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.

NIH fellowships for Kuzirian and Ghiretti support neural development research

Marissa Kuzirian and Amy Ghiretti, graduate students in the lab of Dr. Suzanne Paradis, were each recently awarded Ruth L. Kirschstein National Research Service Awards for Individual Predoctoral Fellows (F31s) from the National Institutes of Health. Marissa’s 2.5-year award from the National Institute of Neurological Disorders and Stroke funds research to explore the role of Semaphorin4D and its receptor, PlexinB1, in regulating inhibitory synapse development and ultimately setting up proper neural connections in the mammalian CNS. Amy’s 2-year award from the National Institute on Drug Abuse funds a collaborative project between the Paradis, Lau, and Van Hooser labs here at Brandeis to elucidate the function of Rem2 in mediating experience-dependent changes in dendritic morphology in a living, intact animal system.

The basis for Marissa and Amy’s work comes from research into neurodevelopmental disorders such as Autism Spectrum Disorders (ASDs), as well as drug abuse and addiction. Proteins that regulate neurodevelopmental processes such as synapse development and dendritic morphology are important in both neurological disorders and drug addiction. Proper communication between neurons depends on the precise assembly and development of synaptic connections. The transmembrane protein Semaphorin4D (Sema4D) is necessary for proper GABAergic synapse formation, as knockdown of expression in the postsynaptic neuron by RNAi leads to a decrease in GABAergic synaptic density in cultured neurons (Paradis et al 2007). Marissa’s work will further explore this role of Sema4D in GABAergic synapse development.

Inhibitory synapses are identified in white along dendrites of a rat hippocampal neuron. Synapses are defined as sites of overlap between the postsynaptic protein GABAA receptor subunit γ2 (red) and the presynaptic protein GAD65 (blue) visualized by immunostaining. Neurons are visualized by immunostaining for MAP2 (green).

Marissa’s preliminary results demonstrate that adding the soluble, extracellular domain of Sema4D to cultured hippocampal neurons is sufficient to drive GABAergic synapse formation. This increase depends on the expression of Sema4D’s receptor, PlexinB1. Thus, Marissa’s work defines PlexinB1 as a novel receptor mediating GABAergic synapse formation in response to Sema4D in the mammalian CNS. The goal of Marissa’s project is to elucidate the role of Sema4D and its receptor, PlexinB1, in GABAergic synapse development. In experiments she proposed, she hypothesizes that Sema4D acts to initiate assembly of GABAergic synaptic proteins such as GABAA receptors and gephyrin through its receptor PlexinB1. This will be tested using a variety of imaging techniques in cultured hippocampal neurons, including confocal and time-lapse imaging, to measure the mobility and accumulation of GABAergic synaptic proteins in neurons after treatment with soluble Sema4D. The experiments will not only greatly expand our understanding of a novel receptor-ligand pair in GABAergic synapse development, it will inform as to some of the basic mechanisms underlying GABAergic synaptogenesis.

Molecular mechanisms, such as the Sema4D-PlexB1 interaction described above, are critical for the ability of the central nervous system (CNS) to respond to extracellular stimuli and make corresponding changes in the structure and function of a neuron. At the behavioral level, this plasticity allows an organism to respond to a changing environment appropriately in order to survive. At the level of individual neurons, this is reflected in changes in gene expression that occur in response to a variety of stimuli, including alterations in neuronal network activity. The goal of Amy’s work is to characterize a direct molecular link between changes in neuronal activity and changes in dendritic morphology.

A neuron in the optic tectum of a Xenopus tadpole; Green Fluorescent Protein expression allows the dendrites to be visualized.

Amy has previously implicated the protein Rem2, a type of signaling molecule known as a GTPase, as a mediator of such neurodevelopmental processes as excitatory synapse formation and dendritic morphology (Ghiretti & Paradis 2011). The expression of Rem2 in individual neurons is upregulated following increased neuronal activity, suggesting that it may serve as a direct link between changes in activity and corresponding changes in the structure and function of neurons. Her recently funded work will utilize Xenopus laevis tadpoles to study the effects of visual experience (by exposing the tadpoles to a light stimulus) on Rem2 expression, and in turn, how Rem2 mediates experience-dependent changes in the morphology of neurons in a region of the brain known as the optic tectum, where visual processing takes place. Ultimately, a full understanding of how Rem2 functions to shape the morphology of neurons in an intact system may help to inform knowledge of how the human brain changes as a result of neurological disorders or drug abuse, and aid in the development of more effective treatments to prevent these changes from occurring.

Koushika (PhD ’99) gains HHMI International Early Career Scientist award

Sandhya P. Koushika, a gradute of Brandeis’s Molecular and Cell Biology program (PhD, 1999), and currently running a lab at the National Center for Biological Sciences in Bangalore, has been named an HHMI International Early Career Scientist. This pilot program of the Howard Hughes Medical Institute seeks to identify scientists working abroad with the potential to become scientific leaders, and awards each with $650,000 over five years to help establish independent research programs. Of 28 scientists from 12 countries so named, Koushika was the only recipient in India. While at Brandeis, Koushika worked in Kalpana White‘s lab on the role of ELAV in neural develeopment in Drosophila. In her postdoc, Koushika switched systems to work in the worm C. elegans, and her lab is currently focused on genetic techniques to study axonal transport, a key feature of nerve cells, in the worm model.

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.

Claude Desplan to speak in Bauer Distinguished Lecturer Series

Claude Desplan, Silver Professor and Professor of Biology at NYU, will visit Brandeis the week of March 21-25 as part of the M.R.Bauer Foundation Distinguished Lecturer Series. Desplan’s work focuses on developmental biology in insects, and is particularly concerned with pattern formation. A recent topic of interest is the development of the neural network that supports color vision in the optic lobe of the fruit fly.

Desplan will speak on Monday, March 21 at 4:00 pm in Gerstenzang 121. The title of his talk will be “Processing of Color Information in Drosophilia”. Desplan will speak again at Neurobiology Journal Club on March 22 at 12:05 pm in Gerstenzang 121.

According to a post at

Desplan is the funniest, nicest guy ever. At first you may not be able to understand him too too easily due to his french accent but after a few days that’s not a problem. Desplan went pretty slow and went over concepts that people didn’t seem to understand. Even then he held very helpful review sessions. Great professor.


Turning germline cells into neurons

Piali Sengupta discusses the most recent research in how nerve cells are programmed to develop in “Cellular reprogramming: chromatin puts on the brake“, published in the Feb 22 issue of Current Biology.

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