Decoding hippocampal signaling deficits after traumatic brain injury

Abstract

There are more than 3.17 million people coping with long-term disabilities due to traumatic brain injury (TBI) in the United States. The majority of TBI research is focused on developing acute neuroprotective treatments to prevent or minimize these long-term disabilities. Therefore, chronic TBI survivors represent a large, underserved population that could significantly benefit from a therapy that capitalizes on the endogenous recovery mechanisms occurring during the weeks to months following brain trauma. Previous studies have found that the hippocampus is highly vulnerable to brain injury, in both experimental models of TBI and during human TBI. Although often not directly mechanically injured by the head injury, in the weeks to months following TBI, the hippocampus undergoes atrophy and exhibits deficits in long-term potentiation (LTP), a persistent increase in synaptic strength that is considered to be a model of learning and memory. Decoding the chronic hippocampal LTP and cell signaling deficits after brain trauma will provide new insights into the molecular mechanisms of hippocampal-dependent learning impairments caused by TBI and facilitate the development of effective therapeutic strategies to improve hippocampal-dependent learning for chronic survivors of TBI.

Fig. 1

The biochemical mechanisms required for hippocampal LTP and memory formation share many similar pathways. During induction of LTP, i.e. the first initial minutes after tetanization (arrow), there is a supralinear entry of calcium via VDCCs and NMDA receptors. This calcium influx activates several protein kinases including the CaMKs, PKA, and PKC. They either directly phosphorylate glutamate receptors to increase conductance through the receptors or phosphorylate proteins involved in the insertion of the receptors in the postsynaptic membrane. This leads to the potentiation of synaptic transmission. During the maintenance of LTP and long-term memory formation, several protein kinases including CaMKIV, ERK1/2, and PKA regulate transcription factors which increase gene transcription to enact structural changes at the synapse to maintain this potentiation.

Fig. 2

A comparison of the deficits in hippocampal LTP elicited by an ERK1/2 inhibitor versus induced by experimental TBI. A MAP kinase kinase (MEK) inhibitor to selectively inhibit ERK1/2 has no effect on the initial potentiation after tetanic stimulation to induce LTP, but blocks maintenance of LTP (a). Adapted from [71]. Moderate TBI results in similar deficits in hippocampal LTP (b). At 2 weeks after TBI, LTP was induced by tetanization of the Schaffer collateral pathway. Although the synaptic response is potentiated in the first few minutes after tetanization, the degree of potentiation in TBI hippocampal slices is not maintained as compared to sham hippocampal slices (C.M.A. and J.D.A. unpublished observations) [, , , , , –68].

Fig. 3

Many cellular signaling pathways are acutely activated after TBI, but rapidly return to non-injured levels. CaMKI, CaMKII, CaMKIV, and ERK1/2 are activated after TBI, whereas PKA activation is reduced. Nearly all of these biochemical changes return to sham, non-injured levels within 3–7 days after brain trauma. Adapted from [87, 88, 91].

Fig. 4

Schematic of how the biochemical signaling pathways that underlie hippocampal LTP are altered after TBI. Pathways that are stimulated are illustrated in black, and pathways that are decreased are denoted in red. TBI induces depolarization of neurons and postsynaptic calcium entry which subsequently activates CaMKK and its downstream substrates CaMKI and CaMKIV. PKC and CaMKII are also activated by the increase in postsynaptic calcium. Downstream of CaMKII is the dendritic mRNA translation factor, CPEB, which is transiently phosphorylated. Whether this leads to an increase in dendritic mRNA translation after TBI is still unknown. In contrast to most pathways, cAMP levels and PKA activation are decreased immediately after TBI. This results in differential effects on the AMPA-type glutamate receptor subunit 1: increased phosphorylation at the CaMKII site (Ser831) and decreased phosphorylation at the PKA site (Ser845). TBI also induces an increase in the neurotrophins BDNF and NGF, which activate ERK1/2 and mTOR. Downstream of ERK1/2 and mTOR are multiple translation and transcription factor signaling pathways, including mitogen-activated protein kinase-interacting kinase 1 (Mnk1), eIF4E, 4E-BP1, p70S6K, and rpS6. CREB phosphorylation increases after TBI, although the exact protein kinase that regulates CREB during TBI is still unknown and likely candidates include p90 ribosomal S6 kinase (p90RSK) and CaMKIV. Modulatory neurotransmitter release and their receptors are depressed after TBI; these include a transient decrease in β-adrenergic receptor levels (β-AR) and acetylcholine receptor binding and levels. Although all of these molecules change rapidly after TBI, most return to basal levels within 2–4 weeks after brain trauma.