Nicotine enhances attention and working memory by activating nicotinic acetylcholine receptors (nAChRs). The prefrontal cortex (PFC) is critical for these cognitive functions and is also rich in nAChR expression. Specific cellular and synaptic mechanisms underlying nicotine's effects on cognition remain elusive. Here we show that nicotine exposure increases the threshold for synaptic spike-timing-dependent potentiation (STDP) in layer V pyramidal neurons of the mouse PFC. During coincident presynaptic and postsynaptic activity, nicotine reduces dendritic calcium signals associated with action potential propagation by enhancing GABAergic transmission. This results from a series of presynaptic actions involving different PFC interneurons and multiple nAChR subtypes. Pharmacological block of nAChRs or GABA(A) receptors prevented nicotine's actions and restored STDP, as did increasing dendritic calcium signals with stronger postsynaptic activity. Thus, by activating nAChRs distributed throughout the PFC neuronal network, nicotine affects PFC information processing and storage by increasing the amount of postsynaptic activity necessary to induce STDP.

Because of fast recovery from synaptic depression and fast-initiated action potentials, neuronal information transfer can have a substantially higher bandwidth in human neocortical circuits than in those of rodents.

The biologically relevant rules of synaptic potentiation were investigated in hippocampal slices from adult rat by mimicking neuronal activity seen during learning behaviours. Synaptic efficacy was monitored in two separate afferent pathways among the Schaffer collaterals during intracellular recording of CA1 pyramidal neurones. The effects of pairing presynaptic single spikes or bursts with postsynaptic single spikes or bursts, repeated at 5 Hz (‘theta’ frequency), were compared. The pairing of ten single evoked excitatory synaptic events with ten postsynaptic single action potentials at 5 Hz, repeated twelve times, failed to induce synaptic enhancement (EPSP amplitude 95 % of baseline amplitude 20 min after pairing; n= 5). In contrast, pairing the same number of action potentials, but clustered in bursts, induced robust synaptic potentiation (EPSP amplitude 163 %; P < 0·01, Student's t test; n= 5). This potentiation was input specific, long lasting (> 1 h; n= 3) and its induction was blocked by an antagonist at NMDA receptors (20‐50 μM D(‐)‐2‐amino‐5‐phosphonopentanoic acid; EPSP amplitude 109 %; n= 6). Presynaptic bursting paired with postsynaptic single action potentials did not induce input specific synaptic change (113 % in the test input vs. 111 % in the control; n= 8). In contrast, postsynaptic bursting when paired with presynaptic single action potentials was sufficient to induce synaptic potentiation when the presynaptic activity preceded the postsynaptic activity by 10 ms (150 vs. 84 % in the control input; P < 0·01; n= 10). These results indicate that, under our conditions, postsynaptic bursting activity is necessary for associative synaptic potentiation at CA1 excitatory synapses in adult hippocampus. The existence of a distinct postsynaptic signal for induction of synaptic change calls for refinement of the common interpretation of Hebb's rule, and is likely to have important implications for our understanding of cortical network operation.

Fragile X syndrome, caused by a mutation in the Fmr1 gene, is characterized by mental retardation. Several studies reported the absence of long-term potentiation (LTP) at neocortical synapses in Fmr1 knockout (FMR1-KO) mice, but underlying cellular mechanisms are unknown. We find that in the prefrontal cortex (PFC) of FMR1-KO mice, spike-timing-dependent LTP (tLTP) is not so much absent, but rather, the threshold for tLTP induction is increased. Calcium signaling in dendrites and spines is compromised. First, dendrites and spines more often fail to show calcium transients. Second, the activity of L-type calcium channels is absent in spines. tLTP could be restored by improving reliability and amplitude of calcium signaling by increasing neuronal activity. In FMR1-KO mice that were raised in enriched environments, tLTP was restored to WT levels. Our results show that mechanisms for synaptic plasticity are in place in the FMR1-KO mouse PFC, but require stronger neuronal activity to be triggered.

The induction rules of synaptic plasticity are important for the functional operation of a neural network. We asked whether such synaptic plasticity rules change during development from juvenile to adult animals. Using perforated patch and whole-cell recordings from CA1 pyramidal cells in hippocampal slices, we demonstrate here that the postsynaptic requirements for induction of associative long-term potentiation (LTP) shift gradually. Presynaptic stimulation paired with single postsynaptic action potentials became progressively less effective at inducing LTP with advancing developmental age until, in adult hippocampus, postsynaptic bursts of action potentials were necessary to induce synaptic potentiation. This developmental change might be accounted for by changes in GABA(A) receptor-mediated inhibition known to occur in the hippocampus during this postnatal period, because blocking GABA(A) receptor-mediated inhibition re-established the effectiveness of single postsynaptic action potentials at inducing LTP in adult hippocampus. These data reveal a gradual shift in the induction rules for LTP, explained by a maturational change in GABAergic inhibition, and could have implications for our understanding of the role of inhibition in information processing in the brain.

The neocortex in our brain stores long-term memories by changing the strength of connections between neurons. To date, the rules and mechanisms that govern activity-induced synaptic changes at human cortical synapses are poorly understood and have not been studied directly at a cellular level. Here, we made whole-cell recordings of human pyramidal neurons in slices of brain tissue resected during neurosurgery to investigate spike timing-dependent synaptic plasticity in the adult human neocortex. We find that human cortical synapses can undergo bidirectional modifications in strength throughout adulthood. Both long-term potentiation and long-term depression of synapses was dependent on postsynaptic NMDA receptors. Interestingly, we find that human cortical synapses can associate presynaptic and postsynaptic events in a wide temporal window, and that rules for synaptic plasticity in human neocortex are reversed compared with what is generally found in the rodent brain. We show this is caused by dendritic L-type voltage-gated Ca 2ϩ channels that are prominently activated during action potential firing. Activation of these channels determines whether human synapses strengthen or weaken. These findings provide a synaptic basis for the timing rules observed in human sensory and motor plasticity in vivo, and offer insights into the physiological role of L-type voltage-gated Ca 2ϩ channels in the human brain.

Spike timing–dependent plasticity (STDP) is a strong candidate for an N-methyl-D-aspartate (NMDA) receptor-dependent form of synaptic plasticity that could underlie the development of receptive field properties in sensory neocortices. Whilst induction of timing-dependent long-term potentiation (t-LTP) requires postsynaptic NMDA receptors, timing-dependent long-term depression (t-LTD) requires the activation of presynaptic NMDA receptors at layer 4-to-layer 2/3 synapses in barrel cortex. Here we investigated the developmental profile of t-LTD at layer 4-to-layer 2/3 synapses of mouse barrel cortex and studied their NMDA receptor subunit dependence. Timing-dependent LTD emerged in the first postnatal week, was present during the second week and disappeared in the adult, whereas t-LTP persisted in adulthood. An antagonist at GluN2C/D subunit–containing NMDA receptors blocked t-LTD but not t-LTP. Conversely, a GluN2A subunit–preferring antagonist blocked t-LTP but not t-LTD. The GluN2C/D subunit requirement for t-LTD appears to be synapse specific, as GluN2C/D antagonists did not block t-LTD at horizontal cross-columnar layer 2/3-to-layer 2/3 synapses, which was blocked by a GluN2B antagonist instead. These data demonstrate an NMDA receptor subunit-dependent double dissociation of t-LTD and t-LTP mechanisms at layer 4-to-layer 2/3 synapses, and suggest that t-LTD is mediated by distinct molecular mechanisms at different synapses on the same postsynaptic neuron.

Patients with depression often suffer from cognitive impairments that contribute to disease burden. We used social defeat-induced persistent stress (SDPS) to induce a depressive-like state in rats and then studied long-lasting memory deficits in the absence of acute stressors in these animals. The SDPS rat model showed reduced short-term object location memory and maintenance of long-term potentiation (LTP) in CA1 pyramidal neurons of the dorsal hippocampus. SDPS animals displayed increased expression of synaptic chondroitin sulfate proteoglycans in the dorsal hippocampus. These effects were abrogated by a 3-week treatment with the antidepressant imipramine starting 8 weeks after the last defeat encounter. Next, we observed an increase in the number of perineuronal nets (PNNs) surrounding parvalbumin-expressing interneurons and a decrease in the frequency of inhibitory postsynaptic currents (IPSCs) in the hippocampal CA1 region in SDPS animals. In vivo breakdown of the hippocampus CA1 extracellular matrix by the enzyme chondroitinase ABC administered intracranially restored the number of PNNs, LTP maintenance, hippocampal inhibitory tone, and memory performance on the object place recognition test. Our data reveal a causal link between increased hippocampal extracellular matrix and the cognitive deficits associated with a chronic depressive-like state in rats exposed to SDPS.