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Glial Cells and Their Functions

  • Definition: Glial cells are non-neuronal cells in the nervous system that do NOT fire action potentials.

Types of Glial Cells

Peripheral Nervous System (PNS)

  • Schwann Cells:

    • Origin: Derived from neural crest cells.

    • Function:

    • Produces myelin sheath around PNS axons.

    • One Schwann cell myelinates only one axon in the PNS.

    • Neuregulin Function:

    • Neuregulins stimulate the proliferation of Schwann cells and bind to tyrosine kinase.

    • Signals through Ras-Raf-MAPK pathways.

    • Expressed in motor neurons to instruct adjacent, uncommitted neural crest cells to become glia rather than neurons (Glial Growth Factors (GFG) are in the neuregulin family).

Central Nervous System (CNS)

  • Astrocytes:

    • Origin: Arise from both dorsal and ventral regions of the neural tube.

    • Function:

    • Communicate with neurons via cell-to-cell adhesion junctions and calcium signaling.

    • Stimulation (via ATP or bradykinin) leads to local elevation of calcium, affecting surrounding astrocytes and neurons.

  • Oligodendrocytes:

    • Origin: Derived from progenitor cells in the ventricular zone of the neural tube.

    • Function:

    • Primary myelin producers in the CNS (can myelinate cortical neuron axons).

    • One oligodendrocyte can myelinate multiple axons in the CNS.

    • Sonic Hedgehog: Specifies oligodendrocyte progenitors in the ventral neural tube.

    • Progenitors require Platelet-Derived Growth Factor (PDGF) for proliferation.

    • Knockout (KO) of PDGF results in fewer O-2A progenitors but the same number of mature oligodendrocytes.

    • Differentiation inhibition observed in rat optic nerve via the Notch pathway to ensure progenitor availability before myelination.

Blood-Brain Barrier

  • Astrocytes also participate in forming the blood-brain barrier.

    • Composition: Tight junctions between capillaries and endothelial cells prevent diffusion of small molecules.

  • Transport Mechanisms:

    • CO2 and O2 diffuse passively.

    • Glucose and amino acids use active transport both ways.

    • Penicillin and organic acids: active transport to blood, passive to the brain.

    • Potassium ions: passive transport in both directions.

Tripartite Synapse

  • Structure: Comprises astrocyte endfeet, presynaptic nerve terminal, and postsynaptic dendrite.

  • Astroglial Endocytosis Model:

    • A dynamin-independent pathway that clears substances such as glutamate, ATP, or beta-amyloid, regulated by calcium concentration.

  • Function: Astrocytes regulate glutamate clearance.

Learning and Memory

  • Learning: Acquisition of altered behavioral response due to environmental stimulus.

  • Memory: The process through which learned information is stored.

  • Recall: The process of retrieval (can be conscious or unconscious) through which behavior is manifested.

Types of Memory

  • Declarative/Explicit Memory:

    • Concerned with facts and events (involves the hippocampus).

  • Implicit/Nondeclarative Memory:

    • Related to emotions, learning, and classical conditioning (involves cerebellum, striatum, cerebral cortex, amygdala).

Long-Term Potentiation (LTP)

  • Definition: Strengthening of synapses as a primary cellular mechanism for learning and memory.

  • Importance: Not memory itself, but a contributor to memory formation.

Experimental Stimulation of LTP

  • High-frequency stimulation (100 Hz) can stimulate:

    • Perforant path from entorhinal cortex to dentate gyrus to CA3 then to ipsilateral CA1.

  • Mechanism:

    • Increased stimulation frequency causes membrane depolarization, relieving the Mg²⁺ block and activating NMDA receptors, leading to LTP.

    • NMDA Mechanism: Involves ligand binding (glutamate or glycine), followed by a voltage-dependent blockade, and subsequent calcium influx into the postsynaptic neuron.

    • APV: Known antagonist of NMDA, blocking LTP.

LTP Phases

  • Induction: Calcium influx into the postsynaptic neuron.

  • Expression: Involves propagation of phosphatase activity and insertion of AMPA receptors.

  • Maintenance: Requires new protein synthesis.

  • Early LTP: Involves CAMKII, PKA, PKC for rapid synaptic changes.

  • Late LTP: Involves CREB, MAPK, BDNF for persistent changes.

LTP vs. Long-Term Depression (LTD)

  • Low Ca²⁺ and Phosphatases correlate with LTD; High Ca²⁺ and protein kinases correlate with LTP.

Presynaptic Vesicle Recycling

  • Continuous recycling of neurotransmitter (NT) sacs (synaptic vesicles) maintains rapid nerve signaling.

Memory Locations

  • Short-term Memory: Mainly involves the hippocampus.

  • Long-term Memory: Primarily occurs in the cortex.

Intellectual Disabilities

  • Definition: IQ of less than 70 with decreased ability to adaptively learn, evident before the age of 18.

Comorbid Disorders

  • Comorbid Axis I Disorders: include ADHD, mood disorders, Pervasive Developmental Disorders (PDD), movement disorders, mental disorders due to general medical conditions.

Risk Factors for Intellectual Disabilities

  • 6 Key Risk Factors:

    1. Alterations in embryonic development.

    2. Environmental influences.

    3. General medical conditions acquired in infancy or childhood.

    4. Hereditary factors.

    5. Existing mental disorders.

    6. Pregnancy or perinatal complications.

Specific Syndromes

  • Down Syndrome:

    • Cause: Nondisjunction on chromosome 21 leading to trisomy, translocation, or mosaic forms.

    • Observation: After age 40, patients show symptoms of Alzheimer’s dementia due to the presence of APP (Amyloid Precursor Protein), linked to beta-amyloid plaques characteristic of Alzheimer’s.

  • Prader-Willi Syndrome:

    • Cause: Deletion on paternal chromosome 15 resulting in uniparental disomy.

    • Symptoms: Excessive hunger, weight gain, temper tantrums, mood disorders, mild to moderate intellectual disability, OCD.

  • Angelman Syndrome:

    • Cause: Uniparental disomy with deletion on maternal chromosome 15, resulting in two paternal UBE3A gene copies.

    • Symptoms: Severe intellectual disability, excessive laughter, lack of speech, jerky arm movements.

    • UBE3A Function: Encodes a protein important for regulating protein degradation.

Medications and Treatments

  • SSRIs (Fluoxetine): Decrease irritability and depression.

  • Antipsychotics (Clozapine): Block D2 dopamine and 5HT serotonin receptors, reducing extrapyramidal side effects (EPSE).

  • EPSE: Movement disorders typically caused by certain medications.