Fast-spiking interneurons and the critical period

How do children learn to play instruments and speak languages so much easier than adults, and why does brain damage result in worse outcomes in the mature brain vs. the young brain?  These questions are central to the study of how “critical periods” are regulated in the brain.


Electron micrograph from a single 70 nm cross-section through a fast-spiking parvalbumin-containing (gold labeling = white dots) presynaptic terminal forming a synapse (red dots) with a pyramidal soma. Original colors are inverted, contours have been raised and membranous structures are highlighted in aqua for ease of visualization. Presynaptic vesicles (colored ovals) within perisomatic fast spiking terminals mostly cluster within ∼200 nm of the synapse, with a few close enough (≤2 nm) to be deemed docked.

Critical periods in brain development define temporal windows when neuronal physiology and anatomy are most sensitive to changes in sensory input or experience (e.g. sound, touch, light, etc.).  The maturation of inhibitory cells that release the neurotransmitter GABA, especially a subset called fast-spiking (FS) interneurons, is thought to gate this period of neuronal ‘plasticity’ in the mammalian primary visual cortex.  However, it has remained unclear what aspects of FS cell development are important for permitting this period of neuronal malleability in the visual cortex. A new paper in Journal of Neuroscience from the Turrigiano lab addresses the question.

To explore how FS cell development might be linked to critical period plasticity, Brandeis postdoc Marc Nahmani and Professor Gina Turrigiano employed a well-established assay for cortical plasticity in visual cortex called monocular deprivation (MD), and measured FS cell connections using confocal and electron microscopy, as well as optogenetic stimulation of the FS cell population (i.e. shining light onto FS cells possessing light-gated channels to make them fire action potentials).

Following up on previous work from the Turrigiano lab (Maffei et al., 2006), they found that MD induces a coordinated increase in FS interneuron to pyramidal cell (the major excitatory output cells of the cortex) pre- and postsynaptic strength.  These changes occur if MD is performed during, but not before the critical period in visual cortex, suggesting they may play a role in gating this period of heightened neuronal plasticity.  Future studies are aimed at determining the timeline for these changes across the extent of the critical period in visual cortex.

see: Nahmani M, Turrigiano GG (2014) Deprivation-Induced Strengthening of Presynaptic and Postsynaptic Inhibitory Transmission in Layer 4 of Visual Cortex during the Critical Period. Journal of Neuroscience 34:2571-2582.

Making new synapses with Sema4D

There are two main types of synaptic connections in the mammalian brain: excitatory glutamatergic synapses and inhibitory GABAergic synapses. The balance between excitatory and inhibitory inputs a neuron receives regulates the overall activity of neuronal networks; disruptions to this balance can cause epilepsy.

A new paper in J. Neuroscience from the Paradis lab shows that treatment of cultured neurons with the extracellular domain of the protein Sema4D causes a rapid increase (i.e. within 30 minutes) in the density of functional GABAergic synapses. Further, addition of Sema4D to neurons drives GABAergic synapse formation through a previously unappreciated mechanism: the splitting of pre-existing assemblies of the Gephyrin scaffolding protein. To our knowledge this is the fastest demonstration of synapse formation reported thus far and has significant implications for our understanding of the mechanisms of GABAergic synapse formation.

Screen Shot 2013-05-26 at 5.03.05 PMWhile the underlying mechanism of epileptogenesis is largely unknown, recurrent seizures emerge when there is an increase in network activity. One possible therapeutic treatment would be to restore normal network activity by increasing network inhibition. In an in vitro model of epilepsy, acute treatment with the protein Sema4D rapidly silences neuronal hyperexcitability, suggesting a possible use of Sema4D as a disease-modifying treatment for epilepsy.

Lead authors on the paper were Marissa Kuzirian, a grad student in the Neuroscience Ph.D. program, and Anna Moore, a Brandeis Neuroscience postdoctoral fellow.

Methylgloxal and anxiety disorder

methylglyoxal, aka pryuvaldehyde

A recent paper in The Journal of Clinical Investigation by researchers from the University of Chicago, working together with Assistant Research Professor of Biochemistry Leigh Plant from Brandeis, reveals a new mechanism for anxiety disorders involving the metabolite methylglyoxal (MG) (right).  The researchers investigated the effect of Glyoxalase 1 (Glo1) expression in mice. Increasing Glo1 copy number, and hence expression, in mice increased anxiety-like behavior. Since Glo1 metabolizes MG, they looked for a direct effect by administering MG, and found it had an anxiolytic effect in the mouse model (n.b.. MG is toxic, so don’t take it to treat anxiety). Inhibitors of Glo1 might therefore have anxiolytic effects, which they showed for the inhibitor S-bromobenzylglutathione cyclopentyl diester

Electrophysiology experiments were conducted to elucidate the mechanism of action of MG, suggesting that it had a GABAergic effect in vivo, and specifically that it is an agonist of the GABAA receptor in multiple neuron types.

So why is a relatively reactive small molecule, normally considered a by-product of glycolysis in animals, acting at neuronal receptors? Can this be exploited with pharmacological methods? What other functions does methylglyoxal have in the nervous system?  It may have many — another very recent paper in Nature Medicine suggests a role for MG in pain sensitivity and diabetic neuropathy, so there may be many interesting parts to this story.

Pre-med undergraduates should take note — keeping track of all those metabolites in glycolysis that you learn about in introductory biochemistry is far from irrelevant to modern medicine!



Glutamatergic and GABAergic

Can you say that three times fast? Glumatergic (excitatory) synapses respond to the neurotransmitter  glutamate, and GABAergic (inhibitory) synapses respond to gamma-aminobutyric acid (GABA).  GABA is formed by decarboxylating glutamate. These are the “workhorse” neurotransmitters in the brain.

Neuroscience grad stduent Marissa Stearns Kuzirian and Assistant Professor of Biology Suzanne Paradis discuss what’s known about  how GABAergic synapses form, and the relationships to the previously better-studied formation of glutamergic synapses, in a new review entitled  “Emerging themes in GABAergic synapse development” in Progress in Neurobiology.

Tuning up inhibition

On Monday, October 18th at 4:00, Karl Kandler, Ph.D. will be our third M.R. Bauer Colloquium speaker for the 2010-2011 academic year. His talk on Tuning Up Inhibition will be presented in Gerstenzang 121. Refreshments will be available at 3:45. Gina Turrigiano is the host.

Karl is interested in how experience refines inhibitory connections in the auditory system. Recent work has shown, among other things, that
GABAergic neurons can co-release glutamate early in development, and that this early glutamate-mediated excitation is necessary for refinement of an auditory map.

Karl Kandler is a professor in the departments of Otolaryngology and Neurobiology at the University of Pittsburgh, School of Medicine. He received his Ph.D. from the University of Tuebingen, Germany.

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