No abstract

Years of intensive investigation have yielded a sophisticated understanding of long-term potentiation (LTP) induced in hippocampal area CA1 by high-frequency stimulation (HFS). These efforts have been motivated by the belief that similar synaptic modifications occur during memory formation, but it has never been shown that learning actually induces LTP in CA1. We found that one-trial inhibitory avoidance learning in rats produced the same changes in hippocampal glutamate receptors as induction of LTP with HFS and caused a spatially restricted increase in the amplitude of evoked synaptic transmission in CA1 in vivo. Because the learning-induced synaptic potentiation occluded HFS-induced LTP, we conclude that inhibitory avoidance training induces LTP in CA1.

Fragile X syndrome, the most common inherited form of human mental retardation, is caused by mutations of the Fmr1 gene that encodes the fragile X mental retardation protein (FMRP). Biochemical evidence indicates that FMRP binds a subset of mRNAs and acts as a regulator of translation. However, the consequences of FMRP loss on neuronal function in mammals remain unknown. Here we show that a form of protein synthesis-dependent synaptic plasticity, long-term depression triggered by activation of metabotropic glutamate receptors, is selectively enhanced in the hippocampus of mutant mice lacking FMRP. This finding indicates that FMRP plays an important functional role in regulating activity-dependent synaptic plasticity in the brain and suggests new therapeutic approaches for fragile X syndrome. Fragile X syndrome is a prevalent form of inherited mental retardation, occurring with a frequency of 1 in 4,000 males and 1 in 8,000 females. The syndrome is also characterized by developmental delay, hyperactivity, attention deficit disorder, and autistic-like behaviors (1). There is no effective treatment for fragile X syndrome.The syndrome is typically caused by a repeat expansion mutation in the FMR1 gene that encodes FMRP, the fragile X mental retardation protein. FMRP is known to associate with translating polyribosomes and a subset of brain mRNAs and is believed to function as a regulator of protein synthesis (2-5). Involvement of FMRP in synaptic plasticity has long been suspected, because polyribosomes, FMR1 mRNA, and FMRP are all present in dendritic spines, the major site of synaptic transmission on cortical neurons (6). The Fmr1 null mutant (knockout) (Fmr1-KO) mouse, which has a behavioral phenotype consistent with fragile X syndrome, provided an opportunity to test this hypothesis. However, protein synthesisdependent late-phase long-term synaptic potentiation (LTP) was found to be unaffected in the hippocampus of mutant mice (7,8).Reexamination of this issue was prompted by recent work showing that local synaptic control of protein synthesis is required for stable expression of a second form of hippocampal synaptic modification: long-term depression (LTD) triggered by activation of group 1 metabotropic glutamate receptors (mGluRs) (9-11). A role for FMRP is this form of synaptic plasticity was further suggested by the fact that FMRP is one of the proteins known to be synthesized in response to mGluR activation (6).We report here that mGluR-dependent LTD (mGluR-LTD) is significantly altered in the hippocampus of Fmr1-KO mice. Rather than a deficit, however, we find that mGluR-LTD is augmented in the absence of FMRP. This finding is consistent with the recent discovery that FMRP normally functions as a negative regulator of translation (5,12,13). We propose that exaggerated LTD and͞or mGluR function are responsible for aspects of the behavioral phenotype in fragile X syndrome, and that antagonists of group 1 mGluRs should be considered as possible therapeutic agents. Materials and MethodsHippocampal slices were ...

LTP and LTD, the long-term potentiation and depression of excitatory synaptic transmission, are widespread phenomena expressed at possibly every excitatory synapse in the mammalian brain. It is now clear that "LTP" and "LTD" are not unitary phenomena. Their mechanisms vary depending on the synapses and circuits in which they operate. Here we review those forms of LTP and LTD for which mechanisms have been most firmly established. Examples are provided that show how these mechanisms can contribute to experience-dependent modifications of brain function.

Maturation of the visual cortex is influenced by visual experience during an early postnatal period. The factors that regulate such a critical period remain unclear. We examined the maturation and plasticity of the visual cortex in transgenic mice in which the postnatal rise of brain-derived neurotrophic factor (BDNF) was accelerated. In these mice, the maturation of GABAergic innervation and inhibition was accelerated. Furthermore, the age-dependent decline of cortical long-term potentiation induced by white matter stimulation, a form of synaptic plasticity sensitive to cortical inhibition, occurred earlier. Finally, transgenic mice showed a precocious development of visual acuity and an earlier termination of the critical period for ocular dominance plasticity. We propose that BDNF promotes the maturation of cortical inhibition during early postnatal life, thereby regulating the critical period for visual cortical plasticity.

No abstract

A hippocampal pyramidal neuron receives more than 10(4) excitatory glutamatergic synapses. Many of these synapses contain the molecular machinery for messenger RNA translation, suggesting that the protein complement (and thus function) of each synapse can be regulated on the basis of activity. Here, local postsynaptic protein synthesis, triggered by synaptic activation of metabotropic glutamate receptors, was found to modify synaptic transmission within minutes.

Fragile X syndrome (FXS) is the most common form of heritable mental retardation and the leading identified cause of autism. FXS is caused by transcriptional silencing of the FMR1 gene that encodes the fragile X mental retardation protein (FMRP), but the pathogenesis of the disease is unknown. According to one proposal, many psychiatric and neurological symptoms of FXS result from unchecked activation of mGluR5, a metabotropic glutamate receptor. To test this idea we generated Fmr1 mutant mice with a 50% reduction in mGluR5 expression and studied a range of phenotypes with relevance to the human disorder. Our results demonstrate that mGluR5 contributes significantly to the pathogenesis of the disease, a finding that has significant therapeutic implications for fragile X and related developmental disorders.