Distinct role of long 3' UTR BDNF mRNA in spine morphology and synaptic plasticity in hippocampal neurons.

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.

PDE-4 inhibition rescues aberrant synaptic plasticity in Drosophila and mouse models of fragile X syndrome.

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.

Role of activity-dependent BDNF expression in hippocampal-prefrontal cortical regulation of behavioral perseverance.

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.

Critical role of promoter IV-driven BDNF transcription in GABAergic transmission and synaptic plasticity in the prefrontal cortex.

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.

Activation of p75NTR by proBDNF facilitates hippocampal long-term depression.

Pro- and mature brain-derived neurotrophic factor (BDNF) activate two distinct receptors: p75 neurotrophin receptor (p75(NTR)) and TrkB. Mature BDNF facilitates hippocampal synaptic potentiation through TrkB. Here we report that proBDNF, by activating p75(NTR), facilitates hippocampal long-term depression (LTD). Electron microscopy showed that p75(NTR) localized in dendritic spines, in addition to afferent terminals, of CA1 neurons. Deletion of p75(NTR) in mice selectively impaired the NMDA receptor-dependent LTD, without affecting other forms of synaptic plasticity. p75(NTR-/-) mice also showed a decrease in the expression of NR2B, an NMDA receptor subunit uniquely involved in LTD. Activation of p75(NTR) by proBDNF enhanced NR2B-dependent LTD and NR2B-mediated synaptic currents. These results show a crucial role for proBDNF-p75(NTR) signaling in LTD and its potential mechanism, and together with the finding that mature BDNF promotes synaptic potentiation, suggest a bidirectional regulation of synaptic plasticity by proBDNF and mature BDNF.

Persistent neural activity in the prefrontal cortex: a mechanism by which BDNF regulates working memory?

Working memory is the ability to maintain representations of task-relevant information for short periods of time to guide subsequent actions or make decisions. Neurons of the prefrontal cortex exhibit persistent firing during the delay period of working memory tasks. Despite extensive studies, the mechanisms underlying this persistent neural activity remain largely obscure. The neurotransmitter systems of dopamine, NMDA, and GABA have been implicated, but further investigations are necessary to establish their precise roles and relationships. Recent research has suggested a new component: brain-derived neurotrophic factor (BDNF) and its high-affinity receptor, TrkB. We review the research on persistent activity and suggest that BDNF/TrkB signaling in a distinct class of interneurons plays an important role in organizing persistent neural activity at the single-neuron and network levels.

Distinct roles of the beta 1-class integrins at the developing and the mature hippocampal excitatory synapse.

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.

Regulation of cortical interneurons by neurotrophins: from development to cognitive disorders.

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.

Protein synthesis is required for synaptic immunity to depotentiation.

De novo protein synthesis and transcription are necessary for the expression of long-lasting synaptic potentiation [long-term potentiation (LTP)] in hippocampal area CA1 and for the consolidation of long-term memory. The stability of LTP and its longevity require macromolecular synthesis at later stages, but a specific role for early protein synthesis has not been identified. Using electrophysiological recording methods in mouse hippocampal slices, we show that multiple trains of high-frequency stimulation provide immediate synaptic immunity to depotentiation. This immunity to depotentiation is dependent on the amount of synaptic stimulation used to induce LTP, it is input specific, and it is prevented by inhibitors of protein synthesis. We propose that local translation mediates input-specific synaptic immunity against depotentiation. We also present evidence suggesting that, in addition to translation, products of transcription can provide cell-wide immunity to depotentiation via heterosynaptic transfer of synaptic immunity between distinct pathways in area CA1. Protein synthesis and transcription may importantly regulate long-term storage of information by conferring synaptic immunity to depotentiation at previously potentiated synapses.

Pharmacological reversal of synaptic plasticity deficits in the mouse model of fragile X syndrome by group II mGluR antagonist or lithium treatment.

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.