Neurotransmission Flashcards
CNS inputs
All connections between peripheral afferents and CNS neurons are excitatory
requires balance by CNS inhibition
processing often involves removing unwanted inputs
Presynaptic inhibition
more selective than post-synaptic
- lower effectiveness of one or a few inputs to an euron
- does not affect other inputs or postsynaptic membrane potential
major pathway in spinal cord
GABA is the major NT
GABAa receptors: Chloride conductance, shunting of AP
GABAb receptors: long -acting; G-protein coupled modulation of K and Ca channels
Axoaxonic, and dendroaxonic interaction
Recurrent inhibition
Autoregulation of motor neuron firing rates
Modulation of motor output by its own activation
Glycine dominant NT, but also GABA
Convergent synaptic input from descending pathways
Renshaw cells involved
Renshaw cell
recurrent inhibition of motor neurons
spinal interneurons
Excited by collaterals from motor neurons, and then inhibit those same motor neurons –> negative feedback
Regulates motor neuron excitability and stabilizes firing rates
Golgi tendon organ
GTO stretch (contraction of muscle) --> afferent axon compressed by collagen fibers --> rate of firing increases Disynaptic GTO inhibition and the Ib inhibitory interneuron = inverse myotactic reflex, "clasp knife reflex" Ib feedback from GTO inhibits contraction of agonist, and facilitates antagonist
Pyramidal/CST
~ 1 million fibers, mostly myelinated
lateral fibers decussate at midbrain (not all cross)
projects to alpha and gamma motor neurons, interneurons
Monosynaptic connections
Also indirect pathways (rubrospinal, reticulospinal)
Reticulospinal tract
Innervates LMN, affected by supraspinal projections
Activity controls posture and strength of reflexes
Interruption in pathway leads to deficits
Interruption of descending input
“releases” spinal interneurons, of which many are inhibitory
Unrestricted flow of excitation reaches motor neurons
- hyperreflexia
- can also affect the sign of reflexes (e.g. Babinski, Bing)
LMN disorder characteristics
flaccid weakness or paralysis decreased or absent monosynaptic reflex muscle denervation, atrophy affects single muscles or small groupw innervated by common nerve cutaneous reflexes normal
UMN disorder characteristics
spastic weakness (increased velocity sensitivity)
exaggerated monosynaptic reflex
clonus (5 Hz)
no signs of denervation, atrophy
large groups affected, organized by halves or quadrants of the body
reversed (Babinski) or absent cutaneous reflexes
Spasticity
Hypertonia
Hyperreflexia
more pronounced in anti-gravity muscles: flexors in the arm, extensors in leg
UMN lesion treatment
Diazepam (Valium)
- antispastic action by increasing frequency of GABAa receptor channel openings, enhancing postsynaptic inhibition in spinal cord
Baclofen: reduces spasticity by activating presynaptic GABAb receptors, inhibiting glutamate release from afferent fibers
Excitotoxicity
Ischemia –> glutamate release –> activation of glutamate receptors –> Na influx –> activation of VaC channels –> influx of Ca –> neuronal injury
Neuronal body vacuolation
cytotoxic edema (failure of pumps, water influx) Prion diseases (spongiform encephalopathy)
Neuromelanin
normal
byproduct of catecholamine synthesis
in neurons of substantia nigra and locus cereleus
differs from skin melanin
Lipofuscin
pigment of aging
in many neurons
Axonal reaction/central chromatolysis
Response of nerve cell body to axonal transection
Swollen cell body with displaced nucleus, dispersed Nissl substance
increased mRNA synthesis –> increased protein synthesis
Wallerian degeneration
degeneration of distal fragment of axon after axonal transection
Axonal retraction balls
damming up of organelles conveyed by axonal transport to proximal stump of axonal transection site
Axonal spheroids
seen in neuroaxonal dystrophies
certain locations in aging
light microscopically similar to, but ultrastructurally different from, axonal retraction balls
Dendritic reactions
abnormalities in number, shape, and size of dendritic spines in mental retardation/epilepsy
Astrocyte function
"scar" cell of CNS support and structure syncytium throughout CNS Energy from glycolysis Glutamate and GAPA uptake pH, osmolarity regulation spatial buffering of K+ glutamine for glutamate synthesis gray matter: protoplasmic White matter: fibrous
Gliosis changes
early: hyperplasia, hypertrophy, upregulation of GFAP
Late: fibrillary gliosis
Astrocytic swelling
Rosenthal fibers
- linear/corkscrew hyaline inclusions
- seen in long-standing gliosis
Astrocytic inclusions
Corpora amylacea
- round inclusions of glycoprotein
- in astrocytic foot processes
- particularly around blood vessels, or near surfaces of CNS
Ependyma reactions
lining of ventricles
destruction of ependymal cells probably not replaced with other ependymal cells
Subventricular glial nodule (Granular ependymitis): non-specific reaction of subventricular astrocytes to ependymal injury/loss
Microglial reactions
CNS cells originally derived from bone marrow
Phagocytic function
Antigen presenting
Activated in response to CNS injury in absence of parenchymal destruction
Turns into macrophages in response to CNS injury with parenchymal destruction
Immune response in the CNS
Class II MHC-controlled
Class I cMHC controlled
Often don’t see T and B cells due to immunological priviledge
Class II MHC-controlled immune response
Normally minimal constitutive Class II MHC in white matter microglia
CD4 TCR recognizes Ag in the context of Class II MHC on the APC
Need other co-stimulatory molecules and receptors
T-cell + APC –> proinflammatory cytokine profile –> immune response to antigen initiated
OR immunomodulatory cytokine profile –> immune response to antigen suppressed
Class I MHC-controlled immune response
Interaction between cytotoxic T-cell and target/APC –> lysis/apoptosis of target cell
Normally constitutive class I MHC on endothelial cells and probably some glia and perivascular cells in the CNS
CD8 TCR recognizes antigen (peptide) in context of Class I MHC on target cell
no intermediary cell to carry out target destruction
CNS immunological privilege
Activated T-cells breach BBB
Unactivated T-cells do not traffic through CNS
Immune response in CNS will only result from a trafficking T-cell if:
- T cell receptor recognizes a specific CNS antigen
- antigen is presented in context of MHC to T-cell
CNS normally has very FEW APCs
Multiple sclerosis pathophys
autoimmune disease of CNS myelin sheath
Gliosis in demyelinated plaques of MS
Inflammation in MS
Lymphocytes monocytes macrophages perivascular inflammation initiation and extension of actively demyelinating plaque --> CD4 T-cells in perivascular spaces
Antigen presentation in MS
Antigen first presented to trafficking activated T-cells by perivascular microglia (Class II MHC)
Subsequent antigen presentation to T-cells by macrophages in plaque
Demyelination in MS
macrophages
- removes myelin lamellae from sheath
- internalized myelin degraded to neutral lipid in macrophage lysosome
Axons are relatively intact
Remyelination in MS
Increased #s of oligodendrocytes and remyelination seen in actively demyelinating MS plaques
Remyelinated myelin also undergoes macrophage attack
Chronic silent MS plaque
little inflammation remains
? due to suppressor cells or immunomodulatory cytokines down-regulating immune response
Plasma cells persist and produce IgG
Lipid-laden macrophages make their way to perivenular spaces, and then to systemic circulation
Numerous demyelinated axons and fibrillary gliosis
some axonal loss