cAMP Responsive Element-Binding Protein Phosphorylation Is Necessary for Perirhinal Long-Term Potentiation and Recognition Memory

Abstract

We established the importance of phosphorylation of cAMP responsive element-binding protein (CREB) to both the familiarity discrimination component of long-term recognition memory and plasticity within the perirhinal cortex of the temporal lobe. Adenoviral transduction of perirhinal cortex (and adjacent visual association cortex) with a dominant-negative inhibitor of CREB impaired the preferential exploration of novel over familiar objects at a long (24 h) but not a short (15 min) delay, disrupted the normal reduced activation of perirhinal neurons to familiar compared with novel pictures, and impaired long-term potentiation of synaptic transmission in perirhinal slices. The consistency of these effects across the behavioral, systems, and cellular levels of analysis provides strong evidence for involvement of CREB phosphorylation in synaptic plastic processes within perirhinal cortex necessary for long-term recognition memory.

The rat perirhinal cortex: A review of anatomy, physiology, plasticity, and function

“…LTP in the perirhinal cortex is associated with an increase in BDNF secretion in the first 5-12 post-stimulation and this LTP can be blocked by inhibiting the BDNF receptor TrkB (Aicardi et al, 2004). Perirhinal LTP can be blocked by inhibiting CREB as shown by adenoviral transduction of a CREB-inhibitor onto perirhinal slices (Warburton et al, 2005) but it appears to be independent of L-type voltage-dependent Ca 2+ channel activation (Seoane et al, 2009). The induction of LTP in the perirhinal cortex has also been demonstrated to be GABA A -dependent as enhancement of GABA A receptor function by lorazepam disrupts the induction of LTP in neurons within layers II/III (Wan et al, 2004).…”

“…Immediate early gene imaging studies have shown that the perirhinal cortex is activated following object recognition tasks (Wan et al, 1999;Aggleton and Brown, 2005;Warburton et al, 2005) and following the presentation of novel visual stimuli (Zhu et al, 1995b(Zhu et al, , 1996(Zhu et al, , 1997, thus indicating that the perirhinal cortex plays a central role in novelty detection. Lesions of the perirhinal cortex have been shown to impair performance in the object recognition task (Ennaceur et al, 1996;) and more recent work has shown that the perirhinal cortex is required for the encoding, consolidation and retrieval of object recognition memory (Winters and Bussey, 2005a,b;Winters et al, 2008).…”

“…Winters and Reid (2010) also demonstrate that this cross-modal integration requires the parietal cortex for processing tactile information whereas the perirhinal seemed to be involved only in processing of visual information. There has been a functional dissociation shown between the roles of the perirhinal cortex and the hippocampus (Aggleton and Brown, 2005). Lesions of the perirhinal cortex result in impairments in recognition but not spatial tasks whereas lesions of the hippocampus result in impairments in spatial but recognition tasks (Ennaceur and Aggleton, 1994;Bussey et al, 2000;Abe et al, 2009).…”

“…In rats, administration of the benzodiazepine lorazepam to the perirhinal cortex impairs recognition memory and when applied to perirhinal slices, it also disrupts both LTP and LTD (Wan et al, 2004). In the perirhinal cortex, antagonism of Ltype voltage-dependent Ca 2+ channels (Seoane et al, 2009) and of CREB signalling (Warburton et al, 2005) have also been shown to impair perirhinal LTD and object recognition memory. Taken together, the evidence would suggest that long-term synaptic plasticity is involved in recognition memory formation.…”

“…Furthermore, transgenic overexpression of the NR2B subunit in hippocampal and cortical neurons enhances performance in an object recognition task yet does not promote LTD in the area CA1 (Wang et al, 2009) which is a conflicting finding compared to the majority of research in this area. There are a large number of molecular mechanisms involved in object recognition memory that are correlated with LTD including L-type voltage-dependent Ca 2+ channels (Seoane et al, 2009), CREB (Warburton et al, 2005), muscarinic cholinergic receptors (Warburton et al, 2003;Massey et al, 2008), GABA receptors (Wan et al, 2004) mGlu receptors (Barker et al, 2006a;Moult et al, 2006), NMDA receptors (Cho et al, 2000Roberts et al, 2009;, kainate receptors (Barker et al, 2006a;Park et al, 2006;Holman et al, 2007) and AMPA receptor internalisation (Griffiths et al, 2008). Therefore, although both LTP and LTDlike processes might be involved in object recognition memory, it would appear that an LTD-like process is the principle physiological mechanism underlying recognition memory.…”