Gaba

-Dr. Ashish Arya Moderator: Dr. M. S. Reddy GABA

Introduction Discovery Synthesis, storage and degradation Receptors Neuropsychiatric implications Drugs

Introduction Gamma Amino Butyric Acid (GABA) is the major inhibitory neurotransmitter of the mammalian CNS. It is broadly distributed in the brain. Implicated in broad range of neuropsychiatric disorders like seizures, anxiety disorders, schizophrenia, alcohol dependence etc.

Discovery In 19th century was know as a metabolite of plant and microorganisms In early 20th century - was isolated as an amino acid in the brain of mouse through paper chromatography. In 1950 Robert and Frankel discovered GABA in human brain. GABA patches: inhibitory effects

Synthesis and Storage Synthesised from amino acid L- Glutamic acid Glutamic acid Decarboxylase (GAD) present in neurons and peripherally in pancreatic islet cells and body fluids. It catalysis the removal of - carboxyl group. GAD 65 and GAD 67 genes encoding GAD

Termination of action GABA transporter (GAT) GAT 1 is identified as a presynaptic receptor. While GAT 2-4 receptor location have yet to be identified. Tiagabine blocks GAT1 receptor increase in synaptic GABA concentration anticonvulsant action.

Termination of action

GABA is catabolised by GABA transaminase (GABA-T). GABA-T is a cell surface, membrane bound enzyme expressed by neurons and glia, oriented towards extracellular compartment. Inhibited by valproic acid and vigabatrin.

Receptors Three major types I. GABA A II. GABA B III. GABA C

GABA A Ligand gated ion channel. Distributed throughout the brain. It is a heteropentamer, made of five subunits with each subunit containing four helical membrane spanning. Ligand binds at the interface between and domain.

There are many different types of GABA A receptors depending on the type of subunit present. Subunits also called isoforms alpha(1-6), beta(1-3), gamma(1-3), delta, epsilon, pi, theta and rho. Different types of GABA A receptors are present in different regions of the brain and at different levels of development.

GABA A receptor when activated, mediates an increase in the conductance. Increase in the influx of Cl- ions causing membrane hyperpolarization. Increase in the threshold for generating action potential. Inhibitory action

Allosteric modulation The site where modulators bind is different from the site of binding of GABA agonist known as allosteric site and the modulator is called allosteric modulator. The modulator has no activity of its own. Positive Allosteric Modulation: ligand binds allosteric site and enhance the action of neurotransmitter. E.g.BZD Negative Allosteric Modulation: ligand binds to the allosteric site while an agonist is also bound and the channel opens less frequently then when

GABA A receptors with alpha 4/6 and delta subunit are insensitive to benzodiazepines. Binds to modulators naturally occurring neurosteroids, alcohol and some general anesthetics. Located extrasynaptically. Regulated by extracelullar GABA molecule that has escaped reuptake and enzymatic destruction Mediate tonic inhibition of postsynaptic neuron Not sensitive to BZD no anxiolytic actions of BZD

GABA A receptor with alpha 1/2/3, beta, gamma 2/3. Postsynaptic in location phasic inhibition. Bursts of inhibition triggered by peak concentration of synaptically released GABA. Sensitive to BZD Anxiolytic actions. Alpha 1 most important for regulating sleep target for various sedative hypnotic agents. Alpha 2/3 most important for regulating anxiety. Abnormal expression of alpha 2, gamma 2 or delta

GABA B Differentiated from GABA A by Insensitive to GABA A antagonist Bicuculline. Activated by Baclofen Member of G-protein couples receptor. Dimer of two seven transmembrane spanning subunits. Widely distributed throughout the CNS.

Located both pre- and post-synaptically. Presynaptically- auto- and hetero-receptor. Inhibits neurotransmitter release. Postsynaptically inhibitory long lasting hyperpolarization by activating K+ channel. GABA B 1 genes GABA B (1A) granule cell layer GABA B (1B) Purkinje cells. GABA B 2 genes

All GABA B agonist and antagonist bind to the extracellular domain of GABA B (1) subunit. GABA B receptor antagonist blocks the action of Gamma Hydroxybutyrate (GHB). GABA C Ligand gated ion channel. Part of the inhibitory Cl- channel. Physiological role is not yet discovered.

Anatomy of the GABA system

Corticolimbic region: Localised in the intrinsic/local circuit neurons Comprise minority of cortical neurons but exhibit profound degree of inhibition on the activity of glutamatergic pyramidal cells. In the cortex, GABAergic interneurons are the primary site of colocalizaton of neuropeptides.

Striatum: GABAergic directly project to the substantia nigra pars reticulata Striatal GABergic neurons also project to the globus pallidus to synapse on the pallidal-subthalamic GABAergic neurons that regulate the excitatory output from the subthalamic nucleus. Cerebellum: In cerebellum, GABAergic Purkinje cells are its main efferent system

Neuropsychiatric implications I. Anxiety disorders Including phobic anxiety disorder, GAD, PTSD, Panic disorder where core feature is some form anxiety or fear coupled with some form of worry. Amygdala central circuit amygdala plays central role in the expression of fear and anxiety. Cortico-Striatal-Thalamo-Cortical (CSTC) loop linked to worry and obsessions across the spectrum of anxiety disorders.

Anxiety can also be triggered by memories stored in the Hippocampus, which activates the Amygdala, in turn causing other brain regions to activated and generate fear. Particular feature of PTSD

GABA is the principal inhibitory neurotransmitter in the brain and serves an important regulatory role in in reducing the activity of many neurons including those in Amygdala and CSTC loop. GABAergic dysfunction has been associated with anxiety disorders, esp with panic disorder. Magnetic Resonant Spectroscopy reveals significant reduction in GABA levels in the ACC and Basal ganglia.

PET scanning reveals highly selective reduction in BZD receptor sites bilaterally in the insular cortex in Panic disorder. Genomwide screen has shown significant linkage at 15q in a region containing GABA a receptor subunit genes and panic disorder.

II. Mood disorders Magnetic Resonant Spectroscopy reveals significant reduction in both GABA and Glutamate in Prefrontal cortex in Major Depressive Disorder. Post mortem studies revealed up regulation of the GABA receptors alpha1 and 2 subunits, consistent with a reduction in GABAergic neurotransmission. Reduced levels of GABA in occipital cortex in episodes of major depressive disorder

In animal studies valproate, carbamazapine, lithium and lamotrigine a/w in increase in GABA turnover in brain. Endocrinal hypothesis: estrogen induces downregulation of GAD resulting in inhibitory action on GABA formation resulting in increased activity of pyramidal cells.

III. Schizophrenia Corticobrainstem glutamate pathways and NMDA receptor function hypothesis Descending glutaminergic pathway projects from cortical pyramidal cells to brainstem neurotransmitter centres inclusing raphe for serotonin, VTA and substantia nigra for dopamine and locus ceruleus for norepinephrine.

The descending corticobrainstem glutamate pathway acts as a brake to the mesolimbic dopamine pathway through an inhibitory GABA interneuron in the VTA. Which are activated by NMDA receptors.

Corticostriatal glutamate pathway (CSTC loop) Descending glutaminergic output from the pyramidal cells in cortex nucleus accumbens in ventral striatum forming first leg of the CSTC loop. Ascending pathway from thalamus to cortex return leg of the CSTC loop. GABA neurons located in the thalamus acts as the sensory filters and prevents too much sensory input from penetrating the thalamus into the cortex.

Dopamine inhibits GABA in CSTC loop reduces the effectiveness of thalamic filter opposes the excitatory input of the glutamate from corticostriatal glutamate projections.

Mesolimbic dopamine hyperactivity reduces thalamic inhibition increases cortical activation NMDA receptor hypofunction in corticostriatal and corticoaccumbens projections sensory overload.

Postmortem studies indicated a reduction in the activity of GAD in the cortex in patients with schizophrenia. Neurochemistry: reduced expression of GAD 67, Parvalbumin-positive GABAergic interneurons and the GABA transporter (GAT). Upregulation of GABA receptors supports hypofunction of presynaptic GABAergic neurons.

Epilepsy In epilepsy, abnormal electrical discharges are due to hyperexcitable neurons with sustained postsynaptic depolarization. Decreased GABA inhibition of cortical excitability is one of the proposed mechanism. Penicllin induced cortical injury causes seizures through decreased GABA inhibition. BZD and barbiturates reduces seizures by enhancing GABA receptor current and valproate through blockade of GABA catabolism.

Reward circuits Mesolimbic dopamine pathway is the final common pathway of reinforcement and reward in the brain. Reactive reward system: bottom up provides motivational and behavioural drive in ascending mesolimbic pathway. Reflective reward system: top down connections from prefrontal cortex down to nucleus accumbens and involved in regulating impulses and keeping some flexibility of choice.

Turning reward into goal directed behaviour The output of the reward system is the completion of CSTC loop. The striatal/accumbens component of reward circuitry has output GABAergic neurons that travel to another part of striatal complex the ventral pallidum. From there the connections go to thalamus and back to prefrontal cortex where behaviours are implemented such as learning and activities in long term rewards and drug seeking behaviour

Alcohol and reward Alcohol reinforcing effects are mediated by its effects specially on mesolimbic reward circuitry. Acts at presynaptic glutamate receptors and voltage sensitive Calcium channels to inhibit glutamate release. Enhance the GABA release by blocking the presynaptic GABA B receptors and acts on postsynaptic GABA A receptors of delta subtypes

Opiate neurons arise from arcuate nucleus and projects to the glutamate and GABA neurons. Alcohol acts on mu opiate receptors which increases the dopamine release in the nucleus accumbens. Persistent abuse and dependency on ethanol result in downregulation of GABA and an upregulation of NMDA receptors such that sudden discontinuation results in hyperexcitable state characterised by delirium tremens.

Nicotine and reward:

Varenicline: nicotine partial agonist

Sleep and Wakefulness CSTC loop regulate the arousal and part by controlling the size of thalamic filter. Sleep wake switch: set of circuit present in hypothalamus that regulate sleep/wake discontinuously like an on/off switch. Tuberomammillary nucleus wake promoter Vantrolateral preoptic nucleus(VLPO) sleep promoter.

Orexin containing neurons of lateral hypothalamus- promotes wakefullness. Melatonin sensitive neurons of the Suprachiasmatic nucleus (SCN) regulates circadian input to the sleep/wake switch.

Insomnia occurs when it fails to filter out sensory input to the cortex in night and daytime sleepiness when it filters out too much sensory input to the cortex in the daytime.

Gaba

Health & Medicine

major depressive

decreased

pyramidal

nucleus accumbens

panic disorder

sensory input

cstc loop

allosteric