PTEN and the Emergence of Cortical Perisomatic Inhibition

Adequate perisomatic inhibition in the cortex, as supplied by parvalbumin-expressing (PV) inhibitory neurons, is fundamental to critical period plasticity and cortical function. Yet, how perisomatic inhibition emerges just at the inception of the critical period to shape the structure and function of cortical circuits is little understood. We report that PTEN in PV cells serves as a regulator of perisomatic inhibition by controlling the expression of EphB4, an inhibitor of PV to pyramidal inhibitory synapse formation. This points to a molecular disinhibitory mechanism for the initiation of the critical period, whereby sensory experience acts on PTEN in PV cells to decrease EphB4 expression in order to reduce the native repulsion between PV presynaptic terminals and pyramidal neuron cell bodies. This would then permit the formation of adequate perisomatic inhibition in cortical circuits. Given the compelling link between deficits in cortical perisomatic inhibition and various psychiatric disorders, such as autism spectrum disorders and schizophrenia, our findings also recommend EphB4 in PV cells as a novel target of therapy

PTEN and the Emergence of Cortical Perisomatic Inhibition

Adequate perisomatic inhibition in the cortex, as supplied by parvalbumin-expressing (PV) inhibitory neurons, is fundamental to critical period plasticity and cortical function. Yet, how perisomatic inhibition emerges just at the inception of the critical period to shape the structure and function of cortical circuits is little understood. We report that PTEN in PV cells serves as a regulator of perisomatic inhibition by controlling the expression of EphB4, an inhibitor of PV to pyramidal inhibitory synapse formation. This points to a molecular disinhibitory mechanism for the initiation of the critical period, whereby sensory experience acts on PTEN in PV cells to decrease EphB4 expression in order to reduce the native repulsion between PV presynaptic terminals and pyramidal neuron cell bodies. This would then permit the formation of adequate perisomatic inhibition in cortical circuits. Given the compelling link between deficits in cortical perisomatic inhibition and various psychiatric disorders, such as autism spectrum disorders and schizophrenia, our findings also recommend EphB4 in PV cells as a novel target of therapy

Pten and EphB4 regulate the establishment of perisomatic inhibition in mouse visual cortex.

Perisomatic inhibition of pyramidal neurons is established by fast-spiking, parvalbumin-expressing interneurons (PV cells). Failure to assemble adequate perisomatic inhibition is thought to underlie the aetiology of neurological dysfunction in seizures, autism spectrum disorders and schizophrenia. Here we show that in mouse visual cortex, strong perisomatic inhibition does not develop if PV cells lack a single copy of Pten. PTEN signalling appears to drive the assembly of perisomatic inhibition in an experience-dependent manner by suppressing the expression of EphB4; PV cells hemizygous for Pten show an ∼2-fold increase in expression of EphB4, and over-expression of EphB4 in adult PV cells causes a dismantling of perisomatic inhibition. These findings implicate a molecular disinhibitory mechanism driving the establishment of perisomatic inhibition whereby visual experience enhances Pten signalling, resulting in the suppression of EphB4 expression; this relieves a native synaptic repulsion between PV cells and pyramidal neurons, thereby promoting the assembly of perisomatic inhibition

Ultrasensitive fluorescent proteins for imaging neuronal activity

Fluorescent calcium sensors are widely used to image neural activity. Using structure-based mutagenesis and neuron-based screening, we developed a family of ultrasensitive protein calcium sensors (GCaMP6) that outperformed other sensors in cultured neurons and in zebrafish, flies and mice in vivo. In layer 2/3 pyramidal neurons of the mouse visual cortex, GCaMP6 reliably detected single action potentials in neuronal somata and orientation-tuned synaptic calcium transients in individual dendritic spines. The orientation tuning of structurally persistent spines was largely stable over timescales of weeks. Orientation tuning averaged across spine populations predicted the tuning of their parent cell. Although the somata of GABAergic neurons showed little orientation tuning, their dendrites included highly tuned dendritic segments (5-40-µm long). GCaMP6 sensors thus provide new windows into the organization and dynamics of neural circuits over multiple spatial and temporal scales

Ultrasensitive fluorescent proteins for imaging neuronal activity

Fluorescent calcium sensors are widely used to image neural activity. Using structure-based mutagenesis and neuron-based screening, we developed a family of ultra-sensitive protein calcium sensors (GCaMP6) that outperformed other sensors in cultured neurons and in zebrafish, flies, and mice in vivo. In layer 2/3 pyramidal neurons of the mouse visual cortex, GCaMP6 reliably detected single action potentials in neuronal somata and orientation-tuned synaptic calcium transients in individual dendritic spines. The orientation tuning of structurally persistent spines was largely stable over timescales of weeks. Orientation tuning averaged across spine populations predicted the tuning of their parent cell. Although the somata of GABAergic neurons showed little orientation tuning, their dendrites included highly tuned dendritic segments (5 - 40 micrometers long). GCaMP6 sensors thus provide new windows into the organization and dynamics of neural circuits over multiple spatial and temporal scales

Flexible, scalable, high channel count stereo-electrode for recording in the human brain

Over the past decade, stereotactically placed electrodes have become the gold standard for deep brain recording and stimulation for a wide variety of neurological and psychiatric diseases. Current electrodes, however, are limited in their spatial resolution and ability to record from small populations of neurons, let alone individual neurons. Here, we report on an innovative, customizable, monolithically integrated human-grade flexible depth electrode capable of recording from up to 128 channels and able to record at a depth of 10 cm in brain tissue. This thin, stylet-guided depth electrode is capable of recording local field potentials and single unit neuronal activity (action potentials), validated across species. This device represents an advance in manufacturing and design approaches which extends the capabilities of a mainstay technology in clinical neurology