HO for Biology of Mental Disorders (BCS 246)
Lecture 12 (10/24; NOTE: lectures 8-10 on Mesulam pp. 1-49)

• Seems this should be obvious but there are still those who would argue
• Further, the study of the brain gets very little attention in psychiatric training (although most all have considerable time spent on psychopharmacology)
• Compares this to cardiologist that ignores the heart in thinking about his practice

• Genetic theories based on the structure of the DNA (deoxyribonucleic acid) molecule and its spontaneous and random mutations and segment recombinations
• Double helix
• Two sugar-phosphate chains held together by bonds between complementary "bases"
• Guanine (G)
• Cytosine (C)
• Adenine (A)
• Thymine (T)
• Base sequences are critical to the construction of all proteins of the body through creation of mRNA and attachment to ribosomes
• Amino acids (20 total) are coded by triplets of bases on mRNA
• Combinations of amino acids form proteins of the body, genes linked to specific proteins
• One DNA molecule per chromosome with 100,000 genes
• Only small part of genetic material actually codes for proteins, much repetitive and involved in stopping/starting of coding etc. with genes turned on and off at different times (even within a day)
• 30-50% of human genome expressed primarily in the brain !!!
• Linkage studies based on a number of techniques that link particular genetic patterns of the affected individual to those of other affected individuals (and not those without illness)
• Highly similar genetic material in affected suggests this region may be involved in the cause of the illness (much of genome now has "markers" that can be used to detect similarities)
• Huntington's disease first neuropsychiatric syndrome found to have a specific (and dominant) genetic defect, this being on chromosome 4
• Problems with genetic linkage studies of psychiatric syndromes include:
• Incomplete penetrance (looks neither dominant or recessive in nature)
• Age of onset of illness problems
• Variable expression of illness related to genetic abnormality (more than one way the genetic abnormality can be expressed, i.e. different "phenotypes" same "genotype")
• Genetic heterogeneity (more than one genetic abnormality "genotype" leading to same illness; or multiple genetic abn. needed [polygenic non-Mendelian inheritance])
• Many studies have shown linkage in psychiatric illnesses (schizophrenia, manic depressive illness) only to have the findings not replicated in other linkage studies with other families
• Could be any of the above problems, but many feel that genetic heterogeneity, incomplete penetrance, and polygenic inheritance most likely causes (age of onset now controlled in most studies)

• Major nutrient for brain activity is glucose (oxidation, see p.50; catabolism, p. 51), with lesser dependence on breakdown of proteins and fatty acids
• Glucose oxidation and catabolism yields ATP (from ADP) which can be used to "fuel" cellular transport and biosynthesis in the brain (catabolism results in lactic acid production)
• Transport of ions across membranes against gradients
• Transport of substances within the neurons
• Formation (biosynthesis) of substances necessary to neural functioning
• Glucose oxidation results in formation of CO2 and water
• Important in that a number of methods of measuring metabolic activity of the brain are based on:
• Oxygen consumption over brain regions, which is correlated with cellular metabolism of the brain (Xenon inhalation method, rather dated)
• Blood flow to brain regions, which is correlated with cellular metabolism in that area due to very sensitive and localized modulation of circulation based on oxygen need
• Actual regional glucose metabolism of the brain (positron emission tomography; PET)

• Double layer structure, composed of lipids (mainly fatty acids) and protein
• The polar (hydrophilic, [likes water]) ends of the lipids align outward from the middle of the membrane so that both the interior and exterior layers are polar and allow polar compounds to enter easily
• The center of the membrane is the non-polar (hydrophobic, [doesn't like water]) end of both
• the outer and inner lipid layer, with this area not allowing polar compounds to cross easily
• Cell membrane is therefore "semi-permeable" with many substances unable to cross without " active transport"
• Ionic imbalances across this membrane are essential for its polarity and "excitability"
• Protein aggregates in the bilayer of lipid make up the "channels" that regulate permeability (actually the site of much of the inflow and outflow of ions)

• Neurons are polar with greater negativity on inside and positivity on outside
• A "resting potential" of approximately 50-60 mV is typical (pictoral representation shows resting potential of -75 mV inside, which is more typical in other texts (vs. 50-60)
• Ions that result in polarization include and this "resting potential" include:
• Sodium (Na+)
• Potassium (K-)
• Chloride (Cl-)
• Organic anions (A-)
• Inside cell: lower concentration of sodium and chloride than outside due to active sodium pump; higher conc. of potassium and organic anions (overall negative charge)
• Sodium pump uses much of the energy of the brain and the resting potential can be seen as an energy store, with neuronal action dependent on it
• Action potential results from the depolarization of membrane on inside to the critical firing level (CFL) or threshold
• Firing or action potential due to rapid opening of sodium channels allowing inflow of sodium (causing relative positivity with loss of negative charges), which also causes other sodium channels to open
• Very rapidly after this, there is an opening of channels allowing outflow of potassium (gated voltage dependent channels) which results in loss of positive ions and "repolarization" of neuron to take place (i.e. return of greater negativity and "resting potential")
• This usually results in a hyperpolarization, with greater negativity than the resting potential and a time that the neuron is very difficult to "fire" (refractory period)
• Depolarization spreads down the nerve axon at a rate generally based on the diameter of the axon (larger axons, faster conduction times); myelinated axons conduct much faster than non-myelinated, this referred to as saltatory conduction (node to node)
• Other substances also important to "healthy" firing and conduction, including magnesium (Mg+) and calcium (Ca+)

• Chemical synapse
• Main synapse of human brain (synaptic cleft)
• Distance across synapse is much greater than for electrical synapse
• vesicles for neurochemicals present in presynaptic terminals
• Time to affect next neuron longer than for electrical but more "flexible"
• Electrical synapse
• Fewer of these in brain
• Much shorter distance from pre to post synaptic neuron
• Faster than chemical synapse but less "flexible" in the information transferred
• Transmission over the synapse results in either excitatory post synaptic potentials (EPSPs) or inhibitory post synaptic potentials (IPSPs). Note: in book called EPPS and IPPS respectively
• Inputs from one synapse not critical
• Summation of all synaptic inputs on a target neuron is what is critical, with predominantly EPSP activity causing greater depolarization (i.e. positivity inside), possibly reaching the CFL, and resulting in the firing of the neuron; vs. overall IPSP predominance and greater polarization and negativity in the cell, and no firing or decreased cell firing
• Calcium very important in cell firing and synaptic release
• Despite firing, there is room for modulation of transmitter release through a number of mechanisms, including calcium content and presynaptic enzyme activity (that produces the transmitter)
• Presynaptic function can also be affected by "autoreceptors" that are stimulated by the released transmitter and "turn down" the neuron as well as other messengers such as nitrous oxide (diffuses back from post synaptic receptor area), which may affect presynaptic neuron through calcium channel changes
• Classical neurotransmission
• Release of transmitter has rapid action on very small area postsynaptically (motor neurons and much of brain neuronal transmission)
• Diffuse neurotransmission
• Transmitter release affects larger area of neurons and for longer time (ex. amines, opiates)