Functional specificity of local synaptic connections in neocortical networks.

Neuronal connectivity is fundamental to information processing in the brain. Therefore, understanding the mechanisms of sensory processing requires uncovering how connection patterns between neurons relate to their function. On a coarse scale, long-range projections can preferentially link cortical regions with similar responses to sensory stimuli. But on the local scale, where dendrites and axons overlap substantially, the functional specificity of connections remains unknown. Here we determine synaptic connectivity between nearby layer 2/3 pyramidal neurons in vitro, the response properties of which were first characterized in mouse visual cortex in vivo. We found that connection probability was related to the similarity of visually driven neuronal activity. Neurons with the same preference for oriented stimuli connected at twice the rate of neurons with orthogonal orientation preferences. Neurons responding similarly to naturalistic stimuli formed connections at much higher rates than those with uncorrelated responses. Bidirectional synaptic connections were found more frequently between neuronal pairs with strongly correlated visual responses. Our results reveal the degree of functional specificity of local synaptic connections in the visual cortex, and point to the existence of fine-scale subnetworks dedicated to processing related sensory information.

Hippocampal place cell firing patterns can induce long-term synaptic plasticity in vitro.

In the hippocampus, synaptic strength between pyramidal cells is modifiable by NMDA receptor (NMDAR)-dependent long-term potentiation (LTP) and long-term depression (LTD), both of which require coincident presynaptic and postsynaptic activity. In vivo, many pyramidal cells exhibit location-specific activity patterns and are known as "place cells." The combination of these factors suggests that synaptic plasticity will be induced at synapses connecting place cells with overlapping firing fields, because such cells fire coincidentally when the rat is in a specific part of the environment. However, this prediction, which is important for models of how long-term synaptic plasticity can be used to encode space in the hippocampal network, has not been tested. To investigate this, action potential time series recorded simultaneously from place cells in freely moving rats were replayed concurrently into postsynaptic CA1 pyramidal cells and presynaptic inputs during perforated patch-clamp recordings from adult hippocampal slices. Place cell firing patterns induced large, pathway-specific, NMDAR-dependent LTP that was rapidly expressed within a few minutes. However, place-cell LTP was induced only if the two place cells had overlapping firing fields and if the cholinergic tone present in the hippocampus during exploration was restored by bath application of the cholinergic agonist carbachol. LTD was never observed in response to place cell firing patterns. Our findings demonstrate that spike patterns from hippocampal place cells can robustly induce NMDAR-dependent LTP, providing important evidence in support of a model in which spatial distance is encoded as the strength of synaptic connections between place cells.

Target-specific expression of presynaptic NMDA receptors in neocortical microcircuits.

Traditionally, NMDA receptors are located postsynaptically; yet, putatively presynaptic NMDA receptors (preNMDARs) have been reported. Although implicated in controlling synaptic plasticity, their function is not well understood and their expression patterns are debated. We demonstrate that, in layer 5 of developing mouse visual cortex, preNMDARs specifically control synaptic transmission at pyramidal cell inputs to other pyramidal cells and to Martinotti cells, while leaving those to basket cells unaffected. We also reveal a type of interneuron that mediates ascending inhibition. In agreement with synapse-specific expression, we find preNMDAR-mediated calcium signals in a subset of pyramidal cell terminals. A tuned network model predicts that preNMDARs specifically reroute information flow in local circuits during high-frequency firing, in particular by impacting frequency-dependent disynaptic inhibition mediated by Martinotti cells, a finding that we experimentally verify. We conclude that postsynaptic cell type determines presynaptic terminal molecular identity and that preNMDARs govern information processing in neocortical columns.

The activity requirements for spike timing-dependent plasticity in the hippocampus.

Synaptic plasticity has historically been investigated most intensely in the hippocampus and therefore it is somewhat surprising that the majority of studies on spike timing-dependent plasticity (STDP) have focused not in the hippocampus but on synapses in the cortex. One of the major reasons for this bias is the relative ease in obtaining paired electrophysiological recordings from synaptically coupled neurons in cortical slices, in comparison to hippocampal slices. Another less obvious reason has been the difficulty in achieving reliable STDP in the hippocampal slice preparation and confusion surrounding the conditions required. The original descriptions of STDP in the hippocampus was performed on paired recordings from neurons in dissociated or slice cultures utilizing single pairs of presynaptic and postsynaptic spikes and were subsequently replicated in acute hippocampal slices. Further work in several laboratories using conditions that more closely replicate the situation in vivo revealed a requirement for multiple postsynaptic spikes that necessarily complicate the absolute timing rules for STDP. Here we review the hippocampal STDP literature focusing on data from acute hippocampal slice preparations and highlighting apparently contradictory results and the variations in experimental conditions that might account for the discrepancies. We conclude by relating the majority of the available experimental data to a model for STDP induction in the hippocampus based on a critical role for postsynaptic Ca(2+) dynamics.

Facilitation of long-term potentiation by muscarinic M(1) receptors is mediated by inhibition of SK channels.

Muscarinic receptor activation facilitates the induction of synaptic plasticity and enhances cognitive function. However, the specific muscarinic receptor subtype involved and the critical intracellular signaling pathways engaged have remained controversial. Here, we show that the recently discovered highly selective allosteric M(1) receptor agonist 77-LH-28-1 facilitates long-term potentiation (LTP) induced by theta burst stimulation at Schaffer collateral synapses in the hippocampus. Similarly, release of acetylcholine by stimulation of cholinergic fibers facilitates LTP via activation of M(1) receptors. N-methyl-D-aspartate receptor (NMDAR) opening during theta burst stimulation was enhanced by M(1) receptor activation, indicating this is the mechanism for LTP facilitation. M(1) receptors were found to enhance NMDAR activation by inhibiting SK channels that otherwise act to hyperpolarize postsynaptic spines and inhibit NMDAR opening. Thus, we describe a mechanism where M(1) receptor activation inhibits SK channels, allowing enhanced NMDAR activity and leading to a facilitation of LTP induction in the hippocampus.

The development of synaptic plasticity induction rules and the requirement for postsynaptic spikes in rat hippocampal CA1 pyramidal neurones.

Coincident pre- and postsynaptic activity induces synaptic plasticity at the Schaffer collateral synapse onto CA1 pyramidal neurones. The precise timing, frequency and number of coincident action potentials required to induce synaptic plasticity is currently unknown. In this study we show that the postsynaptic activity required for the induction of long-term potentiation (LTP) changes with development. In acute slices from adult rats, coincident pre- and postsynaptic theta burst stimulation (TBS) induced LTP and we show that multiple high-frequency postsynaptic spikes are required. In contrast, in acute slices from juvenile (P14) rats, TBS failed to induce LTP unless the excitatory postsynaptic potentials (EPSPs) were of sufficient magnitude to initiate action potentials. We also show that coincident individual pre- and postsynaptic action potentials are only capable of inducing LTP in the juvenile when given at a frequency greater than 5 Hz and that the timing of individual pre- and postsynaptic action potentials relative to one another is not important. Finally, we show that local tetrodotoxin (TTX) application to the soma blocked LTP in adults, but not juveniles. These data demonstrate that somatic spiking is more important for LTP induction in the adult as opposed to juvenile rats and we hypothesize that the basis for this is the ability of action potentials in the postsynaptic CA1 pyramidal neurone to back-propagate into the dendrites. Therefore, the pre- and postsynaptic activity patterns required to induce LTP mature as the hippocampus develops.