NeuroPhys Unit 2

• 1) Tissue forms neural tube
• -Begins as a flat disk = neural plate
• -Three distinct layers
• --Endoderm, Mesoderm, Ectoderm
• 2) Brain formation begins when ends of neural tube close

Thickening of ectoderm on surface of embryo

Edges of plate fold and edges grow toward each other

• When folds touch; cervical region 1st
• "zips" closed rostrally and caudally, open ends=neuropores
• -Becomes spinal cord

• Cells adjacent to neural tube that separate from tube and ectoderm
• -Becomes the PNS
• When crest is developed, tube and crest move inside the embryo

• 1) Cell proliferation
• 2) Cell migration
• 3) Cell differentiation
• 4) Axon extension to targets
• -Axonal growth
• -Fasciculation
• -Axon growth
• 5) Synapse formation
• 6) Synapse elemination
• 7) Synaptic capacity
• 8) Synaptic rearrangement
• 9) Hebbian modification
• 10) Apoptosis

• Ventricular zone
• Cells undergoing DNA replication and division
• Neurons and some glial cells
• Lining of ventricles
• Formed 1st
• Marginal zone
• Processes of cells in ventricular but do not contain their nuclei
• Almost no cell bodies
• Formed 2nd
• Intermediate zone
• Between ventricular and marginal
• Formed last
• Cells migrate here from ventricular zone

• Cell in ventricular zone extends a process up to pia
• Nucleus of cell migrates up toward pial surface (outer edge of Marginal Zone) and DNA is copied
• Nucleus, with 2 complete copies of genetic instructions, settles back to surface (of Ventricular Zone)
• Cell retracts its process from pial surface
• Cell divides in two = two new daughter cells

• Migrate to final location
• -Send slender process to brain surface and hoist selves along
• -Climb along radial glia
• *Cortex formed "inside-out"
• *Neurons differentiate after reaching final location; function depends on area of brain

• Newly generated cell take on appearance and characteristics of a neuron
• -Neuronal differentiation occurs first
• -Followed by astrocyte differentiation
• -Then oligodendrocyte differentiation

• The growth cone
• -Samples environment and searches for chemical cues

Axons growing together stick together

• Chemoattractant
• -Netrin = a protein that attracts neurons in spinal cord to cross the midline
• Chemorepellent
• -Robo = a protein that repels the axon to grow away from the midline

Agrin molecules 'mark the spot'

• Initially, each muscle receives input from several alpha motor neurons 
• During development, all but one are lost
• One to one relationship est.

Space for only a finite number of synapses

• Segregation
• Convergence

• Synaptic plasticity
• -Changing from one pattern to another
• -Synaptic competition causes modification
• -"Neurons that fire together, wire together"

• New cells are born in the ventricular zone
• Migrate through the white matter to the cortex
• Found in the association areas of the temporal and frontal lobes

• "split spine"
• Defect of neural tube where portion fails to form or close
• -Results in defects in the spinal cord or vertebrae
• Level of protrusion correlates with fetus's neurological, motor and sensory deficits

• No definitive known cause
• Environmental and genetic factors
• -Race (whites and hispanics)
• -Family history
• -Folate deficiency
• -Some medications
• --anti-seize medications during pregnancy
• -Diabetes, obesity

• Aka Tethered cord syndrome (TCS)
• Form of Spina Bifida
• Infant born with small dimple in back
• Other signs include small tufts of hair, red marks, hyper pigmented patches, or small lumps
• Often located near S1 and S2
• Spinal cord may not grow the right way as a child ages and result in damage
• Common sx: bladder/bowel incontinence, asymmetrical leg/feet length, back pain

• "Hidden" Spina Bifida
• Mildest and most common form
• Small gap in spine with no sac protruding
• Layer of skin covers the opening to the vertebral column
• Usually no disabilities or symptoms

• Form of Spina Bifida
• Sac of fluid comes through the vertebrae but spinal cord does not
• Spinal fluid and meninges protrude through vertebral opening
• Typically no nerves are damaged
• Minor disabilities may occur

• Form of Spina Bifida
• Most severe
• Sac of fluid containing parts of spinal cord and nerves come through opening in spine causing nerve damage
• Moderate to severe disabilities
• -70-90% also have hydrocephalus

• Sensory loss in legs, feet, or arms
• Decreased strength/paralysis
• Increased spasticity
• Lethargy
• Bowel and bladder dysfunction
• Vision problems
• Scoliosis
• Speech
• Renal, cardiac, and orthopedic deformities
• Clubfoot

• Most are of normal intelligence
• Some have learning disabilities
• Academic ability
• Verbal memory
• Perception

• Alcohol crosses the placenta
• -Baby's BAC is equal to mothers
• -Amniotic fluid prolongs exposure to alcohol
• Alcohol alters development in the womb
• -Interferes with delivery of oxygen and nutrients
• -Disrupt cell differentiation and growth
• -Interrupt DNA and protein synthesis
• -Decreased migration of cells
• Irreversible changes to fetus

• Birth defects
• -Structural -> microcephaly; deformed brain structures
• Respiratory complications
• Renal and genital malformations
• Cardiac malformations
• Orthopedic anomalies
• Neurological/CNS
• Functional

• Small eyes with drooping upper lids
• Short upturned nose
• Flattened maxilla/cheeks
• Small jaw
• Thin upper lip
• Elongated midface
• Microcephaly
• Smooth philtrum

• Autism
• Childhood Disintegrative Disorder
• -A marked regression with multiple areas of functioning after a period of at least two years of normal development
• Pervasive Developmental Disorder - Not Otherwise Specified (PDD-NOS)
• -Exhibits some of symptoms of autism but not all of the symptoms
• -"Catch all" category for those who don't fit in other disorders
• Asperger Syndrome
• -Sometimes considered mild form of autism, but NO language delays, cognitive development delays, or delays in developing self-help skills and environment curiosity

• Abnormal cellular configuration/neural structure
• Underdev. of amygdala and hippocampus which are responsible for emotion, sensory input, and learning
• Deficiency of Purkinje cells in the cerebellum = output from cerebellar cortex
• Vermal lobules Vl and Vll in cerebellum are smaller or larger then normal
• Abnormalities of several regions of brain including frontal/temporal lobes and the cerebellum
• More neurons present in select divisions of the prefrontal cortex
• Abnormal biochemistry
• Elevated levels of serotonin, glutamate, and/or acetylcholine in the blood and cerebral spinal fluid
• Elevated levels of beta-endorphins which increases pain tolerance

• Neurotoxicity
• -Lead, mercury, manganese, pesticides, rubella, inflammatory cytokines
• Medical conditions
• -Fragile X, congenital rubella syndrome
• Combination of genetics and environment

• Connectivity density differs from typically developing brain
• Hypo of hyper connectivity presence as a predictor of severity of symptoms
• Extended CNS inflammatory response, activated microglia and inflammatory mediators damage synaptic connections and cause neuronal cell death

• Social/emotional funtioning
• -eye contact, facial gestures, relationships, no shared interests
• Communication
• -Speech delay or absence, inappropriate social uses of language, echolia
• Behavior
• -Intense restricted interests, strictly prefer routines, repetitive motor mannerisms, non-specific motor abnormalities
• Sensory problems
• -Highly sensitive

• Begins before 3 years old
• -Almost 1/2 saw signs by 12 months
• -80-90% saw signs by 24 months
• No cure
• Early identification = better outcomes 
• Co-morbities (mental retardation, etc.) = poorer outcomes
• Severity of manifestations affect outcomes

• Structural defects in cerebellum
• Part of cerebellum located below foramen magnum (instead of above)
• Possibly hereditary
• Most cases are congenital

• Type l - most common
• Extension of cerebellar tonsils into foramen magnum
• Type ll - classic CM
• Extension of cerebellar and brain stem tissue into foramen magnum
• Myelomeningocele
• Type lll - most serious
• Cerebellum and brainstem herniated into the spinal cord
• Type lV - incomplete/underdeveloped cerebellum
• Cerebellar hypoplasia
• -Parts of cerebellum are missing
• Type O - under debate
• No protrusion of cerebellum, but CM symptoms present

• Hydrocephalus
• -Build up of CSF
• Syringomyelia
• -Fluid accumulation in spinal canal -> Cyst formation

• Asymptomatic: regular MRIs to monitor 
• Mild symptoms: headache and pain medication
• Severe symptoms: surgery

• l: not curable, but treatable and rarely fatal
• ll: can be fatal for infants/children
• lll: increased early mortality or severe neurological deficits 
• lV: high infancy mortality

• Overall decrease in brain volume
• Smaller corpus callosum
• Decreased volume in basal ganglia
• Brian regions involved
• Frontal
• Prefrontal - decreased volume
• Parietal lobe
• Cerebellum - decreased volume

• Present before the age of 12
• Chronic
• Inattentive symptoms
• Hyperactivity/impulsivity symptoms

• Damage to CNS (prenatally, perinatally, or postnatally)
• Causes
• Most often due to loss of oxygen to the brain during dev. or infancy
• Others include infection and metabolic abnormalities
• Brain damage is usually hypoxic or ischemic and leads to atrophy and necrosis of brain

• Spastic
• Damage to pyramidal tracts, motor cortex, or genital cortical damage
• Hyperreflexia, spasticity, spastic diplegia, hemiplegia, or quadriplegia
• Dyskinetic
• Damage to extrapyramidal tract, basal nuclei, or cranial nerve
• Athetoid or choreiform movements, loss of coordination with fine movements, facial grimaces, fluctuating muscle tone
• Ataxic
• Damage to cerebellum
• Loss of balance and coordination, gait disturbance
• Mixed
• Damage to areas listed previously
• Symptoms from more than 1 type
• Most common is spastic-dyskinetic CP

• Motor impairments
• Communication/speech
• -Delays in dev or difficulty speaking
• Cognitive impairments
• -Learning disabilities and behavioral problems
• Visual/Hearing Problems
• -Astigmatism and strabismus
• Reflexes
• Posture
• -Head and trunk righting
• Balance
• -Need both hands for support
• Oral motor function

• Formed by proteins
• Use energy released from ATP breakdown to transport ions across membrane

• Sodium-potassium pumps
• Calcium pumps

• Get net movement of ions from area of high concentration to area of low concentration
• Concentration gradient - ions flow DOWN gradient until EQUAL on both sides

Difference in electrical potential across membrane as ions move

• Conveys info over distances in nervous system
• Cytosol is negative; AP is a reversal of this (briefly becomes + = depolarizes)
• Does not lessen as it moves down axon
• Similar in size and duration for all cells
• Convey info through frequency

• Shared by axons in nervous system of ALL animals
• Membrane potential moves from -65mV to around +40mV

• Rising Phase: rapid depolarization of membrane to around +40mV
• Overshoot: when inside has (+) charge
• Falling Phase: rapid depolarization to (-)
• Undershoot/After-hyperpolarization: last part of falling phase when <-65mV
• Restoration of resting potential

• Dependent on magnitude of depolarizing current
• Limited; increase with increased current BUT limit to rate at which neurons fire APs (max = 1000Hz)

• Absolute Refractory Period (ARP)
• Cannot generate another AP from ˜1 ms
• Relative Refractory Period
• Several seconds at end of ARP when difficult to initiate another AP
• -Requires greater current than usual to get AP

• Depolarization to threshold
• Na+ channels open
• Increase in permeability of Na+
• Na+ into cell = depolarization (rising phase)
• Close Na+ channels, open K+ channels
• Increase permeability of K+
• K+ out of cell = depolarization (falling phase)

• Selective pore to Na+
• Opens and closes based on electrical potential of membrane
• Na+ ion is stripped of most but not all water = whats left helps Na+ pass selectivity filter

• Open with little delay
• Stay open 1msec, then close
• Cannot open again until Vm returns to negative value
• Change from -80 to -65 = little effect
• Change from -65 to -4- = open Na+ channels
• Needs 1000s of these in a square micrometer to get an AP

• Problem with Na+ Channels
• Slowing of Na+ channel inactivation = prolonging of APs
• -Ex. epilepsy with seizures

• In puffer fish
• Clogs Na+ pore = blocks AP
• Paralysis of diaphragm due to nerve and muscle block

• Clams, muscles, shellfish that feed on certain dinoflagellates 
• Blocks sodium channel
• Fatal; paralysis of diagram due to nerve and muscle block

• Skin on Colombian frog
• Causes Na+ channels to open at more negative Vm and stay open longer
• Scrambles AP code/info being sent

• Bind to voltage-gated Na+ channels preventing Na+ from docking there = prevents APs
• Affects smaller axons more then large
• -Smaller are more dependent on all channels functioning 
• -eliminating a few with anesthetic prevent AP in axon = no pain sensation

• Open msec AFTER depolarization = slower to open than Na+ channels
• Help with repolarization (falling phase)

V_m where enough voltage-gated Na+ channels open so permeability of Na+ is > permeability of K+

• Negative potential of Na+ ion
• Driving force on Na+ ions so Na+ ions rush into cell causing rapid depolarization
• (Na+ channels open)

Na+ channels close at positive Vm BUT permeability continues to favor Na+ so Vm goes towards E_Na

• Na+ channels inactivate
• K+ channels open (triggered by depolarization but take 1 msec to open)
• -K+ rushes out of cell so Vm moves toward negative

• Open voltage-gate K+ channels PLUS
• normal membrane permeability to K = Vm toward E_k
• Hyperpolarization UNTIL voltage-gated K+ channels close AND Na+ - K+ pump reestablishes resting potential

• Na+ channels are inactive once cell strongly depolarizes
• Cannot active again (No AP can be generated) UNTIL Vm goes sufficiently negative and Na+ channels then deinactivate

Vm stays hyper polarized until Voltage-gated K+ channels close...so even MORE current would be needed to bring Vm to threshold for AP

• Goes ONE direction = does not turn back
• Can be initiated and move EITHER direction (antidronic conduction) though usually only go one way (orthodronic conduction)
• Velocity varies but typically 10 m/sec

• Na+ current during AP depolarizes patch of membrane just ahead of it
• Speed AP goes down axon depends on how far ahead of AP the depolarization is
• -depends on physical characteristics of axon
• 2 paths (+) charge can take (leaky hose)
• -Down inside of axon
• -Across axon membrane
• Narrow axon with many open membrane pores = slower
• Wide axon and few open pores = faster
• Therefore increased axon diameter = increase AP conduction velocity

• Axon size
• # of voltage-gated channels
• Smaller axons require greater depolarization to reach AP threshold (and are more sensitive to anesthetics)

• Large axons conduct AP faster
• Problem - take up space!
• Solution - insulation of axon = myelin

• Layers of glial cells (Schwann cells in PNS and Oligodendrocytes in CNS)
• Facilitate AP movement down axon = increase conduction velocity
• Not continuous along axon
• Breaks where ions cross membrane to generate APs = Nodes of Ranvier
• Voltage-gated Na+ channels are concentrated at membrane of Nodes

• AP is initiated at the axon hillock
• Electrical activity of the first AP spreads and that triggers nearby voltage-gated channels
• Once triggered, another AP occurs in that affected spot
• That next AP current spreads nearby and initiates another AP

When the AP jumps down the axon from node to node

• Attacks the nerves first; demyelination begins later, after nerves have begun to die
• "Lou Gehrig's disease"
• Most common MND; average onset is late 50s
• Progressive CNS degeneration
• No cure, fatal

• Gene mutations
• Amino acid changes
• Excitotoxicity
• Environmental effects
• Neurofilament protein accumulation in cell body and axon
• Autoimmune reaction
• Lack of neurotrophic factors
• -Proteins responsible for growth and survival of developing neurons and maintenance of mature neurons

• Progressive degeneration of MOTOR neurons
• Affects both upper and lower motor neurons
• UMNs in cortex and corticospinal tracts
• Brainstem nuclei for CNss 5,7,9,10,12
• Anterior horn cells of CS
• Spinocerebellar tracts and posterior column
• NOT sensory neurons

• Early
• Exercise intolerance
• Weak voice
• Decreased respiratory abilities
• Difficulty in walking
• Clumsiness
• Muscle twitches
• Progression
• Spasticity
• Progressive muscle weakness
• Slurred speech = dysarthria
• Difficulty chewing and swallowing = dysphagia
• Upper and lower motor neuron symptoms

• Muscle weakness
• Spasticity
• Hyperreflexia
• -Exaggerated reflexes
• Abnormal reflex
• -Babrinski's sign

• Muscle weakness
• Atrophy
• Fasciculations
• Hypotonia
• Areflexia
• Muscle cramping

• Fine movements of a small area of muscle = twitch
• Result in minor local muscle contractions or uncontrollable twitching of single muscle group served by single motor nerve fiber or filament

• Varies by person; no timeline
• -10% live 10 years, 50% live 3 years
• Eventually can't stand, walk, get out of bed, eat, do ADLs
• Eventually can't breathe
• Little to no cognitive changes but...memory and decisions?

• Chronic, often disabling disease that attacks the CNS
• Causes slowed or blocked transmission of signals resulting in MS symptoms
• Randomness of location of attacks, no 2 pts present with the same symptoms

• Inflammation = main cause of the nerve damage
• -Antibodies that attack oligodendrocytes = demyelination
• -Patches of demyelination called Plaques
• Environmental factors

• Re-myelination
• Oligodendrocytes able to re-create a weaker version of the myelin sheath
• Repeated attacks lead to fewer, less effective re-myelinations
• Eventually hard-plaque is built up around damaged axons = "scleroses"

• Series of relapses and remissions
• Back and forth switch between a worsening and an improving of symptoms 
• During relapse often notice loss of function and dev. new symptoms
• Corticosteroids often used to shorten the duration of relapses
• Most common type

• Slow, steady worsening of symptoms
• Gradually become worse over time, though the rate of worsening varies greatly 
• 10% of MS

• Originally diagnosed with relapsing-remitting MS
• -Have stopped having periods of remission and exp. a slow but steady worsening of symptoms
• About 50% of ppl with relapsing-remitting develop this within 10 years

• Have a steady worsening of symptoms along with exacerbations
• Without periods of remission
• 5% of all ppl with MS

• Symptom onset followed by return to normal
• May never have another onset
• May have ongoing incidents with return to normal

• aka Marburg Variant Multiple Sclerosis
• Particularly aggressive form; very rare
• Swift and relentless decline to significant disability or even death
• Often w/in a few weeks or months

• Patients should avoid high temperatures and excessive exercise
• Elevated body temp interferes with activity of axon proteins resulting in decreased AP conduction

• Shortens lives of women 6 years and men 11 years
• Men more common to have progressive
• Suicide is common
• Most have severest disabilities within 5 years of onset

• Progressive neurodegenerative disease
• Most common form of dementia
• Decline of intellectual abilities due to brain tissue death
• Progresses in stages

• No impairment
• Very mild cognitive decline
• Mild cognitive decline
• Moderate cognitive decline
• Moderately severe cognitive decline
• Severe cognitive decline
• Very severe cognitive decline (late-stage Alzheimer's)

• Structures affected
• Cerebral cortex decreases in size due to cell death
• Hippocampus dramatically shrinks
• Ventricles enlarge
• Wernicke's area
• Frontal lobe
• Limbic system
• Parietal lobe
• Brainstem

• Created by Beta-amyloid proteins that stick together
• Block cell communication at synapses
• Glial Cell Theory
• -Amyloid Plaques = Microglial Immune Response = Inflammation/Chemical response = damage to myelin

• Damage to cell-to-cell transport (ex. nutrients)
• Collapses Tau protein that supports these pathways in healthy cells
• Results in cell death and tissue loss

• Beta-Amyloid build up
• Create hard, nondisolvable plaques
• Block synapse, dysfunctional path, cell death

• Tau Protein Atypical
• -Normally > in axons, now > in body and dendrites
• Microtubules fall apart
• -Move nutrients, removes waste, etc.
• Create Neurofibrillary Tanges in neurons = cell death

• Early Alzheimers - 20+ years before diagnosis
• Begin forming in areas of memory
• Thinking, planning
• Moderate Alzheimers - lasts 2 to 10 years
• Wernicke's Area
• Proprioception, confusion
• Severe Alzheimers - lasts 1 to 5 years
• Communication, recognizing people, ADL's comp
• Cell death over majority of cerebral cortex

• Breakdown of late-stage myelin promotes buildup of toxicamyloid-beta fibrils that deposit in brain and become plaques associated with Alzheimer's disease
• Amyloid products destroy more and more myelin
• Disrupt brain signaling and leading to cell death and clinical signs of Alzheimer's

• Memory loss
• Difficulty with problem sovling
• Challenges completing familiar tasks
• Confusion with place or time
• Vision and spatial relationship problems
• Trouble with words in speaking or writing
• Losing items and the ability to retrace steps
• Impaired judgement
• Withdrawal from social activities or work
• Alterations in mood and personality

• Irreversibly damage; no cure
• Drug treatment can only slow progression of symptoms
• Progresses differently for each situation
• Final phase lasts a couple months to several years
• -Unable to understand language
• -Cant recognize family or friends
• -Unable to perform ADLs

• Acute Ideopathic Polyneuritis = rapid onset irritation or inflammation of many nerves of unknown cause
• Typically occurs days to weeks after viral infection
• Mechanism by which virus leads to GBS is not known

• Peripheral nerves are damaged due to autoimmune response
• Damage to myelin in peripheral nerves = decreased nerve conduction
• Results in weakness or, if damage to axons, paralysis
• Affects motor nerves from spinal cord to muscles (limb movements, respiration, swallowing, speech)
• Affects sensory nerves from skin, muscles and joints to the spinal cord
• Ascending - feet up legs to trunk to upper extremities
• No damage to brain, spinal cord, or cranial nerves

• Decreased hot/cold, textures, light touch, proprioception
• Increased parasthesias (numbness or tingling), pain

• Decreased
• Strength/muscle contraction
• Coordination and balance
• Tendon reflexes
• ROM
• Posture
• Fatigue
• Spasticity
• Incontinence 
• Tremors 
• Ataxia

Muscle atrophy

• Mild: lasts days to weeks
• -Waddling gait
• -Tingling and weakness in extremities
• Severe: weeks to months
• -Paralysis
• -Loss of breathing ability/vent dependent
• -Loss of speech/communication

90% of patients are at their weakest by week 3

• Deterioration/Acute
• Decline, possibly to needing vent
• Lasts up to 4 weeks
• Poor respiratory function, joint and soft tissue pain, progressing weakness, autonomic dysfunction, fear
• Plateau
• Symptoms remain but don't worsen
• Lasts days to weeks
• Pressure areas, sensory loss, low morale, loss of movement, disorientation
• Improvement
• Increased movement
• Lasts up to 2 years
• Weakness, pain, fatigue, lack of postural sensation, tremor, autonomic dysfunction, lability, incomplete recovery

• Synthesized and stored in presynaptic neuron
• Released by presynaptic neuron
• Produces a response in postsynaptic cell
• -Response is same when experimentally applied as that which occurs naturally upon release from presynaptic neuron
• Locally degraded

• NT throughout CNS and at ALL neuromuscular junctions
• Requires enzyme = choline acetyltransferase (ChAT)
• ChAT synthesized in soma and transported down axon
• Only cholinergic neurons use ChAT
• ChAT synthesizes Ach in axon terminal and Act is concentrated in vesicles

• Manufactured by Cholinergic Neurons but also by noncholinergic neurons 
• A degrading enzyme
• Target of nerve gases and insecticides 
• -Disrupts transmission at cholinergic synapses on skeletal and heart muscle
• -Decreased heart rate and BP and respiratory paralysis = death

• Nicotine (agonist) - Curare (antagonist) - Nicotinic Receptor (receptor)
• Muscarine (agonist) - Atropine (antagonist) - Muscarinic receptor (receptor)

• Amino acid precursor for = Dopamine (DA), Norepinephrine (NE), Epinephrine (i.e. adrenaline)
• Found in regions of nervous system that regulate mood, movement, and attention

• Catecholinergic Neurons
• Tyrosine hydroxylase (TH) catalyzes 1st step in catecholamine synthesis
• -TH converts tyrosine to dopa
• Dopa converted to NT Dopamine by dopa decarboxylase

• Catecholinergic neurons
• Contain TH and dopa decarboxylase AND dopaimine B-hydroxylase (DBH)
• -This converts DA to NE

• Catecholinergic neuron
• Phentoalamine N-methyltransferase (PNMT) converts NE to epinephrine
• Released in brain and also by adrenal gland into bloodstream

• Block catecholamine uptake = prolonged NT action in cleft
• After uptake
• -Loaded into vesicles for reuse
• -Destroyed by MAO (enzyme)

• Known as 5-hydroxytryptamine (5-HT)
• Derived from tryptophan
• Important regulators of sleep, mood, emotions

• Tryptophan converted to 5-HTP (precursor)
• This is converted to 5-HT (Serotonin)

• Source of brain tryptophan is blood
• Source of blood tryptophan is diet; grains, meat, dairy

• Amino acids
• Glutamate (Glu)
• Glycine (Gly)
• Gamma-aminobutyric acid (GABA)

• Serve as Its at most CNS synapses
• GABA is unique to neurons that use it as NT
• Glutamate & glycine are synthesized in ALL cells BUT glutamate is 2-3x higher in glutamatergic neurons

• Precursor is Glutamate; enzyme GAD makes GABA from glutamate
• -GAD is widely distributed in brain
• -Major source of synaptic inhibition in nervous system 
• Reuptake by Na+-dependent transporters and metabolized by GABA transaminase

• Key in cellular metabolism 
• Concentrated in many PNS and CNS synapses
• Released in Ca²⁺ spikes
• Packaged with other "classic" NTs in vesicles

• Small lipids released from postsynaptic neurons and act on presynaptic terminals
• "retrograde signaling" so these are "retrograde messengers"
• Serve as feedback system; regulate conventional synaptic transmission
• If postsynaptic cell is inactive, tell the presynaptic cell to slow down

• May be retrograde messenger used to regulate blood flow
• Very small; can diffuse quickly and to many surrounding areas
• Break down quickly

• ATP - energy source for cells
• Amino acids -  make proteins
• NO - causes smooth muscle of blood vessels to relax
• ACh - highest levels are in cornea where are NO Ach receptors
• Serotonin - highest levels NOT in brain but in blood platelets

Mediate fast synaptic transmission in CNS

• Glutamate-gated
• -AMPA
• -NMDA
• GABA-gated
• Glycine-gated

• Amino Acid-gated channel
• Permeable to Na+ and K+, NOT to Ca²⁺
• Activated = allow Na+ into cell = depolarization

• Amino Acid-gated channel
• Excitatory by admitting Na+
• Permeable to Ca2+
• Voltage-dependent = blocked by Mg+ but when stimulated moves Mg+ and Ca2+ enters and K+ moves out

• Cannot generate enough ATP to keep pumps working
• -Membranes depolarize and Ca2+ leaks into cell
• -Ca2+ entry triggers Glutamate release
• -Further depolarizes cell so get even more intracellular Ca2+ = still more glutamate released
• Glutamate at high levels kills neurons by overexciting them = excitotoxicity 
• Linked to ALS and Alzheimer's

• GABA mediates most CNS inhibition
• Glycine mediated the rest
• Both gate a Cl- channel
• Too much inhibition = loss of consciousness and coma
• Too little inhibition = seizure

• Bind to GABA channel
• Benzo increase # of channel openings
• Barb increased duration of channel openings
• Both increase inhibitory Cl- current = stronger IPSPs = increase inhibition

• Affects nerve cells in part of brain controlling muscle movement
• -Dopaminergic neurons in brain slowly degenerate = decreased dopa available so decreased DA
• Progresses gradually; treatable (administer dopa; neurons keep dying so need more and more)

• Electrodes placed in globus pallid us or sub thalamic nucleus
• Connected by wires to pacemaker device in chest called an impulse generator
• When activated, impulse generator then sends signals to inactivate the chosen area of brain that is responsible for symptoms

• Defect in dopamine pathway (connects the substantial nigra to the corpus striatum)
• Involved extrapyramidal system which influences initiation, modulation, and completion of movement
• Reduction of dopamine-creating neurons in the Substantia Nigra
• Upsets normal balance between dopamine and ACh neurotransmitters

• Genetic
• Environmental
• Medication related

• Earliest symptoms can be subtle
• -An arm that doesn't swing when walking
• -A mild tremor in the fingers of one hand
• -Soft, mumbling speech
• -Lack energy, depressed or have trouble sleeping
• -Takes longer to shower, shave, eat or do other routine tasks

• Rhythmic tremors
• Bradykinesia
• -Slowed movement
• -Slowed reaction time
• Akinesia
• Rigidity of muscles
• Loss of postural reflexes
• Decreased muscle strength and speed
• Muscle pain
• Delayed initiation of movements
• Can be unilateral but progress to bilateral
• Loss of automatic movements
• No longer gesture or seem animated when speaking

• Poor balance
• Tendency to fall backward when standing
• Festinating gait
• -Shuffling ambulation with small, quick, hasty steps
• -Appears that the patient is stumbling forward as if they are "chasing" their center of gravity
• Decreased or absent arm swing while walking
• Decreased heel strike
• Decreased trunk rotation
• Decreased stride length
• Increased stance phase
• Cannot stop immediately and unable to turn quickly or change directions without difficulty
• Freezing

• No cure
• Chronic and progressive
• Symptoms vary greatly
• Usually symptoms worsen over an average of 15 years
• If left untreated, can lead to deterioration of almost all brain functions, leading to death
• If treated, life expectancy is new that of normal
• Death may be due to respiratory issues, falls

• Chronic, CNS disorder
• Condition of recurrent, unprovoked seizures
• 2 unprovoked seizures at least 24 hours apart

• Sudden, abnormal electrical activity in the brain
• Results in altered behavior, sensation, or consciousness

• Electrical discharges by groups of neurons in the brain that become abnormally linked
• -While a seizure is occurring, these neurons can fire up to 500 times per second
• -Normal firing rate is about 80 times per second
• Permanent changes in brain tissue cause the brain to be too excitable = brain sends out abnormal signals

Excessive excitation and/or loss of inhibition

• Increased excitatory neurotransmitters (Glutamate)
• Decreased inhibitory neurotransmitters (GABA)
• Alteration in voltage gated ionic channels
• -Channelopathy
• --Slowing of Na+ channel inactivation
• Intra/extracellular ionic alterations in favor of excitation

• Neuron and synapse proliferation before
• Synapse elimination
• Synaptic capacity
• Synaptic rearrangement
• Apoptosis
• More neurons/synapses present than in adults

• Temporary confusion
• Staring spell
• Uncontrollable jerking movements
• Loss of consciousness and awareness
• Seizures depend and vary on type of seizure

• When seizures appear to result from abnormal brain activity in just one area of the brain
• Simple: not affecting awareness (no loss of consciousness) or memory
• Dyscognitive/complex: affect awareness or memory of events before, during and immediately after the seizure, and behavior

• Affect both cerebral hemispheres
• Absence: staring and subtle body movement, brief loss of awareness
• Tonic: stiffening of muscles in back, arms and legs, may fall to floor
• Clonic: rhythmic, jerking muscle movements in neck, face and arms
• Myoclonic: sudden brief jerks or twitches of arms and legs
• Atonic: drop seizures; loss of muscle control causing collapsing/falls
• Tonic-Clonic (grand mal): loss of consciousness, body stiffening and shaking, loss of bladder control