The brain produces two brain-derived neurotrophic factor (BDNF) transcripts, with either short or long 3′ untranslated regions (3′ UTRs). The physiological significance of the two forms of mRNAs ...encoding the same protein is unknown. Here, we show that the short and long 3′ UTR BDNF mRNAs are involved in different cellular functions. The short 3′ UTR mRNAs are restricted to somata, whereas the long 3′ UTR mRNAs are also localized in dendrites. In a mouse mutant where the long 3′ UTR is truncated, dendritic targeting of BDNF mRNAs is impaired. There is little BDNF in hippocampal dendrites despite normal levels of total BDNF protein. This mutant exhibits deficits in pruning and enlargement of dendritic spines, as well as selective impairment in long-term potentiation in dendrites, but not somata, of hippocampal neurons. These results provide insights into local and dendritic actions of BDNF and reveal a mechanism for differential regulation of subcellular functions of proteins.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Neurotrophins have diverse functions in the CNS. Initially synthesized as precursors (proneurotrophins), they are cleaved to produce mature proteins, which promote neuronal survival and enhance ...synaptic plasticity by activating Trk receptor tyrosine kinases. Recent studies indicate that proneurotrophins serve as signalling molecules by interacting with the p75 neurotrophin receptor (p75NTR). Interestingly, proneurotrophins often have biological effects that oppose those of mature neurotrophins. Therefore, the proteolytic cleavage of proneurotrophins represents a mechanism that controls the direction of action of neurotrophins. New insights into the 'yin and yang' of neurotrophin activity have profound implications for our understanding of the role of neurotrophins in a wide range of cellular processes.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Activity-dependent gene transcription, including that of the brain-derived neurotrophic factor (Bdnf) gene, has been implicated in various cognitive functions. We previously demonstrated that mutant ...mice with selective disruption of activity-dependent BDNF expression (BDNF-KIV mice) exhibit deficits in GABA-mediated inhibition in the prefrontal cortex (PFC). Here, we show that disruption of activity-dependent BDNF expression impairs BDNF-dependent late-phase long-term potentiation (L-LTP) in CA1, a site of hippocampal output to the PFC. Interestingly, early-phase LTP and conventional L-LTP induced by strong tetanic stimulation were completely normal in BDNF-KIV mice. In parallel, attenuation of activity-dependent BDNF expression significantly impairs spatial memory reversal and contextual memory extinction, two executive functions that require intact hippocampal–PFC circuitry. In contrast, spatial and contextual memory per se were not affected. Thus, activity-dependent BDNF expression in the hippocampus and PFC may contribute to cognitive and behavioral flexibility. These results suggest distinct roles for different forms of L-LTP and provide a link between activity-dependent BDNF expression and behavioral perseverance, a hallmark of several psychiatric disorders.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Transcription of Bdnf is controlled by multiple promoters, which drive expression of multiple transcripts encoding for the same protein. Promoter IV contributes significantly to activity-dependent ...brain-derived neurotrophic factor (BDNF) transcription. We have generated promoter IV mutant mice (BDNF-KIV) by inserting a GFP-STOP cassette within the Bdnf exon IV locus. This genetic manipulation results in disruption of promoter IV-mediated Bdnf expression. BDNF-KIV animals exhibited significant deficits in GABAergic interneurons in the prefrontal cortex (PFC), particularly those expressing parvalbumin, a subtype implicated in executive function and schizophrenia. Moreover, disruption of promoter IV-driven Bdnf transcription impaired inhibitory but not excitatory synaptic transmission recorded from layer V pyramidal neurons in the PFC. The attenuation of GABAergic inputs resulted in an aberrant appearance of spike-timing-dependent synaptic potentiation (STDP) in PFC slices derived from BDNF-KIV, but not wild-type littermates. These results demonstrate the importance of promoter IV-dependent Bdnf transcription in GABAergic function and reveal an unexpected regulation of STDP in the PFC by BDNF.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Parvalbumin-positive interneurons, which include basket and chandelier cells, represent a unique class of interneurons. By innervating the soma and the axonal initial segment of pyramidal cells, ...these interneurons can elicit powerful control on the output of pyramidal cells and consequently are important for a number of physiological processes in the mammalian brain. Recent evidence indicates that neurotrophins regulate the development and functions of parvalbumin-positive interneurons. Disruption of neurotrophin-mediated regulation of interneurons is thought to contribute to the pathological processes underlying CNS dysfunction. This review brings together recently described roles of neurotrophins in migration, differentiation, synaptogenesis during development, and acute effects of neurotrophins in transmission at inhibitory synapses, Cl- homeostasis, and network activity of cortical interneurons. The authors also discuss the importance of neurotrophin regulation of GABAergic neurons in schizophrenia and epilepsy.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
Integrins are a large family of cell adhesion receptors involved in a variety of cellular functions. To study their roles at central synapses, we used two cre recombinase lines to delete the Itgb1 ...beta1 integrin gene in forebrain excitatory neurons at different developmental stages. Removal of the beta1 integrins at an embryonic stage resulted in severe cortical lamination defects without affecting the cellular organization of pyramidal neurons in the CA3 and CA1 regions of the hippocampus. Whereas the hippocampal neurons underwent normal dendritic and synaptic differentiation, the adult synapses exhibited deficits in responses to high-frequency stimulation (HFS), as well as in long-term potentiation (LTP). Deletion of beta1 integrin at a later postnatal stage also impaired LTP but not synaptic responses to HFS. Thus, the beta1-class integrins appear to play distinct roles at different stages of synaptic development, critical for the proper maturation of readily releasable pool of vesicles during early development but essential for LTP throughout adult life.
Abstract Fragile X syndrome is the leading single gene cause of intellectual disabilities. Treatment of a Drosophila model of Fragile X syndrome with metabotropic glutamate receptor (mGluR) ...antagonists or lithium rescues social and cognitive impairments. A hallmark feature of the Fragile X mouse model is enhanced mGluR-dependent long-term depression (LTD) at Schaffer collateral to CA1 pyramidal synapses of the hippocampus. Here we examine the effects of chronic treatment of Fragile X mice in vivo with lithium or a group II mGluR antagonist on mGluR-LTD at CA1 synapses. We find that long-term lithium treatment initiated during development (5–6 weeks of age) and continued throughout the lifetime of the Fragile X mice until 9–11 months of age restores normal mGluR-LTD. Additionally, chronic short-term treatment beginning in adult Fragile X mice (8 weeks of age) with either lithium or an mGluR antagonist is also able to restore normal mGluR-LTD. Translating the findings of successful pharmacologic intervention from the Drosophila model into the mouse model of Fragile X syndrome is an important advance, in that this identifies and validates these targets as potential therapeutic interventions for the treatment of individuals afflicted with Fragile X syndrome.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Fragile X syndrome (FXS) is the leading cause of both intellectual disability and autism resulting from a single gene mutation. Previously, we characterized cognitive impairments and brain structural ...defects in a Drosophila model of FXS and demonstrated that these impairments were rescued by treatment with metabotropic glutamate receptor (mGluR) antagonists or lithium. A well-documented biochemical defect observed in fly and mouse FXS models and FXS patients is low cAMP levels. cAMP levels can be regulated by mGluR signaling. Herein, we demonstrate PDE-4 inhibition as a therapeutic strategy to ameliorate memory impairments and brain structural defects in the Drosophila model of fragile X. Furthermore, we examine the effects of PDE-4 inhibition by pharmacologic treatment in the fragile X mouse model. We demonstrate that acute inhibition of PDE-4 by pharmacologic treatment in hippocampal slices rescues the enhanced mGluR-dependent LTD phenotype observed in FXS mice. Additionally, we find that chronic treatment of FXS model mice, in adulthood, also restores the level of mGluR-dependent LTD to that observed in wild-type animals. Translating the findings of successful pharmacologic intervention from the Drosophila model into the mouse model of FXS is an important advance, in that this identifies and validates PDE-4 inhibition as potential therapeutic intervention for the treatment of individuals afflicted with FXS.
Integrins are a large family of cell adhesion receptors involved in a variety of cellular functions. To study their roles at central synapses, we used two
cre
recombinase lines to delete the
Itgb1
β1 ...integrin gene in forebrain excitatory neurons at different developmental stages. Removal of the β1 integrins at an embryonic stage resulted in severe cortical lamination defects without affecting the cellular organization of pyramidal neurons in the CA3 and CA1 regions of the hippocampus. Whereas the hippocampal neurons underwent normal dendritic and synaptic differentiation, the adult synapses exhibited deficits in responses to high-frequency stimulation (HFS), as well as in long-term potentiation (LTP). Deletion of β1 integrin at a later postnatal stage also impaired LTP but not synaptic responses to HFS. Thus, the β1-class integrins appear to play distinct roles at different stages of synaptic development, critical for the proper maturation of readily releasable pool of vesicles during early development but essential for LTP throughout adult life.
1 Department of Biology and
2 Neuroscience Graduate Group, University of
Pennsylvania, Philadelphia, PA 19104-6018; Departments of
3 Physiology and
4 Psychiatry, and 5 Centre
for ...Neuroscience, University of Alberta School of Medicine, Edmonton,
Alberta T6G 2H7, Canada
Scharf, Matthew T.,
Newton H. Woo,
K. Matthew Lattal,
Jennie Z. Young,
Peter V. Nguyen, and
Ted Abel.
Protein Synthesis Is Required for the Enhancement of Long-Term
Potentiation and Long-Term Memory by Spaced Training. J. Neurophysiol. 87: 2770-2777, 2002. Spaced
training is generally more effective than massed training for learning
and memory, but the molecular mechanisms underlying this trial spacing
effect remain poorly characterized. One potential molecular basis for
the trial spacing effect is the differential modulation, by distinct
temporal patterns of neuronal activity, of protein synthesis-dependent
processes that contribute to the expression of specific forms of
synaptic plasticity in the mammalian brain. Long-term potentiation
(LTP) is a type of synaptic modification that may be important for
certain forms of memory storage in the mammalian brain. To explore the
role of protein synthesis in the trial spacing effect, we assessed the
protein synthesis dependence of hippocampal LTP induced by 100-Hz
tetraburst stimulation delivered to mouse hippocampal slices in either
a temporally massed (20-s interburst interval) or spaced (5-min
interburst interval) fashion. To extend our studies to the behavioral
level, we trained mice in fear conditioning using either a massed or
spaced training protocol and examined the sensitivity of long-term
memory to protein synthesis inhibition. Larger LTP was induced by
spaced stimulation in hippocampal slices. This improvement of synaptic
potentiation following temporally spaced synaptic stimulation in slices
was attenuated by bath application of an inhibitor of protein
synthesis. Further, the maintenance of LTP induced by spaced synaptic
stimulation was more sensitive to disruption by anisomycin than the
maintenance of LTP elicited following massed stimulation. Temporally
spaced behavioral training improved long-term memory for contextual but not for cued fear conditioning, and this enhancement of memory for
contextual fear was also protein synthesis dependent. Our data reveal
that altering the temporal spacing of synaptic stimulation and
behavioral training improved hippocampal LTP and enhanced contextual
long-term memory. From a broad perspective, these results suggest that
the recruitment of protein synthesis-dependent processes important for
long-term memory and for long-lasting forms of LTP can be modulated by
the temporal profiles of behavioral training and synaptic stimulation.
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