The adult brain is highly plastic and tends to undergo substantial reorganization after injury to compensate for the lesion effects. It has been shown that such reorganization mainly relies on anatomical and biochemical modifications of the remaining cells which give rise to a network rewiring without reinstating the original morphology of the damaged region. However, few studies have analyzed the neurorepair potential of a neurogenic structure. Thus, the aim of this work was to analyze if the DG could restore its original morphology after a lesion and to establish if the structural reorganization is accompanied by behavioral and electrophysiological recovery. Using a subepileptogenic injection of kainic acid (KA), we induced a focal lesion in the DG and assessed in time (1) the loss and recovery of dependent and non dependent DG cognitive functions, (2) the anatomical reorganization of the DG using a stereological probe and immunohistochemical markers for different neuronal maturation stages and, (3) synaptic plasticity as assessed through the induction of in vivo long-term potentiation (LTP) in the mossy fiber pathway (CA3-DG). Our results show that a DG focal lesion with KA leads to a well delimited region of neuronal loss, disorganization of the structure, the loss of associated mnemonic functions and the impairment to elicit LTP. However, behavioral and synaptic plasticity expression occurs in a time dependent fashion and occurs along the morphological restoration of the DG. These results provide novel information on neural plasticity events associated to functional reorganization after damage.

Calcium-calmodulin/dependent protein kinase II (CaMKII) plays an essential role in LTP induction, but since it has the capacity to remain persistently activated even after the decay of external stimuli it has been proposed that it can also be necessary for LTP maintenance and therefore for memory persistence. It has been shown that basolateral amygdaloid nucleus (Bla) stimulation induces long-term potentiation (LTP) in the insular cortex (IC), a neocortical region implicated in the acquisition and retention of conditioned taste aversion (CTA). Our previous studies have demonstrated that induction of LTP in the Bla-IC pathway before CTA training increased the retention of this task. Although it is known that IC-LTP induction and CTA consolidation share similar molecular mechanisms, little is known about the molecular actors that underlie their maintenance. The purpose of the present study was to evaluate the role of CaMKII in the maintenance of in vivo Bla-IC LTP as well as in the persistence of CTA long-term memory (LTM). Our results show that acute microinfusion of myr-CaMKIINtide, a selective inhibitor of CaMKII, in the IC of adult rats during the late-phase of in vivo Bla-IC LTP blocked its maintenance. Moreover, the intracortical inhibition of CaMKII 24 h after CTA acquisition impairs CTA-LTM persistence. Together these results indicate that CaMKII is a central key component for the maintenance of neocortical synaptic plasticity as well as for persistence of CTA-LTM.

Changes in synaptic efficacy and morphology are considered as the downstream mechanisms of consolidation of memories and other adaptive behaviors. In the last decade, neurotrophin-3 (NT-3) has emerged as one potent mediator of synaptic plasticity. In the adult brain, expression of NT-3 is largely confined to the hippocampal dentate gyrus (DG). Our previous studies show that application of high-frequency stimulation (HFS) sufficient to elicit long-term potentiation (LTP) at the DG-CA3 pathway as well as acute intrahippocampal microinfusion of brain-derived neurotrophin factor produce mossy fiber (MF) structural reorganization. Here, we show that intrahippocampal microinfusion of NT-3 induces a long-lasting potentiation of synaptic efficacy in the DG-CA3 projection accompanied by an MF structural reorganization of adult rats in vivo. It is considered that the capacity of synapses to express plastic changes is itself subject to variation depending on previous experience; taking into consideration the effects of NT-3 on MF synaptic plasticity, we thus used intrahippocampal microinfusion of NT-3 to analyse its effects on functional and structural plasticity induced by subsequent MF-HFS sufficient to induce LTP in adult rats, in vivo. Our results show that NT-3 modifies the ability of the MF pathway to present subsequent LTP by HFS, and modifies the structural reorganization pattern. The modifications in synaptic efficacy and morphology elicited by NT-3 at the MF-CA3 pathway were blocked by the presence of a Trk receptor inhibitor (K252a). These findings support the idea that NT-3 actions modify subsequent synaptic plasticity, a homeostatic mechanism thought to be essential for maintaining synapses in the adult mammalian brain.

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