Colin J. Akerman

Depolarizing GABAergic Conductances Regulate the Balance of Excitation to Inhibition in the Developing Retinotectal Circuit In Vivo

Neurotransmission during development regulates synaptic maturation in neural circuits, but the contribution of different neurotransmitter systems is unclear. We investigated the role of GABAA receptor-mediated Cl− conductances in the development of synaptic responses in the Xenopus visual system. Intracellular Cl− concentration ([Cl−]i) was found to be high in immature tectal neurons and then falls over a period of several weeks. GABAergic synapses are present at early stages of tectal development and, when activated by optic nerve stimulation or visual stimuli, induce sustained depolarizing Cl− conductances that facilitate retinotectal transmission by NMDA receptors. To test whether depolarizing GABAergic inputs cooperate with NMDA receptors during activity-dependent maturation of glutamatergic synapses, we prematurely reduced [Cl−]i in tectal neurons in vivo by expressing the Cl− transporter KCC2. This blocked the normal developmental increase in AMPA receptor-mediated retinotectal transmission and increased GABAergic synaptic input to tectal neurons. Therefore, depolarizing GABAergic transmission plays a pivotal role in the maturation of excitatory transmission and controls the balance of excitation and inhibition in the developing retinotectal circuit.

Refining the roles of GABAergic signaling during neural circuit formation

Our understanding of the role of GABA signaling in circuit development is rapidly expanding. Here, we review three recent refinements in our understanding of the diverse roles that GABA plays at different stages of neural circuit formation. First, we discuss recent evidence that depolarizing GABA plays at least a permissive role in promoting both excitatory and inhibitory synaptogenesis in developing neurons (including newly generated neurons in the adult). Next, we discuss recent evidence that GABAergic circuits sculpt the temporal and spatial aspects of synaptic integration. Consequently, early developmental events affecting the establishment of GABAergic circuits will control subsequent activity-dependent refinements of information processing and circuit function. In the third section, we review recent evidence of molecular mechanisms by which GABAergic signaling plays a role in the regulation of the balance between GABAergic and glutamatergic transmission in developing circuits. Throughout the review, we concentrate on the effects of the signaling by GABA(A) receptors, as told from the point of view of the GABA-responsive cells, and do not discuss mechanisms that govern GABA release or activity of GABAergic neurons per se.

Optogenetic silencing strategies differ in their effects on inhibitory synaptic transmission

Optogenetic silencing using light-driven ion fluxes permits rapid and effective inhibition of neural activity. Using rodent hippocampal neurons, we found that silencing activity with a chloride pump can increase the probability of synaptically evoked spiking after photoactivation; this did not occur with a proton pump. This effect can be accounted for by changes to the GABAA receptor reversal potential and demonstrates an important difference between silencing strategies.

Visual experience before eye-opening and the development of the retinogeniculate pathway.

Visual experience before eye-opening is not usually thought to have any developmental significance. Here we show that naturalistic visual stimuli presented through unopened eyelids robustly activate neurons in the ferret dorsal lateral geniculate nucleus. Further, dark-rearing prior to natural eye-opening has striking effects upon geniculate physiology. Receptive field maps after dark-rearing show increased convergence of On- and Off-center responses, and neurons frequently respond to both bright and dark phases of drifting gratings. There is also increased selectivity for the orientation of the gratings. These abnormalities of On-Off segregation can be explained by the finding that the responses of immature On and Off cells to naturalistic stimuli are strongly anticorrelated.

Excitatory Effects of Parvalbumin-Expressing Interneurons Maintain Hippocampal Epileptiform Activity via Synchronous Afterdischarges

Epileptic seizures are characterized by periods of hypersynchronous, hyperexcitability within brain networks. Most seizures involve two stages: an initial tonic phase, followed by a longer clonic phase that is characterized by rhythmic bouts of synchronized network activity called afterdischarges (ADs). Here we investigate the cellular and network mechanisms underlying hippocampal ADs in an effort to understand how they maintain seizure activity. Using in vitro hippocampal slice models from rats and mice, we performed electrophysiological recordings from CA3 pyramidal neurons to monitor network activity and changes in GABAergic signaling during epileptiform activity. First, we show that the highest synchrony occurs during clonic ADs, consistent with the idea that specific circuit dynamics underlie this phase of the epileptiform activity. We then show that ADs require intact GABAergic synaptic transmission, which becomes excitatory as a result of a transient collapse in the chloride (Cl−) reversal potential. The depolarizing effects of GABA are strongest at the soma of pyramidal neurons, which implicates somatic-targeting interneurons in AD activity. To test this, we used optogenetic techniques to selectively control the activity of somatic-targeting parvalbumin-expressing (PV+) interneurons. Channelrhodopsin-2-mediated activation of PV+ interneurons during the clonic phase generated excitatory GABAergic responses in pyramidal neurons, which were sufficient to elicit and entrain synchronous AD activity across the network. Finally, archaerhodopsin-mediated selective silencing of PV+ interneurons reduced the occurrence of ADs during the clonic phase. Therefore, we propose that activity-dependent Cl− accumulation subverts the actions of PV+ interneurons to perpetuate rather than terminate pathological network hyperexcitability during the clonic phase of seizures.

Random synaptic feedback weights support error backpropagation for deep learning

The brain processes information through multiple layers of neurons. This deep architecture is representationally powerful, but complicates learning because it is difficult to identify the responsible neurons when a mistake is made. In machine learning, the backpropagation algorithm assigns blame by multiplying error signals with all the synaptic weights on each neurons axon and further downstream. However, this involves a precise, symmetric backward connectivity pattern, which is thought to be impossible in the brain. Here we demonstrate that this strong architectural constraint is not required for effective error propagation. We present a surprisingly simple mechanism that assigns blame by multiplying errors by even random synaptic weights. This mechanism can transmit teaching signals across multiple layers of neurons and performs as effectively as backpropagation on a variety of tasks. Our results help reopen questions about how the brain could use error signals and dispel long-held assumptions about algorithmic constraints on learning.

The von Restorff Effect in Visual Object Recognition Memory in Humans and Monkeys: The Role of Frontal/Perirhinal Interaction

This study reports the development of a new, modified delayed matching to sample (DMS) visual recognition memory task that controls the relative novelty of test stimuli and can be used in human and nonhuman primates. We report findings from normal humans and unoperated monkeys, as well as three groups of operated monkeys. In the study phase of this modified paradigm, subjects studied lists of two-dimensional visual object stimuli. In the test phase each studied object was presented again, now paired with a new stimulus (a foil), and the subject had to choose the studied item. In some lists one study item (the novel or isolate item) and its associated foil differed from the others (the homogenous items) along one stimulus dimension (color). The critical experimental measure was the comparison of the visual object recognition error rates for isolate and homogenous test items. This task was initially administered to human subjects and unoperated monkeys. Error rates for both groups were reliably lower for isolate than for homogenous stimuli in the same list position (the von Restorff effect). The task was then administered to three groups of monkeys who had selective brain lesions. Monkeys with bilateral lesions of the amygdala and fornix, two structures that have been proposed to play a role in novelty and memory encoding, were similar to normal monkeys in their performance on this task. Two further groups with disconnection lesions of the perirhinal cortex and either the prefrontal cortex or the magnocellular mediodorsal thalamusshowed no evidence of a von Restorff effect. These findings are not consistent with previous proposals that the hippocampus and amygdala constitute a general novelty processing network. Instead, the results support an interaction between the perirhinal and frontal cortices in the processing of certain kinds of novel information that support visual object recognition memory.

State-Dependent Mechanisms of LTP Expression Revealed by Optical Quantal Analysis

The expression mechanism of long-term potentiation (LTP) remains controversial. Here we combine electrophysiology and Ca(2+) imaging to examine the role of silent synapses in LTP expression. Induction of LTP fails to change p(r) at these synapses but instead mediates an unmasking process that is sensitive to the inhibition of postsynaptic membrane fusion. Once unmasked, however, further potentiation of formerly silent synapses leads to an increase in p(r). The state of the synapse thus determines how LTP is expressed.

Adenosine Release during Seizures Attenuates GABAA Receptor-Mediated Depolarization

Seizure-induced release of the neuromodulator adenosine is a potent endogenous anticonvulsant mechanism, which limits the extension of seizures and mediates seizure arrest. For this reason several adenosine-based therapies for epilepsy are currently under development. However, it is not known how adenosine modulates GABAergic transmission in the context of seizure activity. This may be particularly relevant as strong activation of GABAergic inputs during epileptiform activity can switch GABAA receptor (GABAAR) signaling from inhibitory to excitatory, which is a process that plays a significant role in intractable epilepsies. We used gramicidin-perforated patch-clamp recordings to investigate the role of seizure-induced adenosine release in the modulation of postsynaptic GABAAR signaling in pyramidal neurons of rat hippocampus. Consistent with previous reports, GABAAR responses during seizure activity transiently switched from hyperpolarizing to depolarizing and excitatory. We found that adenosine released during the seizure significantly attenuated the depolarizing GABAAR responses and also reduced the extent of the after-discharge phase of the seizure. These effects were mimicked by exogenous adenosine administration and could not be explained by a change in chloride homeostasis mechanisms that set the reversal potential for GABAARs, or by a change in the conductance of GABAARs. Rather, A1R-dependent activation of potassium channels increased the cells membrane conductance and thus had a shunting effect on GABAAR currents. As depolarizing GABAAR signaling has been implicated in seizure initiation and progression, the adenosine-induced attenuation of depolarizing GABAAR signaling may represent an important mechanism by which adenosine can limit seizure activity.

Short-term ionic plasticity at GABAergic synapses.

Fast synaptic inhibition in the brain is mediated by the pre-synaptic release of the neurotransmitter γ-Aminobutyric acid (GABA)and the post-synaptic activation of GABA-sensitive ionotropic receptors. As with excitatory synapses, it is being increasinly appreciated that a variety of plastic processes occur at inhibitory synapses, which operate over a range of timescales. Here we examine a form of activity-dependent plasticity that is somewhat unique to GABAergic transmission. This involves short-lasting changes to the ionic driving force for the post-synaptic receptors, a process referred to as short-term ionic plasticity. These changes are directly related to the history of activity at inhibitory synapses and are influenced by a variety of factors including the location of the synapse and the post-synaptic cells ion regulation mechanisms. We explore the processes underlying this form of plasticity, when and where it can occur, and how it is likely to impact network activity.