Mario Galarreta

A network of fast-spiking cells in the neocortex connected by electrical synapses.

Encoding of information in the cortex is thought to depend on synchronous firing of cortical neurons. Inhibitory neurons are known to be critical in the coordination of cortical activity, but how interaction among inhibitory cells promotes synchrony is not well understood. To address this issue directly, we have recorded simultaneously from pairs of fast-spiking (FS) cells, a type of γ-aminobutyric acid (GABA)-containing neocortical interneuron. Here we report a high occurrence of electrical coupling among FS cells. Electrical synapses were not found among pyramidal neurons or between FS cells and other cortical cells. Some FS cells were interconnected by both electrical and GABAergic synapses. We show that communication through electrical synapses allows excitatory signalling among inhibitory cells and promotes their synchronous spiking. These results indicate that electrical synapses establish a network of fast-spiking cells in the neocortex which may play a key role in coordinating cortical activity.

Frequency-dependent synaptic depression and the balance of excitation and inhibition in the neocortex.

The stability of cortical neuron activity in vivo suggests that the firing rates of both excitatory and inhibitory neurons are dynamically adjusted. Using dual recordings from excitatory pyramidal neurons and inhibitory fast-spiking neurons in neocortical slices, we report that sustained activation by trains of several hundred presynaptic spikes resulted in much stronger depression of synaptic currents at excitatory synapses than at inhibitory ones. The steady-state synaptic depression was frequency dependent and reflected presynaptic function. These results suggest that inhibitory terminals of fast-spiking cells are better equipped to support prolonged transmitter release at a high frequency compared with excitatory ones. This difference in frequency-dependent depression could produce a relative increase in the impact of inhibition during periods of high global activity and promote the stability of cortical circuits.

Electrical synapses between Gaba-Releasing interneurons

Although gap junctions were first demonstrated in the mammalian brain about 30 years ago, the distribution and role of electrical synapses have remained elusive. A series of recent reports has demonstrated that inhibitory interneurons in the cerebral cortex, thalamus, striatum and cerebellum are extensively interconnected by electrical synapses. Investigators have used paired recordings to reveal directly the presence of electrical synapses among identified cell types. These studies indicate that electrical coupling is a fundamental feature of local inhibitory circuits and suggest that electrical synapses define functionally diverse networks of GABA-releasing interneurons. Here, we discuss these results, their possible functional significance and the insights into neuronal circuit organization that have emerged from them.

Electrical and chemical synapses among parvalbumin fast-spiking GABAergic interneurons in adult mouse neocortex

Networks of γ-aminobutyric acid (GABA)ergic interneurons connected via electrical and chemical synapses are thought to play an important role in detecting and promoting synchronous activity in the cerebral cortex. Although the properties of electrical and chemical synaptic interactions among inhibitory interneurons are critical for their function as a network, they have only been studied systematically in juvenile animals. Here, we have used transgenic mice expressing the enhanced green fluorescent protein in cells containing parvalbumin (PV) to study the synaptic connectivity among fast-spiking (FS) cells in slices from adult animals (2–7 months old). We have recorded from pairs of PV-FS cells and found that the majority of them were electrically coupled (61%, 14 of 23 pairs). In addition, 78% of the pairs were connected via GABAergic chemical synapses, often reciprocally. The average coupling coefficient for step injections was 1.5% (n = 14), a smaller value than that reported in juvenile animals. GABA-mediated inhibitory postsynaptic currents and potentials decayed with exponential time constants of 2.6 and 5.9 ms, respectively, and exhibited paired-pulse depression (50-ms interval). The inhibitory synaptic responses in the adult were faster than those observed in young animals. Our results indicate that PV-FS cells are highly interconnected in the adult cerebral cortex by both electrical and chemical synapses, establishing networks that can have important implications for coordinating activity in cortical circuits.

Electrical synapses define networks of neocortical GABAergic neurons

Recent work using paired recording has provided a direct demonstration of functional electrical synapses between neocortical neurons of both juvenile and adult animals. Electrical synapses have been found among GABAergic interneurons but not pyramidal cells. Interestingly, necortical electrical synapses almost exclusively connect GABAergic neurons belonging to the same class. So far, at least five different neocortical networks defined by extensive and selective electrical coupling have been studied in the neocortex. These results could provide important clues to the understanding of functional cortical circuitry.

Electrical Coupling among Irregular-Spiking GABAergic Interneurons Expressing Cannabinoid Receptors

Anatomical studies have shown that the G-protein-coupled cannabinoid receptor-1 (CB1) is selectively expressed in a subset of GABAergic interneurons. It has been proposed that these cells regulate rhythmic activity and play a key role mediating the cognitive actions of marijuana and endogenous cannabinoids. However, the physiology, anatomy, and synaptic connectivity of neocortical CB1-expressing interneurons remain poorly studied. We identified a population of CB1-expressing interneurons in layer II/III in mouse neocortical slices. These cells were multipolar or bitufted, had a widely extending axon, and exhibited a characteristic pattern of irregular spiking (IS) in response to current injection. CB1-expressing-IS (CB1-IS) cells were inhibitory, establishing GABAA receptor-mediated synapses onto pyramidal cells and other CB1-IS cells. Recently, electrical coupling among other classes of cortical interneurons has been shown to contribute to the generation of rhythmic synchronous activity in the neocortex. We therefore tested whether CB1-IS interneurons are interconnected via electrical synapses using paired recordings. We found that 90% (19 of 21 pairs) of simultaneously recorded pairs of CB1-IS cells were electrically coupled. The average coupling coefficient was ∼6%. Signaling through electrical synapses promoted coordinated firing among CB1-IS cells. Together, our results identify a population of electrically coupled CB1-IS GABAergic interneurons in the neocortex that share a unique morphology and a characteristic pattern of irregular spiking in response to current injection. The synaptic interactions of these cells may play an important role mediating the cognitive actions of cannabinoids and regulating coherent neocortical activity.

Cannabinoid Sensitivity and Synaptic Properties of 2 GABAergic Networks in the Neocortex

Distinct networks of gamma-aminobutyric acidergic interneurons connected by electrical synapses can promote different patterns of activity in the neocortex. Cannabinoids affect memory and cognition by powerfully modulating a subset of inhibitory synapses; however, very little is known about the synaptic properties of the cannabinoid receptor-expressing neurons (CB(1)-positive irregular spiking [CB(1)-IS]) in the neocortex. Using paired recordings in neocortical slices, we 1st report here that synapses of CB(1)-IS cells, but not synapses of fast-spiking (FS) cells, are suppressed by release of endocannabinoids from pyramidal neurons. CB(1)-IS synapses were characterized by a very high failure rate that contrasted with the high reliability of FS synapses. Furthermore, CB(1)-IS cells received excitatory inputs less frequently compared with FS cells and made significantly less frequent inhibitory contacts onto local pyramids. These distinct synaptic properties together with their characteristic irregular firing suggest that CB(1)-IS cells play different role in neocortical function than that of FS cells. Thus, whereas the synaptic properties of FS cells can allow them to impose high-frequency rhythmic oscillatory activity, those of CB(1)-IS cells may lead to disruption of fast rhythmic oscillations. Our results suggest that activity-dependent release of cannabinoids, by blocking CB(1)-IS synapses, may alter the role of inhibition in neocortical circuits.

Synchronous versus asynchronous transmitter release: a tale of two types of inhibitory neurons

Inhibitory cortical neurons are thought to generate temporally precise signals important for information processing, but a new study shows that CCK-expressing interneurons continue to release GABA for several hundred milliseconds after bursts of action potentials.

Fast Spiking Cells and the Balance of Excitation and Inhibition in the Neocortex

Excitatory glutamatergic neurons largely outnumber inhibitory ones and account for about 80% of the cells in the neocortex. In addition, the axonal collaterals of excitatory neurons make large number of contacts with neighboring neurons. As a result of these extensive recurrent excitatory circuits, the neocortex is a structure particularly prone to epilepsy. Epileptic activity is characterized by both a dramatic increase in the average firing rate and in synchrony across a large population of neurons. It is well known that blockade of inhibition leads to epileptic activity1, and that drugs (benzodiazepines and barbiturates) that enhance GABA-mediated inhibition are useful in preventing it2. Thus, a fundamental role of inhibitory neurons is to stabilize cortical circuits and prevent epileptic activity. However, the mechanisms that adjust the relative level of excitation and inhibition are only poorly understood. In this chapter, we will discuss our recent experimental investigation of the synaptic and network properties of a subtype of inhibitory interneuron, the fast-spiking cell (FS), that may provide powerful anti-epileptic and stabilizing mechanisms. First, we will discuss the observation that prolonged firing induces much less depression at inhibitory synapses made by FS cells than at excitatory synapses among pyramidal neurons. This difference, which is frequency-dependent, could promote stable activity in cortical networks and prevent runaway excitation. In the second part of the chapter, we will discuss how FS cells are selectively interconnected via electrical synapses. The presence of electrical coupling together with a precise spike transmission between pyramidal and FS cells, may allow these neurons to detect synchronous excitation and increase their firing accordingly.