Neural correlates of external variables provide potential internal codes that guide an animal’s behaviour. Notably, first-order features of neural activity, such as single-neuron firing rates, have been implicated in encoding information. However, the extent to which higher-order features, such as multi-neuron coactivity, play primary roles in encoding information or secondary roles in supporting single-neuron codes remains unclear. Here we show that millisecond-timescale coactivity amongst hippocampal CA1 neurons discriminates distinct millisecond-lived behavioural contingencies. This contingency discrimination was unrelated to the tuning of individual neurons but instead an emergent property of their coactivity. Contingency discriminating patterns were reactivated offline after learning and their reinstatement predicted trial-by-trial memory performance. Moreover, optogenetic suppression of inputs from the upstream CA3 region selectively during learning impaired coactivity-based contingency information in CA1 and subsequent dynamic memory retrieval. These findings identify coactivity as a primary feature of neural firing that discriminates distinct behaviourally-relevant variables and supports memory retrieval.

Group II metabotropic glutamate receptor (mGluR) ligands are potential novel drugs for neurological and psychiatric disorders, but little is known about the effects of these compounds at synapses of the human cerebral cortex. Investigating the effects of neuropsychiatric drugs in human brain tissue with preserved synaptic circuits might accelerate the development of more potent and selective pharmacological treatments. We have studied the effects of group II mGluR activation on excitatory synaptic transmission recorded from pyramidal neurons of cortical layers 2–3 in acute slices derived from surgically removed cortical tissue of people with epilepsy or tumors. The application of a selective group II mGluR agonist, LY354740 (0.1–1 μM) inhibited the amplitude and frequency of action potential-dependent spontaneous excitatory postsynaptic currents (sEPSCs). This effect was prevented by the application of a group II/III mGluR antagonist, CPPG (0.1 mM). Furthermore, LY354740 inhibited the frequency, but not the amplitude, of action potential-independent miniature EPSCs (mEPSCs) recorded in pyramidal neurons. Finally, LY354740 did slightly reduce cells’ input resistance without altering the holding current of the neurons recorded in voltage clamp at -90 mV. Our results suggest that group II mGluRs are mainly auto-receptors that inhibit the release of glutamate onto pyramidal neurons in layers 2–3 in the human cerebral cortex, thereby regulating network excitability. We have demonstrated the effect of a group II mGluR ligand at human cortical synapses, revealing mechanisms by which these drugs could exert pro-cognitive effects and treat human neuropsychiatric disorders.

Persistent anion conductances through GABA A receptors (GABA A R) are important modulators of neuronal excitability. However, it is currently unknown how the amplitudes of these currents vary amongst different cell types in the human neocortex, particularly amongst diverse GABAergic interneurons. We have recorded 101 interneurons in and near layer 1 from cortical tissue surgically resected from both male and female patients, visualised 84 of them and measured tonic GABA A R currents in 48 cells with an intracellular [Cl -] of 65 mM and in the presence of 5 µM GABA. We compare these tonic currents amongst five groups of interneurons divided by firing properties and four types of interneuron defined by axonal distributions; rosehip, neurogliaform, stalked-bouton, layers 2-3 innervating and a pool of other cells. Interestingly, the rosehip cell, a type of interneuron only described thus far in human tissue, and layers 2-3 innervating cells exhibit larger tonic currents than other layer 1 interneurons, such as neurogliaform and stalked-bouton cells; the latter two groups showing no difference. The positive allosteric modulators of GABA A Rs allopregnanolone and DS2 also induced larger current shifts in the rosehip and layer 2-3 innervating cells, consistent with higher expression of the δ-subunit of the GABA A R in these neurons. We have also examined how patient parameters, such as age, seizures, type of cancer and anticonvulsant treatment may alter tonic inhibitory currents in human neurons.The cell type specific differences in tonic inhibitory currents could potentially be used to selectively modulate cortical circuitry. Significance statementTonic currents through GABA A receptors are a potential therapeutic target for a number of neurological and psychiatric conditions. Here we show that these currents in human cerebral cortical GABAergic neurons display cell-type specific differences in their amplitudes 4 which implies differential modulation of their excitability. Additionally, we examine whether the amplitudes of the tonic currents measured in our study show any differences between patient populations, finding some evidence that age, seizures, type of cancer, and anticonvulsant treatment may alter tonic inhibition in human tissue. These results advance our understanding of how pathology affects neuronal excitability and could potentially be used to selectively modulate cortical circuitry.

Diverse neocortical GABAergic neurons specialise in synaptic targeting and their effects are modulated by presynaptic metabotropic glutamate receptors (mGluRs) suppressing neurotransmitter release in rodents, but their effects in human neocortex are unknown. We tested whether activation of group III mGluRs by L-AP4 changes GABAA receptor-mediated spontaneous inhibitory postsynaptic currents (sIPSCs) in two distinct dendritic spine-innervating GABAergic interneurons recorded in vitro in human neocortex. Calbindin-positive double bouquet cells (DBC) had columnar “horsetail” axons descending through layers II-V innervating dendritic spines (48%) and shafts, but not somata of pyramidal and non-pyramidal neurons. Parvalbumin-expressing dendrite-targeting cell (PV-DTC) axons extended in all directions innervating dendritic spines (22%), shafts (65%) and somata (13%). As measured, 20% of GABAergic neuropil synapses innervate spines, hence DBCs, but not PV-DTCs, preferentially select spine targets. Group III mGluR activation paradoxically increased the frequency of sIPSCs in DBCs (to median 137% of baseline), but suppressed it in PV-DTCs (median 92%), leaving the amplitude unchanged. The facilitation of sIPSCs in DBCs may result from their unique GABAergic input being disinhibited via network effect. We conclude that dendritic spines receive specialised, diverse GABAergic inputs, and group III mGluRs differentially regulate GABAergic synaptic transmission to distinct GABAergic cell types in human cortex.

Diverse neocortical GABAergic neurons specialise in synaptic targeting and their effects are modulated by presynaptic metabotropic glutamate receptors (mGluRs) suppressing neurotransmitter release in rodents, but their effects in human neocortex are unknown. We tested whether activation of group III mGluRs by L-AP4 changes GABAA receptor-mediated spontaneous inhibitory postsynaptic currents (sIPSCs) in two distinct dendritic spineinnervating GABAergic interneurons recorded in vitro in human neocortex. Calbindin-positive double bouquet cells (DBC) had columnar "horsetail" axons descending through layers II-V innervating dendritic spines (48%) and shafts, but not somata of pyramidal and non-pyramidal neurons. Parvalbumin-expressing dendrite-targeting cell (PV-DTC) axons extended in all directions innervating dendritic spines (22%), shafts (65%) and somata (13%). As measured, 20% of GABAergic neuropil synapses innervate spines, hence DBCs, but not PV-DTCs, preferentially select spine targets. Group III mGluR activation paradoxically increased the frequency of sIPSCs in DBCs (to median 137% of baseline), but suppressed it in PV-DTCs (median 92%), leaving the amplitude unchanged. The facilitation of sIPSCs in DBCs may result from their unique GABAergic input being disinhibited via network effect. We conclude that dendritic spines receive specialised, diverse GABAergic inputs, and group III mGluRs differentially regulate GABAergic synaptic transmission to distinct GABAergic cell types in human cortex.