal dendritic spines, which in turn may affect synaptic transmission and plasticity.     

GSK3 activity regulates rhythms in hippocampal clock gene expression and synaptic plasticity

Hippocampal rhythms in clock gene expression, enzymatic activity, and long‐term potentiation (LTP) are thought to underlie day–night differences in memory acquisition and recall. Glycogen synthase kinase 3‐beta (GSK3β) is a known regulator of hippocampal function, and inhibitory phosphorylation of GSK3β exhibits region‐specific differences over the light‐dark cycle. Here, we sought to determine whether phosphorylation of both GSK3α and GSK3β isoforms has an endogenous circadian rhythm in specific areas of the hippocampus and whether chronic inhibition or activation alters the molecular clock and hippocampal plasticity (LTP). Results indicated a significant endogenous circadian rhythm in phosphorylation of GSK3β, but not GSK3α, in hippocampal CA1 extracts from mice housed in constant darkness for at least 2 weeks. To examine the importance of this rhythm, genetic and pharmacological strategies were used to disrupt the GSK3 activity rhythm by chronically activating or inhibiting GSK3. Chronic activation of both GSK3 isoforms in transgenic mice (GSK3‐KI mice) diminished rhythmic BMAL1 expression. On the other hand, chronic treatment with a GSK3 inhibitor significantly shortened the molecular clock period of organotypic hippocampal PER2::LUC cultures. While WT mice exhibited higher LTP magnitude at night compared to day, the day–night difference in LTP magnitude remained with greater magnitude at both times of day in mice with chronic GSK3 activity. On the other hand, pharmacological GSK3 inhibition impaired day–night differences in LTP by blocking LTP selectively at night. Taken together, these results support the model that circadian rhythmicity of hippocampal GSK3β activation state regulates day/night differences in molecular clock periodicity and a major form of synaptic plasticity (LTP).     

Dysbindin‐1 loss compromises NMDAR‐dependent synaptic plasticity and contextual fear conditioning

Genetic variants in DTNBP1 encoding the protein dysbindin‐1 have often been associated with schizophrenia and with the cognitive deficits prominent in that disorder. Because impaired function of the hippocampus is thought to play a role in these memory deficits and because NMDAR‐dependent synaptic plasticity in this region is a proposed biological substrate for some hippocampal‐dependent memory functions in schizophrenia, we hypothesized that reduced dysbindin‐1 expression would lead to impairments in NMDAR‐dependent synaptic plasticity and in contextual fear conditioning. Acute slices from male mice carrying 0, 1, or 2 null mutant alleles of the Dtnbp1 gene were prepared, and field recordings from the CA1 striatum radiatum were obtained before and after tetanization of Schaffer collaterals of CA3 pyramidal cells. Mice homozygous for the null mutation in Dtnbp1 exhibited significantly reduced NMDAR‐dependent synaptic potentiation compared to wild type mice, an effect that could be rescued by bath application of the NMDA receptor coagonist glycine (10 μM). Behavioral testing in adult mice revealed deficits in hippocampal memory processes. Homozygous null mice exhibited lower conditional freezing, without a change in the response to shock itself, indicative of a learning and memory deficit. Taken together, these results indicate that a loss of dysbindin‐1 impairs hippocampal plasticity which may, in part, explain the role dysbindin‐1 plays in the cognitive impairments of schizophrenia. © 2013 Wiley Periodicals, Inc.