Assortment of GABAergic plasticity in the cortical interneuron melting pot

Abstract

Cortical structures of the adult mammalian brain are characterized by a spectacular diversity of inhibitory interneurons, which use GABA as neurotransmitter. GABAergic neurotransmission is fundamental for integrating and filtering incoming information and dictating postsynaptic neuronal spike timing, therefore providing a tight temporal code used by each neuron, or ensemble of neurons, to perform sophisticated computational operations. However, the heterogeneity of cortical GABAergic cells is associated to equally diverse properties governing intrinsic excitability as well as strength, dynamic range, spatial extent, anatomical localization, and molecular components of inhibitory synaptic connections that they form with pyramidal neurons. Recent studies showed that similarly to their excitatory (glutamatergic) counterparts, also inhibitory synapses can undergo activity-dependent changes in their strength. Here, some aspects related to plasticity and modulation of adult cortical and hippocampal GABAergic synaptic transmission will be reviewed, aiming at providing a fresh perspective towards the elucidation of the role played by specific cellular elements of cortical microcircuits during both physiological and pathological operations.

Figure 1

Oversimplified scheme of the inhibitory control of cortical pyramidal neurons by several general classes of GABAergic interneurons. Information (pink wide arrow) is transferred from excitatory glutamatergic synapses (red axon terminals) to the pyramidal neuron (red cell) dendrite. Excitation (information) travels along the dendritic tree to the soma and axon initial segment, where it could generate an action potential. Along this dendro-somatic-axonal axis, information can be differently filtered by GABAergic synapses possessing specific basic and plasticity properties. On the left-hand side, interneurons controlling the output are illustrated as different classes of basket and axo-axonic cells. Different GABAergic interneurons controlling the input into pyramidal neurons are shown on the right, as impinging the dendrite(s) at different distances from the soma. Details in the text.

Figure 2

Example of diverse functional classes of inhibitory interneurons. (a) Single-neuron reconstructions of three different interneuron types of the neocortex: a basket cell (left), an axo-axonic cell (middle), and a dendrite-targeting Martinotti cell (right). Axons and somatodendritic compartments are shown in red and black respectively. Modified with permission from [51]. (b) Exampled of similar classes of GABAergic interneurons as in a, but in the hippocampus. modified with permission from [11]. (c) Different hippocampal interneuron classes show distinct properties of synaptic transmission. Examples of depressing (red traces) and facilitating (blue traces) unitary GABAergic responses originating from perisomatic and dendrite-targeting interneurons respectively. The upper red and blue traces are single-trial responses, whereas the bottom traces are averaged of multiple trials. Modified with permission from [52].

Figure 3

Endocannabinoid-dependent plasticity of GABAergic synapses. (a) In cultured hippocampal neurons, eCBs mediate a form of short-term retrograde signaling strongly reducing GABAergic responses. This can be observed by the reduction of unitary inhibitory postsynaptic currents (IPSCs) evoked after a 5 sec-long depolarization (depo) of the postsynaptic neuron. The CB1R antagonist AM281 blocked the depolarization-induced suppression of inhibition (DSI). Time course of DSI is indicated in the right panel. Modified from [105]. For details, see reference [105, 106]. (b) Time course of extracellularly evoked IPSC amplitude in the CA1 area of the hippocampus. Brief depolarizations (white arrows) of the recorded pyramidal cell induce DSI (see Figure 3), whereas high-frequency stimulation (black arrow) of afferent fibers induces LTD of GABAergic responses. Traces correspond to the time points indicated by numbers in the upper graph. Both DSI and LTD induction are blocked by the selective CB1R antagonist AM251 (gray bar, lower graph). Modified with permission from [107].

Figure 4

Endocannabinoid-independent plasticity of GABAergic synapses. (a) Brief train of action potentials (conditioning) in cortical pyramidal cells depresses unitary inhibitory postsynaptic potentials (uIPSPs) evoked by synaptically connected FS interneurons (top traces, from left to right: before, during and after conditioning). This form of short-term retrograde depression is indicated by the black dots during the conditioning paradigm (conditioned response is measured 250 ms after the conditioning stimulus), and it is not blocked by the selective CB1R antagonist AM-251, ruling out the involvement of eCB signaling. (b) Conditioning mediated depression of uIPSPs from FS interneurons (top traces, from left to right: before, during, and after conditioning) is prevented by the nonselective vesicular glutamate transporter Evans Blue (EB) suggesting a critical role for dendritically released glutamate in this form of plasticity. Modified with permission from [119]. For details see [119, 120]. (c, d) Spike timing-dependent plasticity (STDP) results in potentiation (c) and depression (d) of uIPSPs (top) elicited by FS interneurons onto cortical pyramidal cells. Long-term potentiation (LTP) of uIPSP amplitudes (top traces) is obtained when presynaptic FS cell fires 410 ms after the beginning of a brief train of action potentials (10 action potentials at 50 Hz) in the postsynaptic pyramidal cell (c). Conversely, long-term depression (LTD) of uIPSPs is observed when the presynaptic FS cell fired 250 ms after the start of an identical train (d). (c and d): Modified with permission from [121].