Neurotransmitters Pt 2

Neurophysiology: Brain Neurotransmitters

Introduction

  • Presenter: Xiang-Ping Chu, MD, PhD, Department of Biomedical Sciences

  • Key Areas of Focus:

    1. Ion channels, Interaction between Neuron and Glia, and Synaptic Vesicle Synthesis.

    2. Major Neurotransmitter (NT) Synthesis, Storage, Release, Reuptake, and Degradation.

    3. Major Brain Ionotropic and Metabotropic Receptors.

    4. Function of Major NTs and involvement in Neurological and Psychological Diseases.

    5. Regulation of Neurotransmission and their Pharmacological Application.

Major Neurotransmitters

  • Overview of glutamate as the principal excitatory neurotransmitter in the central nervous system (CNS).

Glutamate Receptors

  • Types:

    • Ionotropic Glutamate Receptors (iGluRs):

    • NMDA (N-Methyl-D-Aspartic Acid)

    • AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)

    • Kainate receptors

    • Metabotropic Glutamate Receptors (mGluRs):

    • Three groups with eight subgroups (mGluR1-8)

Glutamate

  • Overview:

    • Major excitatory NT in the CNS.

    • Used by nearly 60% of brain neurons.

AMPA Receptor (AMPAR)

  • Description:

    • iGluR involved in fast excitatory synaptic transmission.

    • Composed of four subunits (GluA1, GluA2, GluA3, GluA4), typically forming heterotetramers.

  • Binding Sites and Permeability:

    • Agonist binding occurs at four sites (one for each subunit).

    • Permeable to Na+, K+, and Ca2+ (availability governed by GluA2).

    • Without GluA2, permeability to Ca2+ is facilitated.

Functions of AMPA Receptors

  1. Fast Excitatory Signaling:

    • Glutamate release from presynaptic neurons activates AMPARs, opening ion channels.

    • Influx of Na+ leads to rapid depolarization (excitatory postsynaptic potential, EPSP).

  2. Synaptic Plasticity:

    • Works alongside NMDA receptors for long-term potentiation (LTP) important for learning and memory.

  3. Modifiability:

    • Neurons can adjust the number and functionality of AMPARs.

    • Phosphorylation enhances activity and responsiveness of AMPARs.

  4. Clinical Relevance:

    • Dysregulation associated with conditions like epilepsy, neurodegeneration, and neuropsychiatric disorders.

    • Investigation of AMPA receptor modulators for therapeutic use in cognitive enhancement and depression treatment.

Phosphorylation of AMPA Receptors

  • Effects:

    • Increases in channel conductance, receptor trafficking to the synapse, and supports LTP.

    • Excessive phosphorylation linked to pathologies like epilepsy.

NMDA Receptor (NMDAR)

  • Description:

    • Activation requires both glutamate and glycine (or D-serine).

    • Involved in synaptic plasticity and memory function.

  • Subunit Composition:

    • Comprising GluN1, GluN2, and GluN3 subunits with variants.

  • Mechanism of Action:

    • Channel allows Ca2+ and Na+ influx.

    • Blocked by Mg2+ at resting membrane potential (RMP).

Functions of NMDA Receptors

  1. Coincidence Detection:

    • Requires simultaneous glutamate binding and postsynaptic depolarization.

    • Acts as an