Neuronal Calcium Imaging, Excitability, and Plasticity Changes in the Aldh2-/- Mouse Model of Sporadic Alzheimer's Disease.

BACKGROUND: Dysregulated signaling in neurons and astrocytes participates in pathophysiological alterations seen in the Alzheimer's disease brain, including increases in amyloid-ß, hyperphosphorylated tau, inflammation, calcium dysregulation, and oxidative stress. These are often noted prior to the development of behavioral, cognitive, and non-cognitive deficits. However, the extent to which these pathological changes function together or independently is unclear. OBJECTIVE: Little is known about the temporal relationship between calcium dysregulation and oxidative stress, as some reports suggest that dysregulated calcium promotes increased formation of reactive oxygen species, while others support the opposite. Prior work has quantified several key outcome measures associated with oxidative stress in aldehyde dehydrogenase 2 knockout (Aldh2-/-) mice, a non-transgenic model of sporadic Alzheimer's disease. METHODS: Here, we tested the hypothesis that early oxidative stress can promote calcium dysregulation across aging by measuring calcium-dependent processes using electrophysiological and imaging methods and focusing on the afterhyperpolarization (AHP), synaptic activation, somatic calcium, and long-term potentiation in the Aldh2-/- mouse. RESULTS: Our results show a significant age-related decrease in the AHP along with an increase in the slow AHP amplitude in Aldh2-/- animals. Measures of synaptic excitability were unaltered, although significant reductions in long-term potentiation maintenance were noted in the Aldh2-/- animals compared to wild-type. CONCLUSION: With so few changes in calcium and calcium-dependent processes in an animal model that shows significant increases in HNE adducts, Aß, p-tau, and activated caspases across age, the current findings do not support a direct link between neuronal calcium dysregulation and uncontrolled oxidative stress.

Spreading depolarization and neuronal damage or survival in mouse neocortical brain slices immediately and 12 hours following middle cerebral artery occlusion.

Whereas many studies have examined the properties of the compromised neocortex in the first several days following ischemia, there is less information regarding the initial 12 h poststroke. In this study we examined live mouse neocortical slices harvested immediately and 12 h after a 30-min middle cerebral artery occlusion (MCAo). We compared nonischemic and ischemic hemispheres with regard to the propensity for tissue swelling and for generating spreading depolarization (SD), as well as evoked synaptic responses and single pyramidal neuron electrophysiological properties. We observed spontaneous SD in 7% of slices on the nonstroked side and 25% in the stroked side following the 30-min MCAo. Spontaneous SD was rare in 12-h recovery slices. The region of the ischemic core and surround in slices was not susceptible to SD induced by oxygen and glucose deprivation. At the neuronal level, neocortical gray matter is surprisingly unaltered in brain slices harvested immediately poststroke. However, by 12 h, the fields of pyramidal and striatal neurons that comprise the infarcted core are electrophysiologically silent because the majority are morphologically devastated. Yet, there remains a subset of diffusely distributed "healthy" pyramidal neurons in the core at 12 h post-MCAo that persist for days poststroke. Their intact electrophysiology and dendritic morphology indicate a surprisingly selective resilience to stroke at the neuronal level. NEW & NOTEWORTHY It is generally accepted that the injured core region of the brain resulting from a focal stroke contains no functioning neurons. Our study shows that some neurons, although surrounded by devastated neighbors, can maintain their structure and electrical activity. This surprising finding raises the possibility of discovering how these neurons are protected to pinpoint new strategies for reducing stroke injury.

Age-Dependent Switch of the Role of Serotonergic 5-HT1A Receptors in Gating Long-Term Potentiation in Rat Visual Cortex In Vivo.

The rodent primary visual cortex (V1) is densely innervated by serotonergic axons and previous in vitro work has shown that serotonin (5-HT) can modulate plasticity (e.g., long-term potentiation (LTP)) at V1 synapses. However, little work has examined the effects of 5-HT on LTP under in vivo conditions. We examined the role of 5-HT on LTP in V1 elicited by theta burst stimulation (TBS) of the lateral geniculate nucleus in urethane-anesthetized (adult and juvenile) rats. Thalamic TBS consistently induced potentiation of field postsynaptic potentials (fPSPs) recorded in V1. While 5-HT application (0.1-10 mM) itself did not alter LTP levels, the broad-acting 5-HT receptor antagonists methiothepin (1 mM) resulted in a clear facilitation of LTP in adult animals, an effect that was mimicked by the selective 5-HT1A receptor antagonist WAY 100635 (1 mM). Interestingly, in juvenile rats, WAY 100635 application inhibited LTP, indicative of an age-dependent switch in the role of 5-HT1A receptors in gating V1 plasticity. Analyses of spontaneous electrocorticographic (ECoG) activity in V1 indicated that the antagonist-induced LTP enhancement was not related to systematic changes in oscillatory activity in V1. Together, these data suggest a facilitating role of 5-HT1A receptor activation on LTP in the juvenile V1, which switches to a tonic, inhibitory influence in adulthood.

NR2B-subunit dependent facilitation of long-term potentiation in primary visual cortex following visual discrimination training of adult rats.

Long-term potentiation (LTP) is an important mechanism thought to mediate changes in synaptic connectivity following various types of experience. We examined the effects of visual discrimination training on LTP in the mature, rodent thalamocortical visual system. Adult rats underwent visual discrimination training in a modified Morris Water Maze containing a Y-maze insert, requiring rats to associate visual cues with the location of a hidden escape platform placed in one of the two goal arms of the Y-maze insert. On the day following successful task acquisition (average of nine training days), rats were anesthetized (urethane), and LTP in the thalamocortical system was characterized. In task-naïve rats, theta-burst stimulation of the lateral geniculate nucleus resulted in modest (∼40%) potentiation of field postsynaptic potentials recorded in the primary visual cortex (V1). Rats trained on the visual discrimination task showed significantly greater levels of LTP (∼60%), an effect that was not seen in rats trained to swim in the maze without a predictive association between visual cues and platform location. An antagonist of the N-methyl-d-aspartate (NMDA) receptor NR2B subunit ([R-(R *,S *)]-α-(4-hydroxyphenyl)-ß-methyl-4-(phenylmethyl)-1-piperidinepropanol hydrochloride (Ro 25-6981); 2 mm, applied locally at the recording site in V1) reversed the training-induced LTP enhancement without affecting LTP in task-naïve rats. An antagonist of metabotropic glutamate receptors [(2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid (LY 341495); 2 mm] was ineffective in reversing the training-induced LTP facilitation. These data suggest that behavioral (visual) training can result in changes in plasticity exhibited by the mature, thalamocortical visual system that require activation of NMDA receptors containing the NR2B subunit.

Selective potentiation of crossed vs. uncrossed inputs from lateral geniculate nucleus to visual cortex by the basal forebrain: potential facilitation of rodent binocularity.

Cholinergic projections originating in the basal forebrain (BF) play important roles in the heterosynaptic facilitation of synaptic strength in various sensory cortices, including the primary visual cortex (V1). Here, using urethane-anesthetized rats, we find that pairing burst stimulation of the BF with single pulse stimulation of the lateral geniculate nucleus (LGN) does not consistently increase field postsynaptic potentials (fPSPs) in V1 elicited by ipsilateral LGN stimulation. However, longer latency fPSPs recorded in V1 in response to stimulation of the contralateral LGN, reflecting crossed, polysynaptic inputs, show significant potentiation when paired with preceding BF stimulation. This synaptic enhancement requires relatively short time intervals between paired BF burst and LGN pulse stimulation (40 ms) and is abolished by systemic or local V1 muscarinic receptor blockade (scopolamine), while systemic nicotinic receptor blockade (mecamylamine) is ineffective. Together, these data provide evidence for a differential capacity for cholinergic/muscarinic-dependent plasticity induction among different signals in V1, with inputs reaching V1 from the contralateral LGN exhibiting potentiation in the face of stable strength in ipsilateral LGN-V1 projections. This preferential readiness for potentiation in crossed fiber systems could serve to amplify binocular responses in V1 elicited by synchronized excitation of ipsi- and contralateral LGN neurons.