Molecular Neurobiology

Understanding the biological mechanisms by which proteins carry out their functions is important for addressing neural circuits that underlie behaviour. I apply a range of robust cutting-edge approaches that are gold-standard in modern neuroscience to understand how synapses and brain circuits function at the molecular level.

Cell surface stability and clustering of proteins at synapses are important facets of signaling and plasticity as synaptic concentrations of proteins critically determine efficacy of synaptic signaling.

Please see below for examples of some of our work on molecular neurobiology.

The synaptic zip code: what determines which subtypes of GABA receptors should localise to synapses?

GABA_A receptor pentamers are constructed from 19 genes. Thankfully for our purposes, only certain receptor subtypes are viable. Importantly, out of these only a small subset of receptors are thought to localise at inhibitory synapses. What makes a receptor synaptic vs extrasynaptic is unknown. Using single particle tracking of quantum dots, we reveal that synaptic localisation dependents on receptor subtype and protein domains.

Synaptic zipcode

A brake in excitability: NMDA receptor activation recruits GABA_B receptors to limit presynaptic excitability

While excitability is an omnipresent feature of nervous tissue, uncontrolled excitability can lead to multiple neurological diseases. Our nervous system has therefore evolved multiple strategies to control excitability in fast (milliseconds) and slow (seconds to hours) timescales. We show that activation of NMDA receptors recruits GABA_B receptors by fast lateral diffusion to the presynaptic terminals to control presynaptic excitability.

Brake in excitability

Destination plasma membrane: single amino acid residues govern cell surface expression of GABA_A receptors

Only a handful of the 19 GABA_Areceptor subunits can exit the endoplasmic reticulum (ER) in mammalian cells for cell surface expression. What prevents major subunits from escaping the ER are unknown. We report that two pharmacologically important amino acid residues in GABA_A receptor α subunits control cell surface expression. Interestingly homomeric subunits express on the cell surface as pentameric ion channels.

To the plasma membrane

Domains of stability: Sushi domains confer distinct trafficking profiles to GABA_B receptor subtypes

Sushi domains are abundantly present in immune cells. The GABA_B receptor was the first GPCR identified to contain this evolutionarily conserved domain in one of the alternatively spliced isoforms. We found that the presence of the Sushi domains in this major subtype of GABA_B receptors confers greater neuronal membrane stability at the soma, dendrites and dendritic spines.

Domains of stability

Stability in pairing up: new role of heterodimerization – greater cell surface stability of GABA_B GPCRs

The GABA_B receptor was the first GPCR reported to require hetorodimerization in order to be functionally active. Heterodimerization is indispensable for function as the GABA binding and G-protein coupling sites reside on two different subunits. We show that in addition to these known facets, heterodimerization increases cell surface stability of GABA_B receptors.

Stability in pairs

Trans-synaptic stability: protein kinase A phosphorylation disperses synaptic neuroligin-2 affecting inhibition

In collaboration with Dr Els Halff and Professor Josef Kittler (University College London, UK) we studied single particle tracking of the trans-synaptic adhesion protein neuroligin-2. Here we identify a crucial role of lateral mobility in dispersal of neuroligin-2 from inhibitory synapses upon PKA phosphorylation that ultimately affects inhibitory neurotransmission efficacy.

Trans-synaptic stability