10 Cohen and pfaff for mitochondria in these cell types, whereby mito- 2.4.3. MITOCHONDRIA AND NEURODEGENERATIVE chondria affect nerve transmission and vice versa. AND PSYCHIATRIC DISORDERS lion ng development, mitochondria appear to func- Mutations in mitochondrial DNA may result in as a determinant of neuronal polarity, in the the maternal transmission of neurologic disorders control of neurite outgrowth, and the differentiation These appear to include some cases of schizophrenia of neurons from precursor cells. They also play a some neuropathies, and retinitis pigmentosa. Mito- role in adult plasticity by influencing neurotransmit- chondrial dysfunction may also be involved in Alz ter release from presynaptic terminals, possibly via heimer's and parkinson's diseases. as well as stroke their role in calcium signaling On the postsynaptic In these cases, age-related changes in neuronal meta neurons for glutamate. Notably, environmental fac- tion may indicate prior age-related changes in tors, which may also influence plasticity, appear to calcium balance and interfere with synaptic plasticity affect mitochondria. Rats kept in an enriched envir- Moreover, accumulation of cytotoxic forms of cer onment, resulting in enhanced performance of a tain proteins implicated in Alzheimer's disease may spatial memory task, display an increase activity of result in mitochondrial dysfunction and/or displace- some mitochondrial proteins. That synaptic activity ment. For example, defects in the human presenilin 1 can alter mitochondrial biochemistry and function is gene, which is implicated in an aggressive form of evidenced by the upregulation of mitochondrial early-onset familial Alzheimer's disease, appear to genes by high-frequency stimulation of a tissue compromise kinesin-based axonal transport in neu- slice from the hippocampus rons Kinesin is a molecular motor important in ante- In terms of ATP many neuronal functions require rograde axonal transport. Neurons with the mutant ergy, including those functions associated with the form of presenilin I display reduced mitochondrial cytoskeletal proteins, as well as those involving phos- density in neuritic processes. In regard to other psy phorylation Calcium influx and its sequestration and chiatric disorders, patients with bipolar disorder release are also essential to neuronal function, and appear to shift their metabolism toward glycolytic- mitochondria are also key players here. The produc- based energy production, as opposed to one that tion of reactive oxygen species by this organelle may involves oxidative phosphorylation. Moreover, be involved in cell signaling, as well as membrane some patients with schizophrenia display fewer mito- lipid peroxidation, which, in turn, alters membrane chondria in specific brain regions, and neuroleptic protein function drugs appear to reverse this phenomenon Mitochondria play a role in apoptosis, a type of programmed cell death. Part of this process is mediated by Bcl-2 family members, which interact 3. CYTOSKELETON DETERMINATION OF with mitochondrial membranes to either increase or NEURONAL FORM decrease their permeability, resulting in apoptosis or, A singular feature of neurons is their overall extra alternatively, stabilize the membrane to check this ordinary length, enabling them to transmit signals process. During the process of apoptosis, mitochon- over great distances. This property is reflected in the drial membranes exhibit increased permeability and polarity of neuronal form and function, which is release cytochrome c Cytochrome c itself can activate governed by regional specialization of the plasma caspase-3, which, in turn, may cleave some protein membrane and by differences in the cytoskeletal com- substrates resulting in cell death. On the other hand, position of dendritic and axonal processes emerging when activated at sublethal levels, some caspases in from the cell body. Although the neuronal cytoskele synapses and dendrites may cleave specific glutamate ton provides a structural framework on which var receptor subunits, thereby modulating synaptic ious organelles and cellular events are organized, it is by no means a static configuration. Throughout the GTP binding protein-coupled receptors for neuro- neuron, molecular alterations in cytoskeletal proteins ransmitters and neuropeptides, glutamate, and neu- reverberate as microscopically visible changes in rotrophic factors can also affect mitochondria via movement of the cytoskeleton, its associated orga second-messenger pathways. These pathways target nelles, and the shape and extent of some of the pro- gene transcription factors, with the possibility of cesses. Although the cytoskeleton permits the general encoding proteins relevant to synaptic and neuronal pattern of individual neurons to remain constant and identifiable, alterations in cytoskeletal dynamicsfor mitochondria in these cell types, whereby mito￾chondria affect nerve transmission and vice versa. During development, mitochondria appear to func￾tion as a determinant of neuronal polarity, in the control of neurite outgrowth, and the differentiation of neurons from precursor cells. They also play a role in adult plasticity by influencing neurotransmit￾ter release from presynaptic terminals, possibly via their role in calcium signaling. On the postsynaptic side, mitochondria appear to affect the sensitivity of neurons for glutamate. Notably, environmental fac￾tors, which may also influence plasticity, appear to affect mitochondria. Rats kept in an enriched envir￾onment, resulting in enhanced performance of a spatial memory task, display an increase activity of some mitochondrial proteins. That synaptic activity can alter mitochondrial biochemistry and function is evidenced by the upregulation of mitochondrial genes by high-frequency stimulation of a tissue slice from the hippocampus. In terms of ATP, many neuronal functions require energy, including those functions associated with the cytoskeletal proteins, as well as those involving phos￾phorylation. Calcium influx and its sequestration and release are also essential to neuronal function, and mitochondria are also key players here. The produc￾tion of reactive oxygen species by this organelle may be involved in cell signaling, as well as membrane lipid peroxidation, which, in turn, alters membrane protein function. Mitochondria play a role in apoptosis, a type of programmed cell death. Part of this process is mediated by Bcl-2 family members, which interact with mitochondrial membranes to either increase or decrease their permeability, resulting in apoptosis or, alternatively, stabilize the membrane to check this process. During the process of apoptosis, mitochon￾drial membranes exhibit increased permeability and release cytochrome c. Cytochrome c itself can activate caspase-3, which, in turn, may cleave some protein substrates resulting in cell death. On the other hand, when activated at sublethal levels, some caspases in synapses and dendrites may cleave specific glutamate receptor subunits, thereby modulating synaptic plasticity. GTP binding protein–coupled receptors for neuro￾transmitters and neuropeptides, glutamate, and neu￾rotrophic factors can also affect mitochondria via second-messenger pathways. These pathways target gene transcription factors, with the possibility of encoding proteins relevant to synaptic and neuronal plasticity. 2.4.3. MITOCHONDRIA AND NEURODEGENERATIVE AND PSYCHIATRIC DISORDERS Mutations in mitochondrial DNA may result in the maternal transmission of neurologic disorders. These appear to include some cases of schizophrenia, some neuropathies, and retinitis pigmentosa. Mito￾chondrial dysfunction may also be involved in Alz￾heimer’s and Parkinson’s diseases, as well as stroke. In these cases, age-related changes in neuronal meta￾bolism as a consequence of mitochondrial dysfunc￾tion may indicate prior age-related changes in calcium balance and interfere with synaptic plasticity. Moreover, accumulation of cytotoxic forms of cer￾tain proteins implicated in Alzheimer’s disease may result in mitochondrial dysfunction and/or displace￾ment. For example, defects in the human presenilin 1 gene, which is implicated in an aggressive form of early-onset familial Alzheimer’s disease, appear to compromise kinesin-based axonal transport in neu￾rons. Kinesin is a molecular motor important in ante￾rograde axonal transport. Neurons with the mutant form of presenilin 1 display reduced mitochondrial density in neuritic processes. In regard to other psy￾chiatric disorders, patients with bipolar disorder appear to shift their metabolism toward glycolytic￾based energy production, as opposed to one that involves oxidative phosphorylation. Moreover, some patients with schizophrenia display fewer mito￾chondria in specific brain regions, and neuroleptic drugs appear to reverse this phenomenon. 3. CYTOSKELETON DETERMINATION OF NEURONAL FORM A singular feature of neurons is their overall extra￾ordinary length, enabling them to transmit signals over great distances. This property is reflected in the polarity of neuronal form and function, which is governed by regional specialization of the plasma membrane and by differences in the cytoskeletal com￾position of dendritic and axonal processes emerging from the cell body. Although the neuronal cytoskele￾ton provides a structural framework on which var￾ious organelles and cellular events are organized, it is by no means a static configuration. Throughout the neuron, molecular alterations in cytoskeletal proteins reverberate as microscopically visible changes in movement of the cytoskeleton, its associated orga￾nelles, and the shape and extent of some of the pro￾cesses. Although the cytoskeleton permits the general pattern of individual neurons to remain constant and identifiable, alterations in cytoskeletal dynamics 10 Cohen and Pfaff