The impact of learning modalities and sleep quality on adolescent mental health: a cross-sectional study.

Activity-dependent changes in synaptic strength are widely regarded as a key mechanism underlying experience-driven refinement of neuronal circuits and memory formation (, ). Synaptic plasticity can manifest in multiple forms, including homo- and heterosynaptic plasticity. Homosynaptic plasticity is expressed only at stimulated synapses, whereas heterosynaptic plasticity involves changes in strength at neighboring unstimulated synapses. Although it is well-established that glutamate NMDA receptors (NMDARs) mediate excitatory synaptic transmission and can undergo long-term potentiation (LTP) and long-term depression (LTD) (, ), most studies have focused on homosynaptic (, ) and heterosynaptic (, , ) plasticity of the AMPA receptor (AMPAR)-mediated component of glutamatergic excitatory transmission. However, whether NMDAR-mediated transmission undergoes heterosynaptic plasticity remains to be investigated. The dentate gyrus is the main input area of the hippocampus (, ). Dentate gyrus granule cells (GCs) receive prominent cortical projections from the medial and lateral entorhinal cortex, which convey context and content-related information, through the medial and lateral perforant pathways (MPP and LPP), respectively (). Activity-dependent changes of these inputs, and their dendritic integration by GCs are critical to dentate gyrus information processing (, , , , ). MPP and LPP inputs onto GCs express robust homosynaptic (, , ) and heterosynaptic (, ) long-term plasticity of AMPAR-mediated transmission. Furthermore, early studies showed that high-frequency stimulation can also trigger homosynaptic NMDAR plasticity in perforant path inputs (, ). Using physiologically relevant patterns of presynaptic and postsynaptic burst activity, a protocol known as burst-timing-dependent plasticity (BTDP), we have recently shown that MPP-GC synapses can undergo robust NMDAR LTP but not NMDAR-LTD (). Whether LPP-GC synapses can express homo- or heterosynaptic NMDAR plasticity is unknown. Here, we examined whether BTDP induction protocols induce NMDAR plasticity at LPP inputs in acute hippocampal slices from rats and mice. We found that LPP-GC synapses do not express homosynaptic NMDAR plasticity but can undergo heterosynaptic plasticity induced by MPP-GC synapses. Conversely, homosynaptic AMPAR-LTP at MPP-GC synapses was accompanied by heterosynaptic AMPAR-LTD at LPP-GC synapses. Heterosynaptic NMDAR-LTP increased LPP-driven GC firing and was blocked by GluN2D antagonism and postsynaptic conditional knockout. To our knowledge, these findings provide the first evidence of heterosynaptic LTP of NMDAR-mediated transmission and suggest that BTDP-induced homosynaptic plasticity at MPP can shape the transfer of information from LPP to GCs, thereby contributing to dentate gyrus-dependent forms of memory.