L8 Synaptic Transmission (Post-synaptic)

Focus of today's lecture includes the chemical synaptic transmission involving voltage-gated Ca$^{2+}$ channels and the generation of the Excitatory Post-Synaptic Potential (EPSP).

A dendritic spine is defined as a small membranous protrusion from a neuron's dendrite, typically receiving synaptic input from a single axon at the synapse. Dendritic spines are classified as postsynaptic receivers.
- Visual Representation: Golgi stained pyramidal neuron demonstrates dendritic spines in hippocampus, illustrating approximate size of 1 µm.
- Functionality: Dendritic spines serve as storage sites for synaptic strength and facilitate the transmission of electrical signals to the neuron's cell body.
Structural Features of Dendritic Spines:
- Comprised of a spine neck and spine head.

Dendritic spines provide functional compartmentalization.
- Definition of Functional Compartmentalization: It refers to the restriction of ionic and biochemical changes to only the activated synapse, ensuring that synaptic changes are input specific.

The synaptic cleft is approximately 20 nm wide, allowing rapid fluctuations in neurotransmitter concentration and facilitating effective synaptic communication.
Postsynaptic Density (PSD): Neurotransmitter receptors are found within the postsynaptic density, where they are anchored and regulated by a complex network of proteins.

Involves the net movement of cations (specifically Na$^{+}$ ions) into the postsynaptic cell, generating an Excitatory Post-Synaptic Potential (EPSP) leading to depolarization of the membrane potential (Vm).
Resting Membrane Potential: Typically around -60 mV to -50 mV, when depolarized due to EPSP, can reach + threshold for action potential

Occurs when there is a net movement of anions into the postsynaptic cell, producing an Inhibitory Post-Synaptic Potential (IPSP) that hyperpolarizes the membrane potential.
Comparison of Potentials:
- Resting membrane potential vs action potential threshold is maintained through different ionic movements, specifically concerning chloride (Cl$^{-}$) ions.

Characteristics:
- A non-essential amino acid synthesized from glutamine via the enzyme glutaminase. It serves as the primary excitatory neurotransmitter in the CNS.
- Over 90% of brain synapses utilize glutamate, primarily targeting dendritic spines with size ~1 µm illustrating
Neurotransmitter Storage and Release:
1. Stored in synaptic vesicles with VGLUT transporters facilitating transfer from cytosol to vesicular storage.
2. Released in a Ca$^{2+}$ dependent manner during presynaptic transmission.
3. Targets include ionotropic (iGluRs) and metabotropic (mGluRs) glutamate receptors.
4. Rapid removal mechanism involves glutamate transporters located on pre- and postsynaptic terminals and astrocytes.

Ionotropic Receptors:
- Classified into subtypes: AMPA (GluA1-4), NMDA (GluN1, GluN2A-D), and Kainate (GluK1-3).
Metabotropic Receptors:
- Grouped into three functional groups (Group I, II, III) with various subunits and subtypes.

AMPA Receptors:
- Permeable primarily to Na$^{+}$ and K$^{+}$ ions, facilitating fast EPSP responses but not typically allowing Ca$^{2+}$.
- Responsible for rapid excitatory synaptic transmission and can be blocked by antagonists such as NBQX and CNQX.
NMDA Receptors:
- Have voltage-dependent Mg$^{2+}$ block, allowing Ca$^{2+}$ influx when depolarized (removal of block). They mediate a slow and long lasting EPSP.
- Critical role in synaptic plasticity, influencing long-term changes in synaptic strength.

GABA (g-aminobutyric acid) is the principal inhibitory neurotransmitter in the brain, contrasting with the excitatory function of glutamate.
GABA Storage & Release:
1. Stored in vesicles via VGAT transporters.
2. Synthesized from glutamate by the enzyme glutamate decarboxylase (GAD), with two isoforms: GAD67 (ubiquitously) and GAD65 (axon terminal specific).
3. Release is Ca$^{2+}$ dependent.
4. Specific targets are GABAA (ionotropic) and GABAB (metabotropic) receptors.
5. Rapid removal involves GABA transporters on various neural components.

Structure: Pentameric (5 subunits), forming a central chloride channel with the binding sites for GABA between the alpha and beta subunits.
Functionality:
- Mediate fast inhibitory synaptic transmission leading to hyperpolarization of the postsynaptic cell, generating IPSPs.
- Blocked by GABAA receptor antagonists like gabazine.

Structure: Comprised of two transmembrane subunits, GABAB1 and GABAB2, coupled with G-protein signaling.
Functionality:
- Mediate slow inhibitory synaptic transmission with effects on potassium channels to hyperpolarize the postsynaptic neuron.

Coactivation of GABAA and GABAB receptors can produce biphasic IPSPs, where initial fast effects transition into slower effects through different pathways.

Paired Pulse Depression (PPD): The first stimulus leads to a stronger response, but the second stimulus results in a diminished response due to GABA released being reduced, attributed to the activation of presynaptic GABAB receptors that inhibit Ca$^{2+}$ channel opening and consequently exocytosis.

Dendritic spines facilitate compartmentalization in synaptic transmission.
Fast excitatory transmission primarily involves AMPA and NMDA receptors of iGluRs.
Inhibitory transmission is managed by GABA through GABAA for quick responses and GABAB for slower transmission.
A clear understanding of these processes underpins the broader knowledge of neuronal communication and synaptic plasticity, essential for grasping neurophysiological functions and disorders.