Role of mGlu5 in Persistent Forms of Hippocampal Synaptic Plasticity and the Encoding of Spatial Experience

Abstract

The metabotropic glutamate (mGlu) receptor family consists of group I receptors (mGlu1 and mGlu5) that are positively coupled to phospholipase-C and group II (mGlu2 and mGlu3) and III receptors (mGlu4-8) that are negatively coupled to adenylyl cyclase. Of these, mGlu5 has emerged as a key factor in the induction and maintenance of persistent (> 24 h) forms of hippocampal synaptic plasticity. Studies in freely behaving rodents have revealed that mGlu5 plays a pivotal role in the stabilisation of hippocampal long-term potentiation (LTP) and long-term depression (LTD) that are tightly associated with the acquisition and retention of knowledge about spatial experience. In this review article we shall address the state of the art in terms of the role of mGlu5 in forms of hippocampal synaptic plasticity related to experience-dependent information storage and present evidence that normal mGlu5 function is central to these processes.

GluN2A or GluN2B subunits of the NMDA receptor contribute to changes in neuronal excitability and impairments in LTP in the hippocampus of aging mice but do not mediate detrimental effects of oligomeric Aβ (1–42)

“…The maintenance of later phases of LTP beginning at around 90 min post-induction, are supported by phospholipase -C coupled (group 1) receptors ( Hagena and Manahan-Vaughan, 2022 ; Mukherjee and Manahan-Vaughan, 2023 ). Group 1 mGlu receptors can functionally interact with NMDAR and alter NMDAR currents ( Rosenbrock et al, 2010 ).…”

Interplay of hippocampal long-term potentiation and long-term depression in enabling memory representations

“…Hippocampal information processing is highly state-dependent, and effects are reflected by changes in the coupling of neuronal oscillations at theta-gamma frequencies [101]. In freely moving rats, identical afferent stimulation frequencies can result in robust LTP, STP, or no change in synaptic efficacy in the absence of any overt change in behaviour, although changes in the coupling of theta-and gamma-frequency neuronal oscillations during the stimulation predict the plasticity outcome [15]. Furthermore, stress changes the thresholds for the induction and maintenance of synaptic plasticity [102][103][104], as can alterations of the action of neuromodulators in the hippocampus [105].…”

“…Studies of the molecular basis of persistent (>24 h) LTP, for example, in the cornu ammonis-1 (CA1) region in vivo have revealed that it can be disambiguated into temporal components comprising STP that requires activation of N -methyl- d -aspartate receptors (NMDAR) and lasts for 30–90 min, depending on the subunit composition of the NMDAR [14]. This early phase of LTP then segues into LTP that lasts for 90–180 min in behaving rodents and requires activation of the metabotropic glutamate receptor, mGlu5 [15]. LTP that lasts for more than 3 h requires brain-derived neurotrophic factor (BDNF) [16], whereas CA1 LTP that lasts for longer than 8 h (referred to as late-LTP) requires both protein translation and transcription [17].…”

“…Strikingly, the same 100 Hz protocol that induces LTP at SC–CA1 synapses in vivo induces LTP of differing profiles depending on whether mossy fibre (MF)–CA3, commissural–associational (AC)–CA3 or Schaffer collateral (SC)–CA1 synapses are stimulated (figure 1 a ) [11,24]. While MF–CA3 LTP is NMDAR-independent in freely behaving rats [34], it requires activation of NMDAR at AC–CA3 [15] or SC–CA1 synapses [20]. Furthermore, although reciprocal heterosynaptic LTP can be induced in lateral perforant path (LPP) and medial perforant path (MPP) inputs to the CA3 in vivo [35], differences in the conditions leading to homosynaptic LTP have been reported in these synapses [36].…”

“…Despite the homogeneity of its electrophysiological induction conditions, the molecular dependency of persistent LTD is very different depending on the hippocampal subfield (electronic supplementary material, table S3 b ). Whereas persistent SC–CA1 and AC–CA3 LTD depend on the activation of NMDAR [15,20], persistent LTD at MF–CA3 synapses [61] or MPP–DG synapses [76] are NMDAR-independent. Furthermore, persistent MPP–DG LTD does not require protein synthesis [76], whereas SC–CA1 and AC–CA1 LTD do [23,61].…”