Afferent Input Selects NMDA Receptor Subtype to Determine the Persistency of Hippocampal LTP in Freely Behaving Mice

Abstract

The glutamatergic N-methyl-D-aspartate receptor (NMDAR) is critically involved in many forms of hippocampus-dependent memory that may be enabled by synaptic plasticity. Behavioral studies with NMDAR antagonists and NMDAR subunit (GluN2) mutants revealed distinct contributions from GluN2A- and GluN2B-containing NMDARs to rapidly and slowly acquired memory performance. Furthermore, studies of synaptic plasticity, in genetically modified mice in vitro, suggest that GluN2A and GluN2B may contribute in different ways to the induction and longevity of synaptic plasticity. In contrast to the hippocampal slice preparation, in behaving mice, the afferent frequencies that induce synaptic plasticity are very restricted and specific. In fact, it is the stimulus pattern and not variations in afferent frequency that determine the longevity of long-term potentiation (LTP) in vivo. Here, we explored the contribution of GluN2A and GluN2B to LTP of differing magnitudes and persistence in freely behaving mice. We applied differing high-frequency stimulation (HFS) patterns at 100 Hz to the hippocampal CA1 region, to induce NMDAR-dependent LTP in wild-type (WT) mice, that endured for <1 h (early (E)-LTP), (LTP, 2–4 h) or >24 h (late (L)-LTP). In GluN2A-knockout (KO) mice, E-LTP (HFS, 50 pulses) was significantly reduced in magnitude and duration, whereas LTP (HFS, 2 × 50 pulses) and L-LTP (HFS, 4 × 50 pulses) were unaffected compared to responses in WT animals. By contrast, pharmacological antagonism of GluN2B in WT had no effect on E-LTP but significantly prevented LTP. E-LTP and LTP were significantly impaired by GluN2B antagonism in GluN2A-KO mice. These data indicate that the pattern of afferent stimulation is decisive for the recruitment of distinct GluN2A and GluN2B signaling pathways that in turn determine the persistency of hippocampal LTP. Whereas brief bursts of patterned stimulation preferentially recruit GluN2A and lead to weak and short-lived forms of LTP, prolonged, more intense, afferent activation recruits GluN2B and leads to robust and persistent LTP. These unique signal-response properties of GluN2A and GluN2B enable qualitative differentiation of information encoding in hippocampal synapses.

Intrinsic cellular and molecular properties of in vivo hippocampal synaptic plasticity are altered in the absence of key synaptic matrix molecules

“…Thus, the slowly developing potentiation that we observed following repeated applications of HFS to the perforant path of wild‐type animals in this study may have recruited NMDA receptors that contain GluN2B and/or L‐type voltage‐gated calcium channels. This likelihood is confirmed by the absence of an early phase of LTP in knockout animals: both NMDA receptors (Ballesteros et al, ) and L‐type voltage‐gated calcium channels (Manahan‐Vaughan et al, ) are required for the induction phase of LTP in vivo. Despite the significantly reduced mRNA expression of GluN2B and Ca v 1.3 in the dentate gyrus of knockout mice, a slowly developing LTP was induced by repeated applications of HFS.…”

“…In freely behaving rats, very strong tetanic stimulation induces a form of LTP that predominantly depends on activation of L‐type voltage gated calcium channels (Ca v 1.3) (Manahan‐Vaughan et al, ), a property that has also been reported in vitro (Grover & Teyler, ), and mice that lack tenascin C also show deficits in this form of LTP (Evers et al, ). In freely behaving mice, the dependency of LTP in the CA1 region is tightly correlated to the afferent stimulation pattern, whereby late (>24 hr) LTP, that is induced by repetitive HFS, requires activation of NMDA receptors that contain GluN2B (Ballesteros et al, ). By contrast, short‐lasting LTP that is induced with milder stimulation patterns requires activation of GluN2A and not GluN2B receptors (Ballesteros et al, ).…”

“…This interpretation is supported by the absence of deficits in LTP induced with milder afferent stimulation in the knockouts. Weaker patterns of HFS result in LTP in the CA1 region of mice in vivo which depends on NMDAR receptors that contain GluN2A (Ballesteros et al, ). In this study, we found that although GluN2A RNA was also reduced in the dentate gyrus, mild HFS resulted in LTP that was not significantly different from LTP in wild‐type animals.…”

“…The gene expression of wt and quadruple KO mice was analyzed with regard to molecules involved in synaptic plasticity in the rodent hippocampus, in vivo. We examined the GluN2A and GluN2B subunits of the N ‐methyl‐ d ‐aspartate (NMDA) receptor (Ballesteros, Buschler, Köhr, & Manahan‐Vaughan, ), the metabotropic glutamate receptor, mGlu5 (Mukherjee & Manahan‐Vaughan, ), and the Cav1.3 subunit of the L‐type voltage‐gated calcium channel (Manahan‐Vaughan et al, ). We also examined expression levels of Homer1, due to its role in associating the NMDA receptor to plasticity‐related proteins at the level of the postsynaptic density (Bertaso et al, ; Shiraishi, Mizutani, Mikoshiba, & Furuichi, ).…”

Less means more: The magnitude of synaptic plasticity along the hippocampal dorso‐ventral axis is inversely related to the expression levels of plasticity‐related neurotransmitter receptors

“…Mechanistically, such differences, in the magnitude of potentiation, may be related to the differential expression of plasticity‐related receptors that we detected along the dorsoventral hippocampal axis as well as to reported differences in ion channel expression. In vivo , GluN2A‐containing NMDARs are important for the induction of the early phase of LTP (E‐LTP, < 1 h), whereas activation of GluN1/GluN2B‐containing NMDARs appear more important for LTP that lasts for longer periods (Ballesteros, Buschler, Köhr, & Manahan‐Vaughan, ). GluN1/GluN2B‐containing receptors also require a higher membrane depolarization for their activation compared with GluN1/GluN2A‐containing receptors (Clarke, Glasgoq, & Johnson, ).…”