4. Inhibitory Synapses and GABAA Receptors

Excitatory Neurons

The majority of neurons (70-80\%) in the brain, primarily utilizing glutamate as their neurotransmitter to facilitate rapid synaptic transmission and information relay.

Glutamate

The principal excitatory neurotransmitter in the central nervous system, affecting various receptor types (AMPA, NMDA, kainate, mGluRs) and generally leading to depolarization and neuronal excitation.

Inhibitory Neurons

Neurons with a distinct, localized function, predominantly using gamma-aminobutyric acid (GABA) as their neurotransmitter to counteract excitatory signals and maintain neural balance.

GABA

The major inhibitory neurotransmitter in the brain, crucial for counteracting excitatory signals and maintaining neural balance.

Excitatory Synapses Location

Typically found on dendritic spines of neurons, such as pyramidal cells in the cerebral cortex.

Inhibitory Synapses Location

Tend to be situated between spines, directly on main dendritic shafts, or, notably, on the cell soma, allowing them to function as powerful gatekeepers near the action potential initiation zone.

Inhibitory Postsynaptic Potential (IPSP)

A transient event (typically 10-20 ms) resulting from inhibitory synapse activation, causing fast hyperpolarization of the postsynaptic neuron and making it less likely to generate an action potential.

Hyperpolarization

A shift in the neuron's membrane potential to a more negative value (e.g., from -60mV to -65mV), moving it further away from the action potential threshold (typically around -55mV).

Characteristics of Inhibitory Neurons

Generally feature short axons, are frequently termed interneurons, and primarily function to fine-tune local electrophysiology by regulating excitatory neuron activity.

Control Overall Excitability of the Brain (Inhibitory Function)

A function of inhibitory synapses to prevent runaway excitation in the brain (e.g., electrical storm), maintaining regulated brain activity and guarding against pathological states like epileptic seizures.

Epileptic Seizure

A pathological condition arising when excitatory neuronal activity overwhelms inhibitory mechanisms, leading to uncontrolled, synchronized neuronal firing across extensive brain regions.

Shape the Firing Patterns of Excitatory Neurons (Inhibitory Function)

A function of inhibition that sculpts precise patterns of action potential firing, indispensable for encoding and processing information by refining temporal and spatial dimensions of neuronal activity.

GABA-A Receptors

Ionotropic (ligand-gated ion channel) receptors typically composed of five subunits that form a central pore selectively permeable to chloride ions (Cl^-), mediating fast IPSPs when GABA binds.

KCC2 Cotransporter

Potassium Chloride Cotransporter 2; a transporter that actively pumps K^+ and Cl^- out of the cell, maintaining a low intracellular Cl^- concentration ([Cl^-] ext{int}), crucial for GABA's inhibitory function in mature neurons.

Chloride Equilibrium Potential (E_{Cl})

The membrane potential at which there is no net flow of chloride ions across the membrane. In mature neurons, it is typically more negative than the resting membrane potential (e.g., -70mV to -80mV), causing Cl^- influx and hyperpolarization when GABA-A receptors open.

Shunting Inhibition

An inhibitory effect of GABA-A receptors even if E_{Cl} equals the resting potential, where the opening of Cl^- channels increases membrane conductance, 'short-circuiting' excitatory currents and making depolarization more difficult.

Benzodiazepines

Drugs (e.g., Valium, Xanax) that act as positive allosteric modulators on GABA-A receptors by increasing the frequency of channel opening when GABA is present, enhancing Cl^- influx and stronger inhibition.

GABA-B Receptors

Metabotropic (G-protein coupled) receptors that, when GABA binds, initiate an intracellular G-protein cascade leading to the opening of potassium (K^+) channels (causing slow hyperpolarization) or inhibition of voltage-gated calcium (Ca^{2+}) channels.

Nicotinic Acetylcholine Receptors (nAChRs)

Ligand-gated ion channels that are characteristically excitatory; they open in response to acetylcholine (ACh), allowing rapid influx of sodium (Na^+) and calcium (Ca^{2+}) ions, leading to depolarization and excitation.

Feedback Inhibition

A circuit mechanism (e.g., basket cells inhibiting pyramidal neurons) where a firing excitatory neuron activates a local inhibitory interneuron, which then inhibits the original excitatory neuron, limiting its firing duration and intensity.

Pyramidal Neurons

Large, excitatory projection neurons in the cerebral cortex crucial for establishing connections between cortical areas, other brain structures, and the spinal cord.

Purkinje Cells

Inhibitory neurons in the cerebellar cortex with extensive dendritic trees that project exclusively to deep nuclear neurons, releasing GABA to temporarily cease deep nuclear neuron firing, sculpting intricate activity patterns for motor control.

Lateral Inhibition

A widespread mechanism in sensory systems (e.g., touch, vision) where strongly excited central neurons activate

What proportion of neurons in the brain are typically inhibitory?

Approximately 20-30\% of neurons, primarily using GABA.

How does GABA cause hyperpolarization in mature neurons?

By opening GABA-A receptors, allowing Cl^- influx due to the low intracellular Cl^- concentration maintained by the KCC2 cotransporter, leading to a more negative membrane potential.

What is the primary difference in the speed of inhibition mediated by GABA-A vs GABA-B receptors?

GABA-A receptors mediate fast IPSPs via ion channels, while GABA-B receptors mediate slow IPSPs via G-protein coupled cascades and potassium channels.

What causes an epileptic seizure from an inhibition perspective?

It occurs when excitatory neuronal activity overwhelms inhibitory mechanisms, leading to uncontrolled, synchronized neuronal firing across extensive brain regions.

Why is the location of inhibitory synapses on the cell soma or main dendritic shafts significant?

This allows them to function as powerful gatekeepers near the action potential initiation zone, effectively controlling neuronal output.

What neurotransmitter do the majority of excitatory neurons primarily use?

Glutamate.

Where are inhibitory synapses typically located, and why is this location significant?

They tend to be situated between spines, directly on main dendritic shafts, or, notably, on the cell soma, allowing them to function as powerful gatekeepers near the action potential initiation zone.

What is an Inhibitory Postsynaptic Potential (IPSP)?

A transient event (typically 10-20 ms) resulting from inhibitory synapse activation, causing fast hyperpolarization of the postsynaptic neuron and making it less likely to generate an action potential.

What defines hyperpolarization in a neuron?

A shift in the neuron's membrane potential to a more negative value (e.g., from -60mV to -65mV), moving it further away from the action potential threshold (typically around -55mV).

What are the general characteristics of inhibitory neurons?

They generally feature short axons, are frequently termed interneurons, and primarily function to fine-tune local electrophysiology by regulating excitatory neuron activity.

What is shunting inhibition?

An inhibitory effect of GABA-A receptors even if E_{Cl} equals the resting potential, where the opening of Cl^- channels increases membrane conductance, 'short-circuiting' excitatory currents and making depolarization more difficult.

How do Benzodiazepines (e.g., Valium, Xanax) affect GABA-A receptors?

They act as positive allosteric modulators by increasing the frequency of channel opening when GABA is present, enhancing Cl^- influx and stronger inhibition.

How do GABA-B receptors mediate inhibition?

When GABA binds, they initiate an intracellular G-protein cascade leading to the opening of potassium (K^+) channels (causing slow hyperpolarization) or inhibition of voltage-gated calcium (Ca^{2+}) channels.

What proportion of neurons in the brain are typically inhibitory?

Approximately 20-30\% of neurons, primarily using GABA.

How does GABA cause hyperpolarization in mature neurons?

By opening GABA-A receptors, allowing Cl^- influx due to the low intracellular Cl^- concentration maintained by the KCC2 cotransporter, leading to a more negative membrane potential.

What is the primary difference in the speed of inhibition mediated by GABA-A vs GABA-B receptors?

GABA-A receptors mediate fast IPSPs via ion channels, while GABA-B receptors mediate slow IPSPs via G-protein coupled cascades and potassium channels.

What causes an epileptic seizure from an inhibition perspective?

It occurs when excitatory neuronal activity overwhelms inhibitory mechanisms, leading to uncontrolled, synchronized neuronal firing across extensive brain regions.

Why is the location of inhibitory synapses on the cell soma or main dendritic shafts significant?

This allows them to function as powerful gatekeepers near the action potential initiation zone, effectively controlling neuronal output.