ABSTRACT
Although ß-amyloid plaques are a well-recognized hallmark of Alzheimer's disease (AD) neuropathology, no drugs reducing amyloid burden have shown efficacy in clinical trials, suggesting that once AD symptoms emerge, disease progression becomes independent of Aß production. Reactive astrocytes are another neuropathological feature of AD, where there is an emergence of neurotoxic (A1) reactive astrocytes. We find that serine racemase (SR), the neuronal enzyme that produces the N-methyl-d-aspartate receptor (NMDAR) co-agonist d-serine, is robustly expressed in A1-reactive neurotoxic astrocytes in the hippocampus and entorhinal cortex of AD subjects and an AD rat model. Furthermore, we observe intracellular signaling changes consistent with increased extra-synaptic NMDAR activation, excitotoxicity and decreased neuronal survival. Thus, reducing neurotoxic d-serine release from A1 inflammatory astrocytes could have therapeutic benefit for mild to advanced AD, when anti-amyloid strategies are ineffective.
Subject(s)
Alzheimer Disease/enzymology , Astrocytes/enzymology , Entorhinal Cortex/enzymology , Hippocampus/enzymology , Racemases and Epimerases/metabolism , Alzheimer Disease/pathology , Animals , Disease Models, Animal , Humans , Rats , Rats, TransgenicABSTRACT
Alzheimer's disease (AD) is a neurodegenerative disease that disproportionately impacts memory and the hippocampus. However, it is unclear how AD pathology influences the activity of surviving neurons in the hippocampus to contribute to the memory symptoms in AD. One well-understood connection between spatial memory and neuronal activity in healthy brains is the activity of place cells, neurons in the hippocampus that fire preferentially in a specific location of a given environment (the place field of the place cell). In the present study, place cells were recorded from the hippocampus in a recently-developed rat model of AD (Tg-F344 AD) at an age (12-20 months) at which the AD rats showed marked spatial memory deficits. Place cells in the CA2 and CA3 pyramidal regions of the hippocampus in AD rats showed sharply reduced spatial fidelity relative to wild-type (WT) rats. In contrast, spiking activity of place cells recorded in region CA1 in AD rats showed good spatial fidelity that was similar to CA1 place cells in WT rats. Oral administration of the M1 muscarinic acetylcholine receptor agonist VU0364572 impacted place cell firing rates in CA1 and CA2/3 hippocampal regions, but did not improve the spatial fidelity of CA2/3 hippocampal place cells in AD rats. The results indicated that, to the extent the spatial memory impairment in AD rats was attributable to hippocampal dysfunction, the memory impairment was more attributable to dysfunction in hippocampal regions CA2 and CA3 rather than CA1.
Subject(s)
Action Potentials/drug effects , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Hippocampus/anatomy & histology , Neurons/pathology , Action Potentials/genetics , Age Factors , Alzheimer Disease/complications , Amyloid beta-Protein Precursor/genetics , Animals , Benzamides/pharmacology , Biphenyl Compounds/pharmacology , Disease Models, Animal , Female , Memory Disorders/etiology , Mutation/genetics , Neurons/drug effects , Presenilin-1/genetics , Rats , Rats, Inbred F344 , Rats, Transgenic , Receptor, Muscarinic M1/agonists , Receptor, Muscarinic M1/metabolism , Recognition, Psychology/drug effectsABSTRACT
Neuronal oscillations in the rat hippocampus relate to both memory and locomotion, raising the question of how these cognitive and behavioral correlates interact to determine the oscillatory network state of this region. Here, rats freely locomoted while performing an object-location task designed to test hippocampus-dependent spatial associative memory. Rhythmic activity in theta, beta, slow gamma, and fast gamma frequency ranges were observed in both action potentials and local field potentials (LFPs) across four main hippocampal subregions. Several patterns of LFP oscillations corresponded to overt behavior (e.g., increased dentate gyrus-CA3 beta coherence during stationary moments and CA1-subiculum theta coherence during locomotion). In comparison, slow gamma (â¼40 Hz) oscillations throughout the hippocampus related most specifically to object-location associative memory encoding rather than overt behavior. The results help to untangle how hippocampal oscillations relate to both memory and motion and single out slow gamma oscillations as a distinguishing correlate of spatial associative memory.
Subject(s)
CA1 Region, Hippocampal/metabolism , CA1 Region, Hippocampal/physiology , CA3 Region, Hippocampal/metabolism , CA3 Region, Hippocampal/physiology , Dentate Gyrus/metabolism , Dentate Gyrus/physiology , Memory/physiology , Action Potentials/physiology , Animals , Electrophysiology , Hippocampus/metabolism , Hippocampus/physiology , Male , Rats , Theta Rhythm/physiologyABSTRACT
Recent research in humans has used formal models of temporal context, broadly defined as a lingering representation of recent experience, to explain a wide array of recall and recognition memory phenomena. One difficulty in extending this work to studies of experimental animals has been the challenge of developing a task to test temporal context effects on performance in rodents. The current study presents results from a novel object recognition memory paradigm that was adapted from a task used in humans and demonstrates a temporal context repetition effect in rats. Specifically, the findings indicate that repeating the first two objects from a once-encountered sequence of three objects incidentally cues memory for the third object, even in its absence. These results reveal that temporal context influences item memory in rats similar to the manner in which it influences memory in humans and also highlight a new task for future studies of temporal context in experimental animals.
Subject(s)
Mental Recall , Recognition, Psychology , Time Factors , Animals , Cues , Exploratory Behavior , Male , Rats , Visual PerceptionABSTRACT
Acetylcholine signaling through muscarinic receptors has been shown to benefit memory performance in some conditions, but pan-muscarinic activation also frequently leads to peripheral side effects. Drug therapies that selectively target M1 or M4 muscarinic receptors could potentially improve memory while minimizing side effects mediated by the other muscarinic receptor subtypes. The ability of three recently developed drugs that selectively activate M1 or M4 receptors to improve recognition memory was tested by giving Long-Evans rats subcutaneous injections of three different doses of the M1 agonist VU0364572, the M1 positive allosteric modulator BQCA or the M4 positive allosteric modulator VU0152100 before performing an object recognition memory task. VU0364572 at 0.1 mg/kg, BQCA at 1.0 mg/kg and VU0152100 at 3.0 and 30.0 mg/kg improved the memory performance of rats that performed poorly at baseline, yet the improvements in memory performance were the most statistically robust for VU0152100 at 3.0 mg/kg. The results suggested that selective M1 and M4 receptor activation each improved memory but that the likelihood of obtaining behavioral efficacy at a given dose might vary between subjects even in healthy groups depending on baseline performance. These results also highlighted the potential of drug therapies that selectively target M1 or M4 receptors to improve memory performance in individuals with impaired memory.
