GluA4 Dependent Plasticity Mechanisms Contribute to Developmental Synchronization of the CA3-CA1 Circuitry in the Hippocampus.

During the course of development, molecular mechanisms underlying activity-dependent synaptic plasticity change considerably. At immature CA3-CA1 synapses in the hippocampus, PKA-driven synaptic insertion of GluA4 AMPA receptors is the predominant mechanism for synaptic strengthening. However, the physiological significance of the developmentally restricted GluA4-dependent plasticity mechanisms is poorly understood. Here we have used microelectrode array (MEA) recordings in GluA4 deficient slice cultures to study the role of GluA4 in early development of the hippocampal circuit function. We find that during the first week in culture (DIV2-6) when GluA4 expression is restricted to pyramidal neurons, loss of GluA4 has no effect on the overall excitability of the immature network, but significantly impairs synchronization of the CA3 and CA1 neuronal populations. In the absence of GluA4, the temporal correlation of the population spiking activity between CA3-CA1 neurons was significantly lower as compared to wild-types at DIV6. Our data show that synapse-level defects in transmission and plasticity mechanisms are efficiently compensated for to normalize population firing rate at the immature hippocampal network. However, lack of the plasticity mechanisms typical for the immature synapses may perturb functional coupling between neuronal sub-populations, a defect frequently implicated in the context of developmentally originating neuropsychiatric disorders.

Developmental switch in the kinase dependency of long-term potentiation depends on expression of GluA4 subunit-containing AMPA receptors.

The AMPA-receptor subunit GluA4 is expressed transiently in CA1 pyramidal neurons at the time synaptic connectivity is forming, but its physiological significance is unknown. Here we show that GluA4 expression is sufficient to alter the signaling requirements of long-term potentiation (LTP) and can fully explain the switch in the LTP kinase dependency from PKA to Ca2(+)/calmodulin-dependent protein kinase II during synapse maturation. At immature synapses, activation of PKA leads to a robust potentiation of AMPA-receptor function via the mobilization of GluA4. Analysis of GluA4-deficient mice indicates that this mechanism is critical for neonatal PKA-dependent LTP. Furthermore, lentiviral expression of GluA4 in CA1 neurons conferred a PKA-dependent synaptic potentiation and LTP regardless of the developmental stage. Thus, GluA4 defines the signaling requirements for LTP and silent synapse activation during a critical period of synapse development.

PACAP-mediated gating of anxiety-controlling circuits.

Combining the use of ex vivo and in vivo optogenetics, viral tracing, electrophysiology and behavioral testing, we show that the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) gates anxiety-controlling circuits by differentially affecting synaptic efficacy at projections from the basolateral amygdala (BLA) to two different subdivisions of the dorsal subdivision of the bed nucleus of the stria terminalis (BNST), modifying the signal flow in BLA-ovBNST-adBNST circuits in such a way that adBNST is inhibited. Inhibition of adBNST is translated into the reduced firing probability of adBNST neurons during afferent activation, explaining the anxiety-triggering actions of PACAP in BNST, as inhibition of adBNST is anxiogenic. Our results reveal how innate, fear-related behavioral mechanisms may be controlled by neuropeptides, PACAP specifically, at the level of underlying neural circuits by inducing long-lasting plastic changes in functional interactions between their different structural components.

Voltage-dependent and -independent block of α-amino-3-hydroxy-5-methylisoxazole-4-propionate receptor channels.

Polyamine-containing toxins and synthetic dicationic derivatives of adamantane and phenylcyclohexyl selectively antagonize Ca(2+)-permeable α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor channels. These compounds demonstrate voltage-dependent open-channel block and are trapped by closed channels. In this study, we describe an alternative mechanism of non-competitive AMPA receptor inhibition caused by 9-aminoacridine and some of its derivatives. These compounds exhibit similar potency against Ca(2+)-permeable and Ca(2+)-impermeable AMPA receptors. The inhibition is largely voltage-independent, binding and unbinding do not require presence of agonist. We conclude that 9-aminoacridine binds to a shallow site in the AMPA receptor, which is located above the activation gate. A comparison of three-dimensional structures of the antagonists suggests that the 'V-like' shape of the hydrophobic headgroup favors voltage-dependent binding to the deep site in the channel pore, whereas the compounds possessing flat aromatic headgroups preferably bind to the shallow site. The characterization of the novel mechanism of AMPA receptor channel antagonism opens a way to develop a new family of pharmacological agents, which can be of scientific and practical importance.

Mechanisms of fear learning and extinction: synaptic plasticity-fear memory connection.

RATIONALE: The ability to memorize threat-associated cues and subsequently react to them, exhibiting escape or avoidance responses, is an essential, often life-saving behavioral mechanism that can be experimentally studied using the fear (threat) conditioning training paradigm. Presently, there is substantial evidence supporting the Synaptic Plasticity-Memory (SPM) hypothesis in relation to the mechanisms underlying the acquisition, retention, and extinction of conditioned fear memory. OBJECTIVES: The purpose of this review article is to summarize findings supporting the SPM hypothesis in the context of conditioned fear control, applying the set of criteria and tests which were proposed as necessary to causally link lasting changes in synaptic transmission in corresponding neural circuits to fear memory acquisition and extinction with an emphasis on their pharmacological diversity. RESULTS: The mechanisms of synaptic plasticity in fear circuits exhibit complex pharmacological profiles and satisfy all four SPM criteria-detectability, anterograde alteration, retrograde alteration, and mimicry. CONCLUSION: The reviewed findings, accumulated over the last two decades, provide support for both necessity and sufficiency of synaptic plasticity in fear circuits for fear memory acquisition and retention, and, in part, for fear extinction, with the latter requiring additional experimental work.

Diminishing fear: Optogenetic approach toward understanding neural circuits of fear control.

Understanding complex behavioral processes, both learned and innate, requires detailed characterization of the principles governing signal flow in corresponding neural circuits. Previous studies were hampered by the lack of appropriate tools needed to address the complexities of behavior-driving micro- and macrocircuits. The development and implementation of optogenetic methodologies revolutionized the field of behavioral neuroscience, allowing precise spatiotemporal control of specific, genetically defined neuronal populations and their functional connectivity both in vivo and ex vivo, thus providing unprecedented insights into the cellular and network-level mechanisms contributing to behavior. Here, we review recent pioneering advances in behavioral studies with optogenetic tools, focusing on mechanisms of fear-related behavioral processes with an emphasis on approaches which could be used to suppress fear when it is pathologically expressed. We also discuss limitations of these methodologies as well as review new technological developments which could be used in future mechanistic studies of fear behavior.

Molecular mechanisms controlling synaptic recruitment of GluA4 subunit-containing AMPA-receptors critical for functional maturation of CA1 glutamatergic synapses.

Synaptic recruitment of AMPA receptors (AMPARs) represents a key postsynaptic mechanism driving functional development and maturation of glutamatergic synapses. At immature hippocampal synapses, PKA-driven synaptic insertion of GluA4 is the predominant mechanism for synaptic reinforcement. However, the physiological significance and molecular determinants of this developmentally restricted form of plasticity are not known. Here we show that PKA activation leads to insertion of GluA4 to synaptic sites with initially weak or silent AMPAR-mediated transmission. This effect depends on a novel mechanism involving the extreme C-terminal end of GluA4, which interacts with the membrane proximal region of the C-terminal domain to control GluA4 trafficking. In the absence of GluA4, strengthening of AMPAR-mediated transmission during postnatal development was significantly delayed. These data suggest that the GluA4-mediated activation of silent synapses is a critical mechanism facilitating the functional maturation of glutamatergic circuitry during the critical period of experience-dependent fine-tuning. This article is part of the Special Issue entitled 'Ionotropic glutamate receptors'.

Mechanisms underlying induction of LTP-associated changes in short-term dynamics of transmission at immature synapses.

While the activity-dependent mechanisms guiding functional maturation of synaptic transmission postsynaptically are well characterized, less is known about the corresponding presynaptic mechanisms. Here we show that during the first postnatal week, a subset of CA3-CA1 synapses express postsynaptically induced LTP that is tightly associated with a robust decrease in synaptic facilitation, consistent with an increase in release probability (P(r)). The loss of facilitation is readily induced by physiologically relevant pairing protocols at immature synapses and is dependent on activation of NMDA-receptors but not L-type calcium channels. The putative pre- and postsynaptic components of neonatal LTP were distinguished in their downstream signaling requirements, PKC activity being selectively needed for the decrease in facilitation but not for synaptic potentiation per se. These data suggest that maturation of glutamatergic synapses involves a critical period during which presynaptic function is highly susceptible to activity-dependent regulation via a PKC-dependent mechanism.