Neurons malfunction

Mental disorders, also called affective disorders, are multi-level, multi-scale and multiple-system diseases (Fig. 7.1). Mental disturbances generally go along with disturbances of autonomous functions. These essentially are (1) sleep disturbances, both sleep duration and sleep pattern, and (2) disturbances of the hypothalamic-pituitary-adrenal (HPA) axis, the so-called stress axis with elevated cortisol levels. It can be expected that disturbances of autonomous control systems as well as mood are caused by neuronal malfunctioning which may concern practically all neuronal levels systemic interactions, neuronal network connections, single neuron dynamics, synaptic transmitters and/or receptors, ion channels, second messengers, and gene expression (Fig. 7.1a). Nevertheless, despite a manifold of data, there are only vague ideas so far about the differences in neuronal dynamics in the brain of a chronically depressed person compared with a person with a sensitive but balanced mood. 

This data, coupled with numerous positive outcome studies of the effectiveness of antidepressants, has led to the development of the monoamine (or biogenic amine) hypothesis of depression. The theory holds that depressive symptoms are ushered in by a malfunction of either norepinephrine (NE) or serotonin (5-HT) neurons, which play critical roles in the functioning of the limbic system and the adjacent hypothalamus. The basic neuronal malfunction is felt to be identical for either NE or 5-HT neurons, thus what follows (a description of the pathophysiology of NE neurons) can also be seen to occur in individuals in whom 5-HT neurons are affected. For reasons that are not well understood, patients with major depression (with vegetative symptoms) appear to suffer from either NE or 5-HT dysfunction, but probably not both simultaneously (although some exceptions exist). 

Bacosides are most popular for their effect on nervous system mainly because of their neuroprotective activities. Neuroprotection signifies the mechanisms and strategies used to protect neuron from degeneration or malfunctioning. Various factors may involve in neuron malfunction (Fig. 120.2). Some of these factors are neuronal injury, exposure to chemical agents, adverse physiological conditions, and different disorders or diseases either decreasing efficiency of proper nervous... 

NHE5. The distribution of this isoform is distinct, being in neuronal-rich areas of the central nervous system. Low levels have also been found in testis, spleen and skeletal muscle. Like the preceding isoforms, NHE5 is found in the plasma membrane and is internalised by clathrin-associated endocytosis into recycling endosomes. The normal role of NHE5 is unknown but its malfunction is speculated to contribute to the development of neurodegenerative disease. 

While there are some reports of increased NMDA and non-NMDA receptor number in various cortical regions of schizophrenics including the prefrontal cortex, there are also indications of impaired glutamate innervation, such as reduction in its neuronal uptake sites (Ishimaru, Kurumaji and Torn 1994). Also it has been found that levels of the mRNA for the NRI subunit of the NMDA receptor in the hippocampus and its D-aspartate binding sites in the temporal cortex are both reduced more on the left than right side in schizophrenic brain. This is another indication of greater malfunction on the left side of the brain and the possibility that some schizophrenic symptoms arise from an imbalance between cross-cortical activity. 

One possibility is that even with a potentially effective drug, the necessary readjustments in the neuronal circuitry to reverse or compensate for the disorder-induced malfunction just requires time. Another hinges on the degree of polarisation of AlO and A9 neurons. 

One of the striking aspects of this toxicity of compounds is selective destruction terminals and the cell bodies that are left intact. Dr. De Souza has recently reported some biochemical evidence for recovery of serotonin. We have now found anatomic evidence for reinnervation of depleted areas by serotonin neurons. But it is going to be a while before we figure out whether their reinnervation is appropriate or perhaps aberrant. Do they end up with complete recovery, do they end up with a better system than they started with or one that malfunctions I think that is an important area for future study. 

Alterations in the ubiquitin-proteasome pathway have been connected to several neurodegenerative diseases (Table 9). In some instances, mutations in specific genes have been linked to the etiology of the disease. Although the perturbations in ubiquitin-proteasome-mediated proteolysis lead to pleiotropic effects on neurons including cell death or degeneration, one of the early effects is believed to be synaptic malfunction. 

There are a myriad of known and suspected mechanisms by which diseases can modify chemical neurotransmission. These can vary from no transmission, as in the case of a degenerated or absent neuron, to too much neurotransmission from a malfunction of the synapse. One of the key consequences of loss of neurons in neuro-degenerative disorders such as Parkinson s disease, Huntington s disease, amyotrophic lateral sclerosis (Lou Gehrig s disease), and Alzheimer s disease, is the fact that no neurotransmission occurs subsequent to neuronal loss (Fig. 4—24). This is a conceptually simple mechanism of disease action with profound consequences. It is also at least in part the mechanism of other disorders, such as stroke, multiple sclerosis, and virtually any disorder in which neurons are irreversibly damaged. 

FIGURE 5—23. Most of the cell bodies for notadrenergic neurons in the brain are located in the brainstem in an area known as the locus coeruleus. This is the headquarters for most of the important notadrenergic pathways mediating behavior and other functions such as cognition, mood, emotions, and movements. Malfunction of the locus coeruleus is hypothesized to underlie disorders in which mood and cognition intersect, such as depression, anxiety, and disorders of attention and information processing. 

Neurons communicate unidirectionally. Information (excitation) is received via the dendrite(s) and is passed through the cell body, along the axon, and out the bouton to the next neuron at a point of close proximity the synapse. The majority of biologically based mental disorders can be traced to abnormalities in neuronal conduction at the synapse. Let s take a look at normal synaptic transmission and then see how this process can malfunction. 

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