Fluorescent puncta representing BDNF—GFP not only moved in the anterograde direction, from nucleus to axon terminals, but also underwent activity-dependent transfer from pre- to postsynaptic neurons across the synapse Kohara et al. In a study by de Azua et al. The structure of BDNF was reported in , a neurotrophin that promotes the survival of neuronal populations located in the central nervous system, or neuronal populations directly connected to it Barde, Activity-induced changes in the central nervous system CNS are widely proposed mechanisms that allow organisms to adapt behaviorally, to learn and remember. Considering the neurodevelopmental hypothesis about schizophrenia, BDNF has been proposed as a candidate to explain part of the pathogenesis of this disease. This argues strongly for the neurotrophins playing a role in a final stage of maturation of the vesicle release mechanism.
The behavioral alterations seen in MAM offspring vary according to the gestational day GD of MAM administration in a sequential manner: at GD17 changes similar as those seen in schizophrenia have been observed, with impaired acquisition of learning at GD17 or later. The presence of Trk or neurotrophin homologs in some, but not all, invertebrates may provide important clues for understanding the evolution of complex nervous systems as has been suggested by Barde
The behavioral evidence implicating BDNF in spatial learning and memory has revealed a role in the acquisition, consolidation, and subsequent recall of information. According to Pedrini et al.
Virtually all areas of cognition in schizophrenia are altered to some degree. In the hippocampus of rats presented with enriched environments, BDNF levels are also increased Falkenberg et al.
There is also evidence suggesting that PKA and PKC can modify synaptic proteins involved with vesicular release machinery, further modifying transmitter release during subsequent activity.
This hypothesis is mainly based on new experimental evidence showing that psychiatric disorders are associated with neuronal atrophy and cell loss, impairments of structural plasticity and cellular resilience due to neurodevelopmental disturbances and morphological abnormalities of the brain.
Ample evidence for presynaptic release of neurotrophins is found in the developing avian visual system von Bartheld et al. All the neurotrophins bind with high affinity to members of a family of receptor tyrosine kinases, the Trk family. Evidence increasingly suggests that schizophrenia is a subtle disorder of brain development Ross et al. In fact, BDNF has been shown to have effects on hippocampal physiology by acting pre-, post-, and perisynaptically for review, see Poo
Patients with better neurocognitive performance had only memory deficits, while patients with lower cognitive performance were affected in both memory deficits and executive functions. BDNF immunoreactivity has been localized to large dense-core vesicles in hippocampal neurons Fawcett et al. Synapse Deregulation in Schizophrenia Over the last decades, convergent findings from various areas of investigation have suggested that alterations of synaptic transmission and neuronal connectivity might be the core feature of schizophrenia Frankle et al. In addition to these in vitro manipulations, and more relevant to learning and memory, BDNF expression is also regulated in vivo by various environmental interactions. These examples will be discussd in more detail below. Giusetto, S.
Therefore, alterations in BDNF may contribute to altered brain development, failures in neuroplasticity, and synaptic disconnectivity, and explain at least in part some of the morphological, neurochemical, and cytoarchitectonic abnormalities found in the brains of patients with schizophrenia Durany and Thome, ; Shoval and Weizman, ; Buckley et al. It has since been reported thatBDNF mRNA levels in the dentate gyrus are increased in rats with good retention at 1, 3, and 6 h posttraining, when compared with poor-retention rats undergoing Morris water-maze training Ma et al.
Interestingly, although multiple exposures of 5-HT are sufficient to remove ApCREB2, other external signals, such as neurotrophins, are transduced through the MAP kinase signaling cascade Nakamura et al. In studies with treatment-naive patients who had their first psychotic episode, Buckley et al.
Furthermore, BDNF expression is modulated in the hippocampus by a variety of neurotransmitter and neuromodulatory systems, all of which have been implicated in hippocampal-dependent learning. In one of the developmental animal models of schizophrenia, treatment of pregnant rat dams with methylazoxymethanol acetate MAM , an anti-mitotic and anti-proliferative agent that methylates DNA does not affect litter size or pup body weight, but selectively affects brain development. Although it is well established that many of the cellular and molecular mechanisms underlying synaptic plasticity are conserved between invertebrates and vertebrates, there are, as yet, very few neurotrophic factors identified in invertebrate species. Consistent with its ligand localization and signaling at synapses, TrkB immunoreactivity was detected in neuronal cell bodies, along axons and dendritic shafts, as well as at excitatory synapses in both the axon terminals and dendritic spines of hippocampal neurons Drake et al.
The goal of this review is to present some of the primary evidence for the participation of neurotrophins in synaptic plasticity. More recently, Donald Hebb proposed a cellular mechanism for associative learning postulating that coincident activity at given synaptic junctions modifies the properties of those synapses, thereby increasing their efficiency Hebb Table 1 shows selected examples of both novel and homologous invertebrate molecules. These findings highlight the role of BDNF and its receptor in a crucial aspect of the neuronal circuitry of schizophrenia that is particularly related to alterations in cognitive functioning. This conditional knockout approach circumvents the always-present issue of potential developmental defects in constitutive knockout mice, at least to the extent that the period of genetic intervention spans only from approximately the second postnatal week to the time of behavioral testing a few weeks later. This argues strongly for the neurotrophins playing a role in a final stage of maturation of the vesicle release mechanism.