Developmental changes in plasticity, synaptic, glia and connectivity protein levels in rat dorsal hippocampus

Abstract

Thus far the identification and functional characterization of the molecular mechanisms underlying synaptic plasticity, learning, and memory have not been particularly dissociated from the contribution of developmental changes. Brain plasticity mechanisms have been largely identified and studied using in vitro systems mainly derived from early developmental ages, yet they are considered to be general plasticity mechanisms underlying functions -such as long-term memory- that occurs in the adult brain. Although it is possible that part of the plasticity mechanisms recruited during development is then re-recruited in plasticity responses in adulthood, systematic investigations about whether and how activity-dependent molecular responses differ over development are sparse. Notably, hippocampal-dependent memories are expressed relatively late in development, and the hippocampus undergoes and extended developmental post-natal structural and functional maturation, suggesting that the molecular mechanisms underlying hippocampal neuroplasticity may actually significantly change over development. Here we quantified the relative basal expression levels of sets of plasticity, synaptic, glia and connectivity proteins in rat dorsal hippocampus, a region that is critical for the formation of long-term explicit memories, at two developmental ages, postnatal day 17 (PN17) and PN24, which correspond to a period of relative functional immaturity and maturity, respectively, and compared them to adult age. We found that the levels of numerous proteins and/or their phosphorylation, known to be critical for synaptic plasticity underlying memory formation, including immediate early genes (IEGs), kinases, transcription factors and AMPA receptor subunits, peak at PN17 when the hippocampus is not yet able to express long-term memory. It remains to be established if these changes result from developmental basal activity or infantile learning. Conversely, among all markers investigated, the phosphorylation of calcium calmodulin kinase II α (CamKII− α− and of extracellular signal-regulated kinases 2 (ERK-2), and the levels of GluA1 and GluA2 significantly increase from PN17 to PN24 and then remain similar in adulthood, thus representing correlates paralleling long-term memory expression ability.

Astrocyte glycogen and lactate: New insights into learning and memory mechanisms

“…Recently, we showed that IA experiences in infant rats, although apparently forgotten, are actually stored over the long‐term in a latent form, as these memories can be reinstated later in life if reminders are experienced (Travaglia, Bisaz, Sweet, Blitzer, & Alberini, ). Contrary to what had been suggested previously, we found that the infant hippocampus (at postnatal day 17, PN17) is highly responsive and engaged in learning, and makes a necessary contribution to the formation of the latent, long‐lasting memories by recruiting molecular mechanisms typical of critical periods (Travaglia, Bisaz, Cruz, & Alberini, ; Travaglia et al, ). Hence, we suggested that, as in other brain functions and systems, the episodic learning system undergoes a critical period, during which the hippocampal system acquires functional competence through experience (Alberini & Travaglia, ).…”

Influence of postnatal glucocorticoids on hippocampal-dependent learning varies with elevation patterns and administration methods

“…Interestingly, examination of control groups indicated that for both placebo pellet controls and untreated controls there was a significantly higher rate of neurogenesis for males than females. Although not significant for the other control groups, this post-SHRP increased rate of neurogenesis for males is consistent with a growth spurt period in hippocampus (Bayer, 1980; Bayer & Altman, 1974; Travaglia et al, 2016) and makes the decrease in neurogenesis for corticosterone-pellet-males even more significant. It is possible that the increased rate of neurogenesis during this developmental window produces a vulnerability to glucocorticoid perturbation specifically in males, though given the relatively high level of neurogenesis in males receiving a placebo pellet and the small sample size of untreated controls, these results must be considered preliminary until replicated.…”

“…Developmentally, the ability to acquire trace eyeblink conditioning emerges postnatally and becomes robust by about 28 days of age in the rat, corresponding to the prolonged maturation of hippocampal and cortical circuits during the first several weeks (Ivkovich et al, 2000b; Travaglia et al, 2016). If corticosterone’s effects are mediated by hippocampus, we should see deficits similar to those reported by Ivkovich and Stanton (2001) where hippocampal lesions on postnatal day 10 impaired subsequent trace eyeblink conditioning on Days 25–26 but not delay eyeblink conditioning at matching inter-stimulus intervals.…”

Postnatal LPS Challenge Impacts Escape Learning and Expression of Plasticity Factors Mmp9 and Timp1 in Rats: Effects of Repeated Training

“…Meanwhile, striking differences between early stage and adult molecular and functional organization of the hippocampus question the relevance of these molecular mechanisms, as these adult plasticity markers are poorly expressed during early-life (Travaglia et al 2016). These concerns are supported by numerous in vitro findings showing opposing, stimulatory effects of pro-inflammatory cytokines on plasticity molecules, such as CaMKII, tyrosine kinases, mitogen-activated protein kinases (MAPKs), protein kinase C (PKC), phosphoinositide-3 kinase (PI3K) and transcription factors such as nuclear factor kappa B (NF-κB) and activator protein 1 (AP-1) (Rosenberg 2002; Wu et al 2004, 2009).…”