Enhanced dentate gyrus synaptic plasticity but reduced neurogenesis in a mouse model of amyloidosis.

Long-term potentiation (LTP) and neurogenesis in the dentate gyrus (DG) are correlated forms of hippocampal plasticity which share, under physiological conditions, common regulatory mechanisms. In Alzheimer's disease (AD), their alterations are potentially associated with the early cellular pathology and cognitive decline. We analyzed DG LTP and neurogenesis in B6.152H mice, an amyloid precursor protein and presenilin 2 double-transgenic mouse model of amyloidosis and observed that DG LTP was strongly enhanced before and after amyloid plaque formation. Whereas proliferation of DG neuronal progenitor cells was unchanged, survival of newborn neurons was strongly decreased already before plaque formation. As similar alteration of neurogenesis was observed in PS2APP mice without changes in DG LTP (Richards et al. 2003), this study suggests that enhanced synaptic plasticity did not rescue impaired neurogenesis, and supports decreased survival of newborn neurons as an early event associated with AD detectable even before plaque formation.

Group III metabotropic glutamate receptors as autoreceptors in the cerebellar cortex.

1. Group III metabotropic glutamate receptors (mGluRs) of the subtype 4a are localized within presynaptic active zones of cerebellar parallel fibre (PF)-Purkinje cell (PC) synapses. In order to investigate the conditions necessary for group III mGluR autoreceptor-activation by synaptically released glutamate, we characterized the effects of selective agonists and antagonists on excitatory postsynaptic currents (EPSCs) evoked by several distinct PF stimulation patterns. 2. The group III mGluR-selective agonist L-AP4 depressed evoked EPSCs at PF-PC synapses in rat brain slices with an EC(50) of 2.4 microM and maximum inhibition of 80%. This L-AP4-induced depression was antagonized by the group III mGluR-selective antagonist MSOP with an estimated equilibrium dissaciation constant of 12.5 microM. 3. Paired-pulse or four-pulse PF stimulations did not activate presynaptic group III mGluRs as revealed by the lack of effect of 1 mM MSOP on relative test EPSC amplitudes with latencies of 250-500 ms. The potentiation of a test EPSC evoked 200-500 ms after a short tetanic burst (100 Hz for 60 ms), was also unchanged in the presence of MSOP. 4. Endogenous autoreceptor-activation was revealed only during prolonged stimulation trains (10 Hz for 4.4 s), where, in the presence of 1 mM MSOP, the EPSC amplitudes were enhanced by 15%. 5. These observations support an autoreceptor function of group III mGluRs and a role in short-term synaptic plasticity at PF synapses. However, the low to moderate activation levels observed, despite the close spatial relation with glutamate release sites, suggests that additional mechanisms regulate receptor activation.

Differential regulation of synaptic transmission by mGlu2 and mGlu3 at the perforant path inputs to the dentate gyrus and CA1 revealed in mGlu2 -/- mice.

Group II metabotropic glutamate (mGlu) receptors can act as presynaptic autoinhibitory receptors at perforant path inputs to the hippocampus under conditions of high frequency synaptic activation. We have used mGlu2 -/- mice to examine the relative roles of mGlu2 and mGlu3 in the regulation of perforant path synaptic transmission mediated by both the selective group II receptor agonist, DCG-IV, and by synaptically released glutamate. Field excitatory postsynaptic potentials evoked by stimulation of either the perforant path inputs to the dentate gyrus mid-moleculare or the CA1 stratum lacunosum moleculare were inhibited by DCG-IV with IC(50) values and maximum percentage inhibition of: 169 nM (60%) and 41 nM (72%) in wild-type mice and 273 nM (19%) and 116 nM (49%) in mGlu2 -/- mice, respectively. Activation of presynaptic group II mGlu autoreceptors by synaptically released glutamate, as revealed by a LY341495-mediated increase in the relative amplitude of a test fEPSP evoked after a conditioning burst, was observed in both the dentate gyrus and the stratum lacunosum of wild-type, but not mGlu2 -/- mice. These observations demonstrate that activation of mGlu3 receptors can regulate synaptic transmission at perforant path synapses but suggest that mGlu2 is the major presynaptic group II autoreceptor activated by synaptically released glutamate.