The nature of an endophenotype is biologically defined on the basis of neuropsychological, cognitive, neurophysiological, neuroanatomical, biochemical, and brain data. Endophenotype is an internal phenotype, which is a set of objective characteristics of an individual that are not visible to the unaided eye. A given phenotype would not be limited to a patient with a particular diagnosis; for instance, schizophrenia might also be found in patients with other diagnoses, such as depression or bipolar disorder.

The human brain contains approximately 100 billion nerve cells or neurons. In general, neurons are composed of four morphologically identified regions: (1) the cell body or soma, which contains the nucleus and can be considered the metabolic center of the neuron; (2) the dendrites, which are processes that arise from the cell body, branch extensively, and serve as the major recipient zones of input from other neurons; (3) the axon, which is a single process that arises from a specialized portion of the cell body (the axon hillock) and conveys information to other neurons; and (4) the axon terminals, which are fine branches near the end of the axon and that form contacts (synapses) generally with the dendrites or the cell bodies of other neurons, release neurotransmitters, and provide a mechanism for interneuronal communication. Most neurons in the human brain are considered to be multipolar in that they give rise to a single axon and several dendritic processes.

Research has shown that in a significant number of patients with schizophrenia, the prefrontal cortex exhibits a reduced density of interneurons in layer 2. Additionally, these patients show an upregulation of GABA_A receptor binding, a potential functional compensation, as well as a relative deficiency of nitric oxide synthase (NOS)-expressing neurons. These observations have led to the hypothesis that schizophrenia is due to reduced GABAergic activity. The origin of GABA interneurons from the ganglionic eminences and their association with specific patterning genes raises new genetic models of disease causation and possible strategies for disease intervention.

The cell bodies of the serotonergic neurons are located in the midline raphe nuclei of the brainstem. The dopamine neurons are located in the midbrain substantia nigra and the ventral tegmental areas as well as in the periaqueductal gray, hypothalamus, olfactory bulb, retina, and kidney. The norepinephrine and epinephrine producing neurons are found in the pons and medulla in two major clusters: the locus ceruleus and the lateral tegmental noradrenergic nuclei. These neurons are also found in the adrenal medulla. Histaminergic cell bodies are located within the region of the posterior hypothalamus termed the tuberomammillary nucleus.

This degeneration characteristically results in a depletion of GABA, the brain’s major inhibitory neurotransmitter, and acetylcholine. Huntington’s disease is an autosomal-dominant neurodegenerative disorder characterized by cognitive and physical decline. Its etiology involves an abnormal expansion of a trinucleotide repeat on chromosome 4. MRI classically reveals bilateral atrophy of the caudate nucleus and putamen of the basal ganglia. CT scan further reveals a prominence of the lateral ventricles as a result of surrounding atrophy. Huntington’s disease has a gradual onset between the ages of 30 to 50 years. Key features of the disease include progressive subcortical dementia, chorea (rapid, involuntary, dance-like movements), depression, and psychosis. Dysfunction of GABAergic neurotransmission has further been implicated in anxiety disorders, schizophrenia, alcohol dependence, and seizure disorders. Pick’s disease is due to an accumulation of tau proteins, which lead to degeneration of the frontal and temporal lobes. Onset of Pick’s disease is between the ages of 40 to 60 years and initial signs include personality change, language impairment, and memory loss. Vascular or multi-infarct dementia presents acutely with cognitive decline following a cerebrovascular event and has a stepwise progression. Creutzfeldt-Jakob disease is a rare spongiform encephalopathy accompanied by rapidly progressive dementia and hallucinations. It is caused by an accumulation of prions leading to nerve cell death. Normal-pressure hydrocephalus clinically presents with the triad of dementia, incontinence, and gait disturbance. It is due to poor reabsorption of CSF and characterized by widening of the lateral ventricles.

Neuropeptides represent the most diverse class of signaling molecules in the CNS. They have a role in the hypothalamic regulation of pituitary hormone secretion. They also have an array of direct or neuromodulatory effects, ranging from modulating neurotransmitter release and neuronal firing patterns to the regulation of emotionality and complex behavior. More than 100 unique biologically active neuropeptides have been identified in the brain, a subset of which is presented in Table 1.1.