Neuroscience
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For over two decades it has been increasingly appreciated that synaptic plasticity mechanisms are subject to activity-dependent metaplastic regulation. In recent years it has also become apparent that astrocytes are active partners with neurons at synapses, and have the capability to powerfully regulate synaptic plasticity. However, the field of astrocyte-mediated metaplasticity is still very much in its infancy. ⋯ This contribution may be particularly important given that altered plasticity in the hippocampus is a hallmark of several disease states. The known ways by which astrocytes exert metaplasticity are reviewed here, and hypothetical mechanisms of astrocyte-mediated metaplasticity are considered for the benefit of future investigation. The latter half of this review focuses on what part these mechanisms, and others, may play in the diseased or injured hippocampus, and how this might contribute to the altered cognition seen in several pathologies common to the hippocampus.
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The hippocampus is strongly implicated in the psychotic symptoms of schizophrenia. Functionally, basal hippocampal activity (perfusion) is elevated in schizophrenic psychosis, as measured with positron emission tomography (PET) and with magnetic resonance (MR) perfusion techniques, while hippocampal activation to memory tasks is reduced. ⋯ We interpret these observations to implicate a reduction in the influence of a ubiquitous gene repressor, repressor element-1 silencing transcription factor (REST) in psychosis; REST is involved in the age-related maturation of the NMDA receptor from GluN2B- to GluN2A-containing NMDA receptors through epigenetic remodeling. These CA3 changes in psychosis leave the hippocampus liable to pathological increases in neuronal activity, feedforward excitation and false memory formation, sometimes with psychotic content.
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Neuroplasticity involves molecular and structural changes in central nervous system (CNS) throughout life. The concept of neural organization allows for remodeling as a compensatory mechanism to the early pathobiology of Alzheimer's disease (AD) in an attempt to maintain brain function and cognition during the onset of dementia. The hippocampus, a crucial component of the medial temporal lobe memory circuit, is affected early in AD and displays synaptic and intraneuronal molecular remodeling against a pathological background of extracellular amyloid-beta (Aβ) deposition and intracellular neurofibrillary tangle (NFT) formation in the early stages of AD. Here we discuss human clinical pathological findings supporting the concept that the hippocampus is capable of neural plasticity during mild cognitive impairment (MCI), a prodromal stage of AD and early stage AD.
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Multiple sclerosis (MS) is a progressive inflammatory autoimmune disease that is characterized by demyelination and axonal damage in the nervous system. One obvious consequence is a cumulative loss of muscle control. However, cognitive dysfunction affects roughly half of MS sufferers, sometimes already early in the disease course. ⋯ However, in the late phase, LTP was impaired and LTP-related spatial memory was impaired. In contrast, LTD and hippocampus-dependent object recognition memory were unaffected. These data suggest that in an animal model of MS hippocampal function becomes compromised as the disease progresses.
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Methylphenidate (MPH) is a widely prescribed stimulant drug for the treatment of attention deficit hyperactivity disorder (ADHD) in children and adolescents. Its use in this age group raises concerns regarding the potential interference with ongoing neurodevelopmental processes. Particularly the hippocampus is a highly plastic brain region that continues to develop postnatally and is involved in cognition and emotional behavior, functions known to be affected by MPH. ⋯ Irrespective of the age of treatment, MPH affected topological features of ventral hippocampal functional networks. Thus, chronic oral treatment with a therapeutically relevant dose of MPH preferentially affected the ventral part of the hippocampus and induced contrasting effects in adolescent and adult rats. The differences in behavior were paralleled by opposite effects on adult neurogenesis and granule cell proliferation.