A hebbian form of long-term potentiation dependent on mGluR1a in hippocampal inhibitory interneurons

Abstract

Hippocampal inhibitory interneurons play important roles in controlling the excitability and synchronization of pyramidal cells, but whether they express long-term synaptic plasticity that contributes to hippocampal network function remains uncertain. We found that pairing postsynaptic depolarization with theta-burst stimulation induced long-term potentiation (LTP) of putative single-fiber excitatory postsynaptic currents in interneurons. Either postsynaptic depolarization or theta-burst stimulation alone failed to induce LTP. LTP was expressed as a decrease in failure rates and an increase in excitatory postsynaptic current amplitude, independent of N-methyl-d-aspartate receptors, and dependent on metabotropic glutamate receptors subtype 1a. LTP was induced specifically in interneurons in stratum oriens and not in interneurons of stratum radiatum/lacunosum-moleculare. Thus, excitatory synapses onto specific subtypes of inhibitory interneurons express a new form of hebbian LTP that will contribute to hippocampal network plasticity.

Figure 1

LTP in oriens interneurons. (A) Graph of EPSCs amplitude from a representative cell showing LTP after TBS paired with depolarization (TBS + depo; protocol shown above and delivered at time indicated by black triangle and vertical line). Examples of control and potentiated EPSCs (10 consecutive responses) at 30 min after induction (Right). Superimposed average EPSCs (bottom traces; n = 64 responses each, failures included) from control and 30 min after induction also show LTP. (B) Histograms for all cells showing the significant increase in amplitude of average EPSCs (failures included) up to 30 min after induction (B1), significant decrease in failure rate (B2), and significant increase in EPSC amplitude (failures excluded) (B3). (C) Significant reduction in EPSC amplitude (excluding failures) by 10 μM NHPP-spermine and complete block by 20 μM 6-cyano-7-nitroquinoxaline-2,3-dione (n = 5 oriens cells). Representative example of EPSCs partially mediated by Ca²⁺-permeable AMPA receptors and entirely by AMPA/KA receptors. In this and the following figures, * indicate significantly different from control.

Figure 2

No LTP with synaptic stimulation or postsynaptic depolarization alone. (A) TBS alone (A1) did not significantly change the amplitude of average EPSCs, or the failure rate and amplitude of EPSCs (A2). (B) Example from an oriens cell showing no effect of TBS on EPSC amplitude. Consecutive individual traces and superimposed average EPSCs (failures included) illustrate the absence of LTP 30 min after TBS alone. (C) Postsynaptic depolarization alone (C1) did not induce LTP in oriens interneurons. The amplitude of average EPSCs or the failure rate and amplitude of EPSCs were not significantly changed 30 min after depolarization (C2).

Figure 3

LTP is NMDAR-independent and mGluR1a-dependent. (A1) Graph from a representative cell showing LTP of EPSCs induced by TBS + depo in 100 μM AP5. Individual traces and average EPSCs (failures included) show the increase in EPSCs at 30 min after induction relative to control. (A2) Data for all cells in AP5, illustrating the significant change in amplitude of average EPSCs (failures included), failure rate, and amplitude of EPSCs (failures excluded) up to 30 min after TBS + depo. (B) Block of LTP by the group I/II mGluR antagonist E4CPG. Data from a representative cell (B1) and histograms for all oriens interneurons (B2) show that in 500 μM E4CPG the amplitude of average EPSCs, as well as the failure rate and amplitude of EPSCs, were unchanged after TBS + depo. (C) Block of LTP by the other group I/II antagonist MCPG and the mGluR1a antagonist LY367385. Histograms for all oriens cells showing that, in MCPG or LY367385, TBS + depo did not induce significant change in amplitude of average EPSCs (failures included), as well as failure rate or amplitude of EPSCs (failures excluded).

Figure 4

LTP is cell-type specific. (A) Graph and traces from a representative oriens interneuron, showing LTP at 30 min after TBS + depo in ACSF with 2 mM Ca²⁺/Mg²⁺. (B) Histograms for all oriens cells in 2 mM Ca²⁺/Mg²⁺, showing the significant decrease in failure rate and significant increase in amplitude of EPSCs (failures excluded) after TBS + depo. (C) Representative example of the absence of LTP in a radiatum interneuron. Graph and traces show that EPSCs were unchanged after TBS + depo. (D) Histograms for all radiatum interneurons showing that the failure rate and amplitude of EPSCs (failures excluded) were unaffected by TBS + depo. (E) Summary histogram for all cells in 2 mM Ca²⁺/Mg²⁺, showing that the amplitude of average EPSCs (failures included) was significantly increased 30 min after TBS + depo in oriens interneurons (ORI) and pyramidal cells (PYR) but not in radiatum interneurons (R/LM).

Figure 5

Camera lucida reconstructions of biocytin-filled interneurons. (A and B) Representative examples of horizontal (A) and vertical (B) subtypes of oriens interneurons showing LTP. Data from the cell in A shown in Fig 1A. (C and D) Examples of stratum radiatum interneurons without LTP. Data from the cell in D shown in Fig 4C. ALV, alveus; ORI, oriens; PYR, pyramidale; RAD, radiatum; L-M, lacunosum-moleculare; MOL, dentate gyrus molecular layer, and DG, granule cell layer. (Scale bars = 50 μm.)