Abstract EN:

Mutations in more than 80 human chromosome X-linked genes have bcen implicated in mental retardation (MR), a condition defined by an overall reduction in cognitive abilities estimated to affect 1 -3% of the population. Consistent with human genetics, most genetic mouse models of X linked MR display learning and memory deficits. It is still largely unc\ear, however, how mutations in MR genes interfere with the function and plasticity of neuronal circuits. Activity-dependent long-term potentiation (LTP) of glutamatergic synaptic transmission, the most extensively studied neuronal corrc1ate ofleaming and memory, is not systematically affected across different MR mouse models. Because previous studies have predominantly focused on L TP at Schaffer -collateralCA 1 synapses in the hippocampus, which is expressed by postsynaptic mechanisms, this raises the possibility that other forms of LTP might more faithfully report the functional deficits associated with mutations in MR genes. Apart from postsynaptic CAl-type LTP, a second major form ofLTP is mediated by presynaptic expression mechanisms. Presynaptic LTP has been described in many brain areas involved in learning and memory inc\uding the hippocampus, striatum, cerebellum and amygdala. Surprisingly, it is not known whether mutations in MR genes affect presynaptic LTP. The lateral amygdala (LA), key brain area necessary for the acquisition of conditioncd fear responses, receives Iwo main scnsory inputs originating in cortex and thalamus. Although, thalamo- and cortico-LA pathways converge onto the same postsynaptic dendrites of LA principal neurons, they fundamentally differ in terms of the mechanisms underlying LTP expression. LTP at thalamo-LA synapses is very similar to hippocampal Schaffer-collateral-CAI LTP in the sense that its expression relies on postsynaptic AMPA receptor trafficking. In contrast, we showed that LTP at cortico-LA synapses, very much like its counterparts in other brain areas, is predominantly expressed by a presynaptic, cAMPIPKAdependent increase in the probability of re1ease. Taking advantage of this preparation which allows for direct comparison ofpre- and postsynaptic forms ofLTP in the same neurons, 1 examined thalamo- and cortico-LA L TP in five mouse models of X linked MR. We found that constitutive lack of oligophrenin 1 (Op/ml) interfered with presynaptic, but not with postsynaptic LTP. Loss ofpresynaptic LTP was caused by the complete uncoupling ofcAMP/PKA signaling from vesic\e release. Impaired presynaptic LTP was also observed in mice deficient for ribosomal S6 kinase 2 (rsk2), interleukin-l receptor accessory protein-like 1 (iIJrapIJ) and Rab GDP-dissociation inhibitor 1 (Gdil), three other X-linked MR genes encoding for presynaptic proteins involved in the modulation of release probability. Although the overall lack of presynaptic LTP was indistinguishable belween different MR models, it was caused by distinct deficits in LTP induction or expression. This suggests that presynaptic LTP is susceptible to disruption at multiple levels, and that disruption of presynaptic plasticity may be an important factor contributing to the etiology of MR. To address this question, 1 examined presynaptic cortico-LA LTP in mice deficient for methyl CpG-binding protein 2 (mecp2), an epigenetic factor controlling DNA transcription and involved in the severe neuro-developmental disorder Ret! syndrome (RTT). In absence of MeCP2, both synaptic maturation and synaptic elimination were exaggerated albeit still specific to cortical projections. Surprisingly, associative LTP was unaffected at MeCP2 deficient synapses suggesting that synaptic maintenance rather than activity-dependent synaptic leaming may be causal in RTT physiopathology. In summary, our fmdings reveal that lack of associative presynaptic LTP may not represent a common phenotype across different genetic mouse models of X-Iinked MR, excJuding therefore a causal relationship belween impaired LTP and cognitive disabilities.