Biology subjects

Bergold, P. J.

Publications and source records attributed to Bergold, P. J..

3 recordsLinked to original sources

bioRxiv2025

PKMζ-PKC{iota}/{lambda} double-knockout reveals the atypical PKCs are crucial for hippocampal late-LTP and spatial long-term memory

PKM{zeta}, a persistently active atypical PKC (aPKC) isoform, is thought to maintain late-phase long-term potentiation (late-LTP) and long-term memory. However, PKM{zeta}-knockout mice still exhibit hippocampal LTP and spatial memory while lacking neocortical LTP, questioning whether this kinase is fundamental to enduring synaptic potentiation and memory. Tsokas et al. (2016) showed the other aPKC, PKC{iota}/{lambda}, likely compensates for PKM{zeta} during maintenance in the hippocampus of PKM{zeta}-null mice. In wild-type mice, PKC{iota}/{lambda} drives early-LTP and short-term memory, while PKM{zeta} compensates for PKC{iota}/{lambda} knockout by supporting both early- and late-phase processes. Here we show PKC{iota}/{lambda} persistently increases during maintenance in two mouse models: PKM{zeta}-conditional knockout (cKO) mice, and double-knockout mice carrying both conditional deletion of PKC{iota}/{lambda} and constitutive loss of PKM{zeta}. In the double-knockout mice, PKC{iota}/{lambda} was measured while the kinase was still present, prior to its inducible ablation, to characterize its compensatory upregulation in late-LTP before removal. To test whether this compensation was functional, we ablated PKC{iota}/{lambda} in the hippocampus of the double-knockout mice. The double-knockout eliminated late-LTP, whereas individual knockout of either aPKC alone showed normal-appearing LTP. Double-knockout also abolished spatial long-term memory without affecting short-term memory. Thus, when PKM{zeta} is absent, PKC{iota}/{lambda} persists to maintain hippocampal late-LTP and long-term memory.

neuroscience↗

bioRxiv2024

Increased protein kinase Mζ expression by Minocycline and N-acetylcysteine restoreslate-phase long-term potentiation and spatial learning after closed head injury in mice

Cognitive deficits frequently arise after traumatic brain injury. The murine closed head injury (CHI) models these deficits since injured mice cannot acquire Barnes maze. Dosing of minocycline plus N-acetylcysteine beginning 12 hours post-CHI (MN12) restores Barnes maze acquisition by an unknown mechanism. Increased hippocampal synaptic efficacy is needed to acquire Barnes maze, synaptic long-term potentiation (LTP) models this increased synaptic efficacy in vitro. LTP has an early phase (E-LTP) lasting up to one hour that is mediated by second messengers that is followed by a late phase (L-LTP) that needs new synthesis of protein kinase M zeta (PKM{zeta}). PKM{zeta} has constitutive kinase activity because it lacks the autoinhibitory regulatory domain found in other PKCs. Due to its constitutive activity, the amount of PKM{zeta} kinase activity is determined by PKM{zeta} protein levels. We report that CHI bilaterally decreases PKM{zeta} levels in the CA3 and CA1 hippocampus. MN12 increases CA1 PKM{zeta} expression. CHI inhibits E-LTP in slices from the ipsilesional hippocampus and inhibits L-LTP in slices from both hippocamppi. MN12 treatment reestablishes both E-LTP and L-LTP in slices from the injured MN12-treated hippocampus. The restoration of L-LTP from injured MN12-treated hippocampus is mediated by PKM{zeta} because L-LTP is blocked by the specific PKM{zeta} inhibitor, {zeta}-stat. Hippocampal {zeta}-stat infusions also prevents Barnes maze acquisition in injured, MN12-treated mice. These data suggest that post-injury minocycline plus N-acetylcysteine targets PKM{zeta} to improve synaptic plasticity and cognition in mice with closed-head injury.

neuroscience↗

bioRxiv2021

Delayed dosing of minocycline plus N-acetylcysteine reduces neurodegeneration in distal brain regions and restores spatial memory after experimental traumatic brain injury

Multiple drugs to treat traumatic brain injury (TBI) have failed clinical trials. Most drugs lose efficacy as the time interval increases between injury and treatment onset. Insufficient therapeutic time window is a major reason underlying failure in clinical trials. Few drugs have been developed with therapeutic time windows sufficiently long enough to treat TBI because little is known about which brain functions can be targeted if therapy is delayed hours to days after injury. We identified multiple injury parameters that are improved by first initiating treatment with the drug combination minocycline (MINO) plus N-acetylcysteine (NAC) at 72 hours after injury (MN72) in a mouse closed head injury (CHI) experimental TBI model. CHI produces spatial memory deficits resulting in impaired performance on Barnes maze, hippocampal neuronal loss, and bilateral damage to hippocampal neurons, dendrites, spines and synapses. MN72 treatment restores Barnes maze acquisition and retention, protects against hippocampal neuronal loss, limits damage to dendrites, spines and synapses, and accelerates recovery of microtubule associated protein 2 (MAP2) expression, a key protein in maintaining proper dendritic architecture and synapse density. These data show that in addition to the structural integrity of the dendritic arbor, spine and synapse density can be successfully targeted with drugs first dosed days after injury. Retention of substantial drug efficacy even when first dosed 72 hours after injury makes MINO plus NAC a promising candidate to treat clinical TBI.

neuroscience↗