Synaptic plasticity in the central nervous system (CNS) is a fundamental basis for defining neuronal circuitries and network function. Synaptic strength can either be potentiated or depressed. These long-term changes are linked to modification at both pre- and postsynaptic neuronal compartments. The longstanding dogma of the pure neuronal origin of synaptic plasticity is now questionable. Several lines of evidence indicate that glial cells play a more pivotal role in driving synaptic plasticity than previously assumed.
The first synapse between nociceptive primary afferent C-fibres and lamina I neurons in the spinal dorsal horn is a key site for adaptive changes in nociceptive pathways. Activity-dependent long-term potentiation (LTP) of synaptic strength at this first synapse is a well-defined cellular model for chronic pain hypersensitivities such as hyperalgesia.^ ^The inherent activity-dependent nature of this model, however, fails to explain certain aspects of chronic pain conditions observed in clinics, i.e. secondary hyperalgesia, wide-spread pain or pain after opioid-withdrawal.
The present project aimed at elucidating the effects of diverse activation patterns of glial cells on synaptic transmission between nociceptive C-fibres and spinal lamina I neurons in an electrophysiological approach. We observed that glial cells have a mode-dependent capacity to modify nociceptive transmission in a bidirectional way. We used 2′(3′)-O-(4-Benzoylbenzoyl)-ATP triethylammonium salt (BzATP)-induced P2X7 receptor (P2X7R) signalling to investigate the effect of combined activation of both microglia and astrocytes on synaptic transmission. Activation of glial P2X7R under blockade of adenosine 1 receptor (A1R) signalling induced LTP at 60 % of all C-fibre inputs tested.^ The BzATP-induced LTP was accompanied by a decrease of the paired pulse ratio (PPR) indicative of a presynaptic modulation. Specific blockade of P2X7R signalling blocked the induction of LTP and the concomitant reduction of PPR. Previously, we showed that selective activation of microglia alone using fractalkine (FKN) signalling induces a facilitation of nociceptive transmission without inducing LTP. In contrast, here we showed that specific activation of spinal astrocytes alone using uncaging-induced inositol 1,4,5-trisphosphate (IP3) signalling in astrocytic networks induced a long-term depression (LTD) at all C-fibre inputs tested. The uncaging protocol failed to induce LTD when glial cell metabolism was blocked by fluoroacetate (FC) or when IP3 was omitted. No change in PPR was observed suggesting a postsynaptic expression of LTD.^
We present a new concept of synaptic plasticity showing that glial cell activation alone is capable of enabling long-term changes of synaptic strength in nociceptive pathways and that depending on the pattern of activation a bidirectional modulation of synaptic plasticity can be elicited.