Abstract
The hippocampus plays a central role in memory formation in the mammalian brain. Its ability to encode information is thought to depend on the plasticity of synaptic connections between neurons. In the pyramidal neurons constituting the primary hippocampal output to the cortex, located in area CA1, firing of presynaptic CA3 pyramidal neurons produces monosynaptic excitatory postsynaptic potentials (EPSPs) followed rapidly by feedforward (disynaptic) inhibitory postsynaptic potentials (IPSPs). Long-term potentiation (LTP) of the monosynaptic glutamatergic inputs has become the leading model of synaptic plasticity, in part due to its dependence on NMDA receptors (NMDARs), required for spatial and temporal learning in intact animals. Using whole-cell recording in hippocampal slices from adult rats, we find that the efficacy of synaptic transmission from CA3 to CA1 can be enhanced without the induction of classic LTP at the glutamatergic inputs. Taking care not to directly stimulate inhibitory fibers, we show that the induction of GABAergic plasticity at feedforward inhibitory inputs results in the reduced shunting of excitatory currents, producing a long-term increase in the amplitude of Schaffer collateral-mediated postsynaptic potentials. Like classic LTP, disinhibition-mediated LTP requires NMDAR activation, suggesting a role in types of learning and memory attributed primarily to the former and raising the possibility of a previously unrecognized target for therapeutic intervention in disorders linked to memory deficits, as well as a potentially overlooked site of LTP expression in other areas of the brain.
Highlights
Plasticity of synaptic connections between neurons in the hippocampus is thought to play a central role in learning and memory
Being careful not to directly stimulate inhibitory fibers while making whole-cell recordings in hippocampal slices from 2 month old rats, we found that feedforward inhibition does reduce excitatory postsynaptic potentials (EPSPs) amplitude, and that disinhibition at feedforward synapses, expressed as a depolarization of the reversal potential for GABAA receptor (GABAAR)-mediated currents [14] contributes to the increase in EPSP amplitude seen during Long-term potentiation (LTP) expression
To calculate the EPSP-inhibitory postsynaptic potentials (IPSPs) delay, the delay between the onset of the Schaffer collateral-evoked pyramidal cell EPSP and the interneuron AP (0.396.33 ms, n = 10) was added to the delay between the intracellularly-evoked interneuron AP and the resulting pyramidal unitary IPSP [0.9060.07 ms; same cells (n = 10); Figure 1B]. This gave an EPSP-IPSP onset delay of 1.36.3 ms (n = 10), much briefer than the mean rise time to 90% amplitude of pharmacologically isolated Schaffer collateral-evoked EPSPs [6.16.3 ms; no correlation was observed between 90% amplitude and rise time (r2 = 0.00595, p = 0.623, n = 43); data not shown]
Summary
Plasticity of synaptic connections between neurons in the hippocampus is thought to play a central role in learning and memory. When presynaptic CA3 pyramidals fire, the EPSP recorded in CA1 is followed in less than 2 ms by a disynaptic IPSP [6] originating from basket cells targeting the somatic compartment [7]. This delay between EPSP and IPSP is only half as long as the rise time of unitary EPSPs evoked by single cell firing in CA3 [8]. Feedforward inhibition should reduce EPSP amplitude recorded at the soma, as demonstrated for unitary EPSPs between pairs of CA3 neurons [10] It follows that disinhibition, if expressed at feedforward synapses, would reduce the shunting of excitatory currents, leading to an increase in EPSP amplitude
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