Excitatory and Inhibitory AAs

How is L-Glutamate, the main excitatory NT, synthesised?

Made from glutamine (from astrocytes) by glutaminase or by the conversion of α-ketoglutarate into glutamate by GABA transaminase

How is glutamate inactivated?

When it is uptaken by EAAT of the presynaptic neurons or glial cell where

If taken up by presynaptic neuron it can be repackaged into vesicles (by VGLUT)

If taken up by glial cells it is converted into glutamine (via glutamine synthase) and passed back to the neuron where it can be remade into glutamate and repackaged into vesicles

What are the receptors for glutamate?

AMPA, Kianite, NMDA, mGluR

What are AMPA receptors?

Tetrameric ionotropic receptor with 3TMDs and one which does not span the membrance causing the carboxyl group to be intracellular (subunits GluA1-4)

It is linked to a non-specific monovalent cation channel that (lots of Na in and little K out) has a reversal potential of 0mV which is the voltage when there is no net change in charge produced by influxing and effluxing ions

Since it is an ionotropic receptor it mediates fast EPSPs - since the RMP of a neuron is is ~70mV when the channel opens there is a huge influx of Na into the cell which causes the neuron to depolarise (causing the classic fast EPSP trace seen in patch clamp studies)

Agonist = AMPA (synthetically made)

Antagonist = CNQX

What are kainate receptors?

Tetrameric receptor made from four subunits from GluK1-5

Rapidly desensitise - when glutamate binds they rapidly stop responding to further glutamate presence

Can be located pre and postsynaptically with functions including

• Aid in axonal conductance

• Role in modulation of presynaptic release of NT (affect VG Ca channels)

• Role in postsynaptic depolarisation

• Tend to be in extrasynaptic region and therefore only respond to strong stimuli which causes large NT release and therefore NT reaches extrasynaptic region (role is plasticiy bc it responds to strong signals)

What are NMDA receptors?

Tetrameric ionotropic receptors made from 2xGluN1 and 2xGluN2(A-D) with 3TMD producing an internal carboxyl group

Linked to non-specific cation channel with a reversal potential of 0mV that allows Na and Ca to enter and K to leave cell

Generates fast EPSPs (slower than AMPA)

Agonist = NMDA

Antagonist = AP5

NMDA undergoes a Ca switch which changes subunit composition - neonatal synapses have majority of 1/2B which produces slower responses but adults have majority of 1/2A which produces faster responses

The GluN1 subunit causes the Mg channel block - Mg is similar to Ca but slightly bigger which allows it at negative membrane potentials to enter the NMDA ion channel however it is too big to pass fully therefore blocks ion flow through the channel (seen as flickering) - as the membrane potential increases Mg is repelled and channel conductance is unimpeded (changes IV curve shape)

GluN1 subunit also causes glycine to work as a cofactor (positive allosteric modulator which binds to allosteric site) therefore when glycine and NMDA are present together it produces a large increased response

Ketamine can block the pore of the NMDA integral ion channel blocking conductance

What are mGluR receptors?

7TM GPCR which can be coupled to Gq (excitation) or Gi (inhibition) both of which are directly linked to ion channels

Made up of subunits mGluR1-8 where

• Group 1 (mGluR1 + 5) link to Gq and are postsynaptic

• Group 2 (mGluR2 + 3) link to Gi and are presynaptic

• Group 3 (mGluR4 + 6 + 8) link to Gi and are presynaptic

• Group 2 and 3 have different pharmacology (agonist and antagonists) and different distribution

Agonist = ACPD (Grp 1+2)

Antagonist = MCPG (non-selective)

Electrophysiological actions include

• Blocks afterhyperpolarisation (Ca activated K currents) which is important for firing rate

• Blocks M current (leaky K current) which causes slow EPSP

• Blocks VG Ca channels

All actions are neuromodulatory as through GPCR and 2nd messengers

Describe the physiology and pathophysiology of mGluR receptors

Slow excitatory neuromodulation and transmission, synaptic plasticity

Fragile X syndrome, Schizophrenia, PD

Describe the physiology and pathophysiology of AMPA receptors

Mediates most fast EPSPs

Epilepsy

Describe the physiology and pathophysiology of kainate receptors

Presynaptically modulates release and postsynaptically mediates EPSPs

Schizophrenia, depression and autism

Describe the physiology and pathophysiology of NMDA receptors

Fast EPSPs, Ca switch, anaesthesia and LTP

Epilepsy and excitotoxicity

What are the main inhibitory AAs?

GABA is the main inhibitory NT

Glycine is inhibitory in the brain stem and SC

How is GABA synthesised, recycled and broken down?

Glutamic acid decarboxylase converts glutamate into GABA

GABA is taken up by GAT1 on neurons and GAT3 on astrocytes

GABA is metabolised by GABA transaminase

What receptors does GABA work on?

GABA A and GABA B receptors

Describe GABA_A receptors

Pentameric ionotropic receptor with intregral Cl ion channel which generates a fast IPSP

Made from (6α, 3β, 3γ, δ, ε, θ, π, ρ) - typically 2α, 2β, γ

Has a reversal potential of -75mV (+ve compared to RMP of -65/70mV) therefore when GABA binds and the channel opens Cl ions are driven into the cell

Agonist = muscimol

Antagonist = bicucilline (competitve for GABA binding site) or picrotoxin (non-competitive as blocks pore of channel)

Modulated by (GABA must be bound too, modulators each have own binding site)

• Benzodiazepines increase frequency of opening

• Barbituates increase length of opening

• Alcohol increases the freq and dur of opening of specific αβγ combos

Describe GABA_B receptors

Heterodimeric metabotropic 7TMD receptor

Made up of two subunits - GABA_B1 and GABA_B2

Gi coupled

• Postsynaptically (γi) opens K channels with RP of -90mV causing K ions to leave cell = slow IPSP

• Presynaptically block VG Ca channels to prevent NT release

Agonist = baclofen

Antagonist = phaclofen

Detail the physiology and pathophysiology of GABA transmission

Fast and slow IPSPs

Epilepsy (decreased GABA transmission)

Epilepsy treatment (↑synthesis = progabide, ↓breakdown = valproate, enhance GABA action = benzodiazepines)

Tranquilisers (Benzos)

Anaesthesia (Barbs)

Alcoholism alters GABA circuits

How is glycine synthesised

Serine is converted to glycine by serine hydroxymethyltransferase

Describe the glycine receptor

Pentameric ionotropic receptor with intergral Cl ion channel

Made from 3α₁ and 2β subunits (foetal = 5α₂ subunits)

Reversal potential of -75mV therefore when glycine binds and the channel opens Cl ions flow into cell causing fast IPSP

Agonist = glycine

Antagonist = strychnine

Highly present in grey matter of SC

What is the physiological/pathopysiological role of glycine and glycine Rs?

Renshaw glycinergic cells in SC are key in motor control - they release glycine onto α-motor neurons which have collaterals which signal to renshaw cells to switch themselves off allowing twicth contractions and preventing spasms

Spastic patients show no strychnine (causes convulsions as prevents inhibition of movement) binding suggesting no glycine Rs on α-motor neurons