Lecture 8: GABAnergic System

GABA

y-aminobutyric acid, inhibitory transmitter in CNS; 3 types → GABAA-C; glycine in PNS

GABA Synthesis

glutamate → glutamic acid decarboxylase (GAD) → GAD65 + GAD67

GABA Levels

abnormal in mood disorders; increase w/supplements; conflicts of interest are apparent (not strong evidence that supplements increase GABA) → passage across BBB questioned

GABAARs

ionotropic, ligand-gated channels, Cl- ions; fast inhibition (hyperpolarizing(-)/shunting), 5 subunits 2 a (1-6), 2b (1-3), and 1y (1-3), 𝛅, π, Θ, or ε

GABAAR Abundance

preferred stoichiometry of 2a;2b;y or 𝛅; some subtypes more common

GABAAR Localization

synaptic (strong but transient) or extrasynaptic (weak but always on) regions

Synaptic

axBxy2 and axBxy3; strong but transient, less sensitive; strong, brief current → IPSCs (inhibitory post-synaptic current); AP-dependent GABA in high amounts

Extrasynaptic

a4Bx𝛅, a6Bx𝛅, a5Bxy2, axBx; weak but always on; learning/memory targets; more sensitive, weak associative currents; outside the synapse, exposed to low levels of GABA, less directly related

Excitatory/Inhibitory Signals

excitatory → EPSP; inhibitory → firing less likely, IPSP

Signal Summation

one neuron receives many signals → summated → exceeds threshold → neuron fires; inhibitory signalling decreases firing likelihood

GABAAR Reduce Excitability

patching cell to measure activity → stimulating with currents

THIP and Picrotoxin

THIP ( agonist) → activate GABA = ↓ excite; picrotoxin → block GABA = ↑ excite

Neuroactive Steroids

hormones; vary during development (puberty) + reproduction (postpartum) w/stress;

Neuroactive Steroids - GABA

increase activity of 𝛅GABAA (positive allosteric modulators)

Positive Allosteric Modulators

bind receptor at site diff than ligand binding → affect activity when it binds to something else; ex. NAS → GABAy not at main binding site but will increase activity of receptor

Brexanolone/Zulresso

neuroactive steroids with anxiolytic and antidepressant properties; PPD

GAT

GABA transporter; GAT1 + GAT3 abundant; neurons (GAT1), astrocytes (GAT2); antiseizure drug

Astrocytes

GAT2, role in regulation of levels in the extracellular space

GABAARs Controversy

some GABAARs don’t require GABA to open (spontaneous, ligand-independent); shifts during development (early → GABA excitatory); net effect of signalling depends on ionic imbalance

Interneurons

modulate sensory/motor cells, short range projections (reflexes); synapse on many areas;

GABA - Interneurons

GABA signalling restricts excitability and shapes neuronal oscillations

ASMs

antiseizure medication; disorder of excitation; enhanced inhibitory transmission, reduced excitation via glutamate, and inhibit voltage-gated Na + Ca channels (APs)

GABA - Neurodevelopment

brain development (GAT67-KO) and adult neurogenesis; early NS/adult NS diff

GABA - Drugs

anxiolytic, memory-imparing, sedative-hypnotics, anesthetic, antiepileptic, pain; doses matter; benzodiazepines, barbiturates, anesthetics, alcohol, anticonvulsants; benzodiazepine > barbiturate

Synapses

modifiable; changes in synaptic strength, with use; contributes to learning

Synaptic Strengthening

Bliss + Lomo in HPC; high-freq stimulation of synaptic connections → stronger

LTP

long-term potentiation, experience-dependent, neural correlate of learning; HPC → dentate gyrus

LTP Experiment

stimulate 50x @ 100Hz, what was a weak response will elicit a strong response with training → increase in EPSP strength; GABA = ↓ LTP; GABA inhibition = ↑ LTP

LTP - Memory

in NS (HPC, C, striatum, SC); correlated with learning and memory; learning linked to LTP development; deficits in learning/memory linked to deficits in LTP;

LTP - Synapse

activity-dependent variations in synaptic strength (LTP) may be a fundamental mechanism by which we acquire and modify all behaviours

LTP - GABAARs

GABA agonists (THIP) impairs LTP, antagonists (picrotoxin) increase LTP; baseline differences in LTP in brain areas due to GABAergic tone; ex. Weak in DG because lots of GABA resistance

LTP - GABA Summary

LTP + HPC→ learning/memory; GABA → ↓ LTP; GABA = ↓ learning/memory (X)

a5KO - Memory

GABA = ↓ learning/memory; a5KO → ↑ learning in Morris water/fear conditioning tasks

𝛅KO - Memory

GABA ≠ ↓learning/memory; 𝛅KO → enhance fear conditioning, improved learning, same task

GABAARs - Memory

drugs → increase GABA (anesthetics, benzodiazepines, alcohol) impair memory; linked to activation of a5GABAARs and 𝛅GABAARs; states of increased GABAARs expression = impaired memory

States of Increased GABAA

inflammation (a5), traumatic brain injury (𝛅), and reproductive cycle (𝛅)

Reproductive Cycles

hormones metabolized to neuroactive steroids; hormonal levels factor in 𝛅GABAR FN

Diestrus

peak in steroid levels during diestrus → linked to memory impairments, changes absent in 𝛅KO; neuroactive steroids → increase 𝛅GABA activity → memory impairment

Distinguishing Experience

X/X’ similar but own neural reps; large diff→ useful in discriminating experience

Pattern Separation

to maximize discrimination, brain transforms X and X’ → X and Y; involves DG, HPC; similar inputs → differentiated → better discrimination; not perf, need to recognize stuff as similar

GABA - Memory Discrimination

inhibition critical to pattern separation → loss of inhibition associated with impaired discrimination; DG hyperactivity = reduced pattern separation → cognitive impairment in dementia; a5KO and 𝛅KO → poor pattern separation, treat diff environments as similar; receptors in DG implicated

GABA Role

1) receptor subtype (a5, 𝛅); 2) learning task ( behaviours enhanced by removing inhibition, some disrupted), 3) sex of animal; 𝛅 receptor diff role in females due to reproductive states; 4) physiological state

Anxiety Disorders

generalized anxiety disorder (limiting), panic disorder, phobias (common)

Related Disorders but Independent

OCD and PTSD

Amygdala Role

limbic system structures (amygdala, hypothalamus, OFC, cingulate gyrus, hippocampus)

Amygdala + Anxiety

activated during arousing states (emotion), lesions reduce fear/anxiety (Patient SM), inhibiting amygdala (with drugs) reduces anxiety; many anxiolytics increase GABAAR by affecting amygdala

GABA - Mood

low GABARs in psychological disorders, GABA levels low in depression; reduced 𝛅 and y2 subunit-containing GABARs linked to anxiety; GAD65-KO → elevated anxiety levels

𝛅KO + PPD

deletion of 𝛅GABAAR subunit associated with depression-like PPD; treatment is steroid; increased immobility in porsolt forced swim test, poor maternal behavioural (pups die, bad nests);

Summary of GABA Signalling

1) receptors involved in many disorders 2) disorders involve alterations; natural variations in GABA signalling contribute to natural variations in mood (puberty, post-partum); increased GABA signalling = reduced anxiety, decreased GABA signalling = increased anxiety + depression; modulating GABARs with drugs affects anxiety

Drugs affecting GABA

spectrum of effects related to dose; many drugs for anxiety, not just GABA

Anxiety - GABA Drugs

Benzodiazepines + SSRIs; Valium or Xanax; GAD, panic, OCD, SAD, withdrawal

Pain

private experience associated with injury or feeling that injury has occurred; adaptive → danger/withdraw

Acute Pain

brief, overlaps with healing following injury; normal, more manageable

Chronic Pain

persistent beyond healing period for injury; ex. Migraine, diabetic neuropathy, arthritis

Chronic Pain Cause

following injury, lasting changes in nociceptive signaling system; sustained activation of peripheral nociceptive fibers → CNS hyperactivity

Nociceptive Signalling

convert info in NS to psychological experience of pain

Pain Pathways

primary afferent-second order sensory synapse in dorsal horn; activity of dorsal horn neurons modulated by interneurons; loss of interneurons following injury cause chronic pain

Inhibitory Balance Changes

1) death of interneurons increase pain; 2) with changes in transport across the membrane, inhibitory signals lose their value, becoming insufficiently inhibitory or even excitatory

Central Sensitization

even if inhibition is stable, increases in excitation can amplify pain-related signals; signaling at synapse may increase in strength after injury or other stimulation forms

Drugs for Pain

GABA signaling may regulate pain and GABARs target for analgesic drugs; activation of 𝛅GABAARs activation = analgesic effects;

Gabapentin

known for analgesic effects, increase 𝛅GABAAR expression