Computational and Molecular Properties of Starburst Amacrine Cell Synapses Differ With Postsynaptic Cell Type

A presynaptic neuron can increase its computational capacity by transmitting functionally distinct signals to each of its postsynaptic cell types. To determine whether such computational specialization occurs over fine spatial scales within a neurite arbor, we investigated computation at output synapses of the starburst amacrine cell (SAC), a critical component of the classical direction-selective (DS) circuit in the retina. The SAC is a non-spiking interneuron that co-releases GABA and acetylcholine and forms closely spaced (<5 μm) inhibitory synapses onto two postsynaptic cell types: DS ganglion cells (DSGCs) and neighboring SACs. During dynamic optogenetic stimulation of SACs in mouse retina, whole-cell recordings of inhibitory postsynaptic currents revealed that GABAergic synapses onto DSGCs exhibit stronger low-pass filtering than those onto neighboring SACs. Computational analyses suggest that this filtering difference can be explained primarily by presynaptic properties, rather than those of the postsynaptic cells per se. Consistent with functionally diverse SAC presynapses, blockade of N-type voltage-gated calcium channels abolished GABAergic currents in SACs but only moderately reduced GABAergic and cholinergic currents in DSGCs. These results jointly demonstrate how specialization of synaptic outputs could enhance parallel processing in a compact interneuron over fine spatial scales. Moreover, the distinct transmission kinetics of GABAergic SAC synapses are poised to support the functional diversity of inhibition within DS circuitry.

Using ephaptic coupling to estimate the synaptic cleft resistivity of the calyx of Held synapse.

At synapses, the pre- and postsynaptic cell get so close that currents entering the cleft do not flow exclusively along its conductance, gcl. A prominent example is found in the calyx of Held synapse in the medial nucleus of the trapezoid body, where the presynaptic action potential can be recorded in the postsynaptic cell in the form of a prespike. Here, we developed a theoretical framework for ephaptic coupling via the synaptic cleft. We found that the capacitive component of the prespike recorded in voltage clamp is closely approximated by the second time derivative of the presynaptic action potential. Its size scales with the fourth power of the radius of the synapse, explaining why intracellularly recorded prespikes are uncommon in the CNS. We show that presynaptic calcium currents can contribute to the prespike and that their contribution is closely approximated by the scaled first derivative of these currents. We confirmed these predictions in juvenile rat brainstem slices, and used the presynaptic calcium currents to obtain an estimate for gcl of ~1 μS. We demonstrate that for a typical synapse geometry, gcl is scale-invariant and only defined by extracellular resistivity, which was ~75 Ωcm, and by cleft height. During development the calyx of Held develops fenestrations. These fenestrations effectively minimize the cleft potentials generated by the adult action potential, which would otherwise interfere with calcium channel opening. We thus provide a quantitative account of the dissipation of currents by the synaptic cleft, which can be readily extrapolated to conventional, bouton-like synapses.

Postsynaptic cell firing triggers bidirectional metaplasticity depending on the LTP induction protocol

Cell firing has been reported to variably up- or down-regulate subsequently induced long-term potentiation (LTP). The aim of this study was to elucidate the parameters critical to driving each direction of the metaplasticity effect. The main focus was on the commonly used theta-burst stimulation (TBS) and high-frequency stimulation (HFS) protocols that are known to trigger distinct intracellular signalling cascades. To study action potential (AP)-induced metaplasticity, we used intracellular recordings from CA1 pyramidal cells of rat hippocampal slices. Somatic current injections were used to induce theta-burst firing (TBF) or high-frequency firing (HFF) for priming purposes, while LTP was induced 15 min later via TBS of Schaffer collaterals in stratum radiatum. TBS-LTP was inhibited by both priming protocols. Conversely, HFS-LTP was facilitated by HFF priming but not affected by TBF priming. Interestingly, both priming protocols reduced AP firing during TBS-LTP induction and this effect correlated with the reduction of TBS-LTP. However, LTP was not rescued by restoring AP firing with somatic current injections during the TBS. Analysis of intrinsic properties revealed few changes, apart from a priming-induced increase in the medium after-hyperpolarisation (HFF priming) and a decrease in the EPSP amplitude/slope ratio (TBF priming) which could in principle contribute to the inhibition of TBS-LTP by reducing depolarisation and associated Ca2+ influx following synaptic activity or AP backpropagation. Overall, these data indicate that the more physiological TBS protocol for inducing LTP is particularly susceptible to homeostatic feedback inhibition by prior bouts of postsynaptic cell firing.

Primary and secondary motoneurons use different calcium channel types to control escape and swimming behaviors in zebrafish

The escape response and rhythmic swimming in zebrafish are distinct behaviors mediated by two functionally distinct motoneuron (Mn) types. The primary (1°Mn) type depresses and has a large quantal content (Qc) and a high release probability (Pr). Conversely, the secondary (2°Mn) type facilitates and has low and variable Qc and Pr. This functional duality matches well the distinct associated behaviors, with the 1°Mn providing the strong, singular C bend initiating escape and the 2°Mn conferring weaker, rhythmic contractions. Contributing to these functional distinctions is our identification of P/Q-type calcium channels mediating transmitter release in 1°Mns and N-type channels in 2°Mns. Remarkably, despite these functional and behavioral distinctions, all ∼15 individual synapses on each muscle cell are shared by a 1°Mn bouton and at least one 2°Mn bouton. This blueprint of synaptic sharing provides an efficient way of controlling two different behaviors at the level of a single postsynaptic cell.

Primary and secondary motoneurons use different calcium channel types to control escape and swimming behaviors in zebrafish

The escape response and rhythmic swimming in zebrafish are distinct behaviors mediated by two functionally distinct motoneuron (Mn) types. The primary (1°Mn) type depresses, has a large quantal content (Qc), and a high release probability (Pr). Conversely, the secondary (2°Mn) type facilitates and has low and variable Qc and Pr. This functional duality matches well the distinct associated behaviors, with the 1°Mn providing the strong, singular C-bend initiating escape and the 2°Mn confers weaker, rhythmic contractions. Contributing to these functional distinctions is our identification of P/Q type calcium channels mediating transmitter release in 1°Mns and N type channels in 2°Mns. Remarkably, despite these functional and behavioral distinctions, all ~15 individual synapses on each muscle cell are shared by a 1°Mn bouton and at least one 2°Mn bouton. This novel blueprint of synaptic sharing provides an efficient way of controlling two different behaviors at the level of a single postsynaptic cell.

Influence of the Activation of NMDA Receptors on the Resting Membrane Potential of the Postsynaptic Cell at the Neuromuscular Junction

Impaired function or insufficient expression of glutamate N-methyl-D-aspartate (NMDA) receptors underlies a number of brain pathologies; these receptors are, therefore, regarded as a pharmacological target for many neuroactive drugs. It was shown that in the CNS, this type of glutamate receptors participate in the processes of neuronal excitation, synaptic plasticity [1, 2], and excitotoxicity in neurodegenerative diseases and are also involved in the pathogenesis of epilepsy and seizures. However, until recently, the presence and activity of NMDA receptors beyond the CNS had never been considered. This research shows that activation of NMDA receptors at the mammalian neuromuscular junction alters the resting membrane potential of the postsynaptic cell evoked by cation entry through the receptor-associated channel.

Autism-associated neuroligin-4 mutation selectively impairs glycinergic synaptic transmission in mouse brainstem synapses

In human patients, loss-of-function mutations of the postsynaptic cell-adhesion molecule neuroligin-4 were repeatedly identified as monogenetic causes of autism. In mice, neuroligin-4 deletions caused autism-related behavioral impairments and subtle changes in synaptic transmission, and neuroligin-4 was found, at least in part, at glycinergic synapses. However, low expression levels precluded a comprehensive analysis of neuroligin-4 localization, and overexpression of neuroligin-4 puzzlingly impaired excitatory but not inhibitory synaptic function. As a result, the function of neuroligin-4 remains unclear, as does its relation to other neuroligins. To clarify these issues, we systematically examined the function of neuroligin-4, focusing on excitatory and inhibitory inputs to defined projection neurons of the mouse brainstem as central model synapses. We show that loss of neuroligin-4 causes a profound impairment of glycinergic but not glutamatergic synaptic transmission and a decrease in glycinergic synapse numbers. Thus, neuroligin-4 is essential for the organization and/or maintenance of glycinergic synapses.

Hippocampus: Intrinsic Organization

The hippocampus, together with the subiculum, represent an associational area of the cerebral cortex that is intimately involved in mnemonic processes. Through its connections with other areas of the temporal lobe, the prefrontal cortex (PFC) and subcortical areas, it contributes to the encoding, association, consolidation, and recall of representations of the external and internal world in the combined firing rates and spike timing of glutamatergic pyramidal and granule cells. Pyramidal cell assemblies are formed and segregated from other assemblies by the dynamic strengthening and weakening of glutamatergic synaptic weights both on pyramidal cells and GABAergic interneurons. Interneurons, generate postsynaptic cell domain and brain state–dependent rhythmic changes in excitability, which are key for the formation, consolidation, and recall of representations. The chapter attempts to allocate explicit roles for some GABAergic neurons, based on their firing patterns in vivo as observed in identified neurons.