Stress response and PTSD Dendritic spines, post-synaptic structures receiving mainly excitatory input, are sensitive to experiences in development including stress episodes or drugs. Studies have shown that prenatal stress reduces complexity, length, and spine frequency of layer II/III pyramidal<unk> s in rat and primate models. Dendritic atrophy has been described in hippocampal formation and prefrontal cortex in both models. Chronic stress has been shown to reduce the arbor complexity and total dendritic length of<unk>  trees of CA3 pyramidal neurons in the hippocampus as well. Chronic stress-induced changes in behavior have usually been attributed to changes in the hippocampus which is a primary neural target of glucocorticoids and is involved in many of the behaviors altered by corticosteroid administration. Both chronic stress and corticosteroid administration result in extensive atrophy of<unk> s of pyramidal neurons in hippocampal area CA3, and these dendrites do not atrophy when cyanoketone (a corticosteroid blocker) is given. This dendrite atrophy is mediated by both glutaminergic and serotonergic systems (administration of either NMDA receptor antagonist CGP 43487 or serotonin uptake inhibitor tianeptine prevents atrophy). Cell death has been reported to prolonged treatment. Stress hormones in small doses do not themselves cause damage but magnify effects of other dangerous agents, including excitotoxins, hypoglycemia, hypoxia and ischemia. Damaging effects of stress in these neurons are thought to be related to expression of brain-derived neurotrophic factor (BDNF), the expression of which is reduced in stressed conditions and increased with the administration of anti-depressants. The prefrontal cortex is also a target for the glucocorticoids in stress (3Hdexamethasone binds to receptors in frontal and prefrontal cortex at about 75% of concentration of hippocampus). Endogenous regulation of corticosteroid receptors is indicated by altered binding of the previously mentioned compound in the prefrontal cortex with administration of corticosteroids. Furthermore, regulation of stress activities involves the prefrontal cortex. Lesions in rat prefrontal cortices impair spontaneous alternation, radial maze performance, and passive avoidance. In primates these impair inhibition of line-of-sight responses. Chronic administration of corticosteroids decreases 5-HT1A receptor binding, 5-HT2 receptor binding, serotonin levels, and expression of neural cell adhesion molecule (a cell-surface macromolecule involved in regulating aspects of synapse stabilization). These changes indicate structural change follows stress hormone elevation. Studies of dendritic morphological changes indicate that elevation of stress hormones in layer II-III of the prefrontal cortex causes no observable change in the structure or distribution of basal dendrites. The<unk> s, however, show a significant redistribution in stress-hormone treated animal brains, which is measured using Scholl analysis. Scholl analysis estimates the amount and distributions of dendrite material by counting numbers of intersections of dendrites with an overlay of concentric rings centered at the soma. Medial prefrontal cortex layer II-III pyramidal neurons showed significant reorganization with a 21% increase in proximal<unk>  arbors and a decrease of 58% in distal<unk>  arbors. These results are in contrast to the changes in the hippocampal CA3 dendritic arbors, in which only regressive changes were observed. One possible explanation proposed in these studies is that the atrophy of distal dendrites in II-III layer pyramidal neurons results directly from the loss of input from changed CA3 pyramidal neurons, as both CA1 and CA3 project directly into the medial prefrontal cortex. It has been determined from electrophysiological data that excitatory synapses on proximal<unk> s of prefrontal cortex pyramidal neurons serve to amplify excitatory post-synaptic potential (EPSP) signals generated in distal<unk> s. This suggests that reduction in distal dendrite mass due to the stress hormone elevation may result in an increase in proximal<unk>  complexity as the proximal<unk> s attempt to offset the reduced distal<unk>  signals. Serotonergic alterations and alterations in glutamate release in the prefrontal cortex indicate that the neurochemical mechanisms altering structure in both the hippocampus and prefrontal cortex are similar. The division of management between extrinsic and intrinsic inputs to the dendrites in the piriform cortex (mentioned above) is also seen to a lesser degree in the medial prefrontal cortex. This indicates that stress-induced changes to<unk> s increase the relative emphasis of intra-cortical signals at the expense of extra-cortical signals. In studies of hierarchical animals, it was observed that the dominant and subordinate animals show the same degree of dendritic reorganization, indicating that the dendritic atrophy with stress is not degree-dependent. Metabolic disease In neurometabolic diseases, distended storage neurons are markedly swollen and pear shaped, with the nucleus and the nissl bodies displaced toward the<unk> s. Examples of neuron metabolic storage diseases are the sphingolipid storage diseases which typically involve malfunctioning hydrolases in the lysosomes responsible for the degradation of these lipids: #type 2 and type 3 Gaucher disease #GM1 gangliosidosis and GM2 gangliosidosis This swelling is shown, for instance, in Tay–Sachs disease, a GM2 accumulation due to defective beta-hexosaminidase. Visible in this disorder are large mega-neurite formations. Epilepsy Cellular mechanisms It has been indicated that there is a "chicken and egg" issue in the study of models relating to epilepsy because on the one hand the models are used to study the genesis of epilepsy and on the other they are used to study changes in prolonged events. The question arises, therefore, of whether the resulting data of the models indicated an exaggerated defect responsible for the genesis of seizures or whether the data indicated systemic changes to normal tissue after prolonged seizure activity. Calcium currents, normally prominent in CA1 hippocampal neurons are increased in response to status epilepticus. There is evidence that current in T-type calcium channels is increased specifically in<unk> s. The hypothesis is that this phenomenon creates a situation in which fast sodium spikes in the soma back-propagate into the dendrites, whereby they detonate bursting. Dendritic potentials (DPs) also undergo changes. Elicitation of DPs during seizure activity showed that they were much smaller than controls. However, DPs elicited just after seizure termination lasted for longer periods, indicating that suppression of the DP is correlated with the seizure activity itself. Glutamate is an excitatory neurotransmitter capable of causing a metabolic injury to neurons. In the hippocampus, GABAergic neurons have been found vulnerable to excitotoxic action of glutamate at the kainate receptor. These receptors are most dense in sectors CA3 and CA2 of the hippocampus, where nanomolar (nM) concentrations of kainic acid have been associated with pronounced and persistent depolarization of CA3 pyramidal neurons. This involving the conduction of excitatory activity along the mossy fiber projections from the area dentate granule cells to the CA3 neurons. Stimulation of this receptor type has been associated with paroxysmal spikes similar to seizures. Plasticity in CA1 pyramidal cells and interneurons has been related to CA1 roles in epileptogenesis. CA1 is hyperexcitable when the CA3 region is damaged. Reduction of both GABAA and GABAB IPSPs occurs. GABA interneurons, though intact, become less easily activated. Seizure input from the EC to the dentate gyrus is filtered for both ictal and normal activity patterns, while CA3 cells impose an inter-ictal profile, reinforcing abnormal activity. Hyperventilation leads to a marked surface negative direct current shift due to depolarization of the<unk> c trees of the cortical pyramidal cells. This shift is likely to represent the increased excitability of the cortical neuronal networks and may explain the resultant potential epileptogenicity. Certain anti-epileptic drugs have the opposing effect of reducing surface negativity in normal controls. Temporal lobe epilepsy Changes in expression of potassium channels and of potassium currents have been described in a model of temporal lobe epilepsy. In this model, there is downregulation of the A-type encoding Kv4.2 channel. This channel is involved in limiting backpropagation of action potentials and in reducing the transfer of excitatory postsynaptic potentials (EPSPs) from<unk> s into the soma. In the same model, the aforementioned upregulation of t-type calcium channels also has been shown to result in increased burst behavior in neurons in the hippocampus. Infantile seizures and associated memory impairment Neuronal death does not appear to contribute to the learning deficits in rats with infant seizures. CA3 neurons in the tetanus toxin model of early onset epilepsy, however, show a reduction in the branching complexity of basal dendrites as well as a decrease in the spine density on both the<unk> s and the basal dendrites. Similar data have been taken from epileptic human patients during surgical procedures. In neocortical and hippocampal foci, a decrease in length and branching complexity of dendritic arbors and a reduction in the branching complexity of the remaining dendrites were observed. The chronic alumina cream model of epilepsy in primates has produced similar data. Because dendrites and their spines are sites of excitatory synaptic input onto neurons, the results suggest that the glutaminergic synaptic transmission may be reduced. As these are sites active in long-term potentiation (LTP) and other alterations in synaptic transmission that underlie learning and memory, changes at these sites could explain learning and memory deficits associated with both early-onset and long-term epilepsy. Schizophrenia In individuals with schizophrenia, post-mortem analysis has indicated a decrease of GABAergic cells and activity in the hippocampus. Human neocortical heterotopia Heterotopia
Apical dendrite
Basal dendrite
Specific granule
Azurophilic granule
Growth cone
Axon terminal
Cortical minicolumn
Inner plexiform layer