Brain-derived neurotrophic factor restores synaptic plasticity in a knock-in mouse model of Huntington's disease.

Asymptomatic Huntington's disease (HD) patients exhibit memory and cognition deficits that generally worsen with age. Similarly, long-term potentiation (LTP), a form of synaptic plasticity involved in memory encoding, is impaired in HD mouse models well before motor disturbances occur. The reasons why LTP deteriorates are unknown. Here we show that LTP is impaired in hippocampal slices from presymptomatic Hdh(Q92) and Hdh(Q111) knock-in mice, describe two factors contributing to this deficit, and establish that potentiation can be rescued with brain-derived neurotrophic factor (BDNF). Baseline physiological measures were unaffected by the HD mutation, but LTP induction and, to a greater degree, consolidation were both defective. The facilitation of burst responses that normally occurs during a theta stimulation train was reduced in HD knock-in mice, as was theta-induced actin polymerization in dendritic spines. The decrease in actin polymerization and deficits in LTP stabilization were reversed by BDNF, concentrations of which were substantially reduced in hippocampus of both Hdh(Q92) and Hdh(Q111) mice. These results suggest that the HD mutation discretely disrupts processes needed to both induce and stabilize LTP, with the latter effect likely arising from reduced BDNF expression. That BDNF rescues LTP in HD knock-in mice suggests the possibility of treating cognitive deficits in asymptomatic HD gene carriers by upregulating production of the neurotrophin

Physiological Activation of Synaptic Rac > PAK Signaling Is Defective in a Mouse Model of Fragile-X Syndrome

The abnormal spine morphology found in Fragile-X Syndrome (FXS) is suggestive of an error in the signaling cascades that organize the actin cytoskeleton. We report here that physiological activation of the small GTPase Rac1 and its effector p-21 activated kinase (PAK), two enzymes critically involved in actin management and functional synaptic plasticity, is impaired at hippocampal synapses in the Fmr1-knockout (KO) mouse model of FXS. Theta burst afferent stimulation (TBS) caused a marked increase in the number of synapses associated with phosphorylated PAK in adult hippocampal slices from wild-type, but not Fmr1-KO, mice. Stimulation-induced activation of synaptic Rac1 was also absent in the mutants. The polymerization of spine actin that occurs immediately after theta stimulation appeared normal in mutant slices but the newly formed polymers did not properly stabilize, as evidenced by a prolonged vulnerability to a toxin (latrunculin) that disrupts dynamic actin filaments. Latrunculin also reversed long-term potentiation when applied at 10 min post-TBS, a time point at which the potentiation effect is resistant to interference in wild-type slices. We propose that a Rac>PAK signaling pathway needed for rapid stabilization of activity-induced actin filaments, and thus for normal spine morphology and lasting synaptic changes, is defective in FXS

Origins of an intrinsic hippocampal EEG pattern.

Sharp waves (SPWs) are irregular waves that originate in field CA3 and spread throughout the hippocampus when animals are alert but immobile or as a component of the sleep EEG. The work described here used rat hippocampal slices to investigate the factors that initiate SPWs and govern their frequency. Acute transection of the mossy fibers reduced the amplitude but not the frequency of SPWs, suggesting that activity in the dentate gyrus may enhance, but is not essential for, the CA3 waves. However, selective destruction of the granule cells and mossy fibers by in vivo colchicine injections profoundly depressed SPW frequency. Reducing mossy fiber release with an mGluR2 receptor agonist or enhancing it with forskolin respectively depressed or increased the incidence of SPWs. Collectively, these results indicate that SPWs can be triggered by constitutive release from the mossy fibers. The waves were not followed by large after-hyperpolarizing potentials and their frequency was not strongly affected by blockers of various slow potassium channels. Antagonists of GABA-B mediated IPSCs also had little effect on incidence. It appears from these results that the spacing of SPWs is not dictated by slow potentials. However, modeling work suggests that the frequency and variance of large mEPSCs from the mossy boutons can account for the temporal distribution of the waves. Together, these results indicate that constitutive release from the mossy fiber terminal boutons regulates the incidence of SPWs and their contribution to information processing in hippocampus

Origins of an Intrinsic Hippocampal EEG Pattern

Sharp waves (SPWs) are irregular waves that originate in field CA3 and spread throughout the hippocampus when animals are alert but immobile or as a component of the sleep EEG. The work described here used rat hippocampal slices to investigate the factors that initiate SPWs and govern their frequency. Acute transection of the mossy fibers reduced the amplitude but not the frequency of SPWs, suggesting that activity in the dentate gyrus may enhance, but is not essential for, the CA3 waves. However, selective destruction of the granule cells and mossy fibers by in vivo colchicine injections profoundly depressed SPW frequency. Reducing mossy fiber release with an mGluR2 receptor agonist or enhancing it with forskolin respectively depressed or increased the incidence of SPWs. Collectively, these results indicate that SPWs can be triggered by constitutive release from the mossy fibers. The waves were not followed by large after-hyperpolarizing potentials and their frequency was not strongly affected by blockers of various slow potassium channels. Antagonists of GABA-B mediated IPSCs also had little effect on incidence. It appears from these results that the spacing of SPWs is not dictated by slow potentials. However, modeling work suggests that the frequency and variance of large mEPSCs from the mossy boutons can account for the temporal distribution of the waves. Together, these results indicate that constitutive release from the mossy fiber terminal boutons regulates the incidence of SPWs and their contribution to information processing in hippocampus

Origins of an Intrinsic Hippocampal EEG Pattern

Sharp waves (SPWs) are irregular waves that originate in field CA3 and spread throughout the hippocampus when animals are alert but immobile or as a component of the sleep EEG. The work described here used rat hippocampal slices to investigate the factors that initiate SPWs and govern their frequency. Acute transection of the mossy fibers reduced the amplitude but not the frequency of SPWs, suggesting that activity in the dentate gyrus may enhance, but is not essential for, the CA3 waves. However, selective destruction of the granule cells and mossy fibers by in vivo colchicine injections profoundly depressed SPW frequency. Reducing mossy fiber release with an mGluR2 receptor agonist or enhancing it with forskolin respectively depressed or increased the incidence of SPWs. Collectively, these results indicate that SPWs can be triggered by constitutive release from the mossy fibers. The waves were not followed by large after-hyperpolarizing potentials and their frequency was not strongly affected by blockers of various slow potassium channels. Antagonists of GABA-B mediated IPSCs also had little effect on incidence. It appears from these results that the spacing of SPWs is not dictated by slow potentials. However, modeling work suggests that the frequency and variance of large mEPSCs from the mossy boutons can account for the temporal distribution of the waves. Together, these results indicate that constitutive release from the mossy fiber terminal boutons regulates the incidence of SPWs and their contribution to information processing in hippocampus

Knife cuts through the projections from entorhinal cortex to hippocampus (perforant path) do not affect SPW activity in field CA3.

<p><b><i>A</i></b>, Schematic of a slice from the temporal hippocampus illustrating the location of the knife sections used in the present studies: cut #1 separates the hippocampus from the entorhinal cortex while cut #2 is through the mossy fibers (dark gray) at the entrance to the hilus (m.f: mossy fiber pathway; dg: dentate gyrus). <b><i>B</i></b>, Baseline SPWs recorded from CA3 stratum pyramidale (top). Recordings collected at least 30 minutes after severing the perforant path (bottom). <b><i>C</i></b>, Mean rate and power (± SEM) of SPWs for a group of five slices prior to and following cuts through the perforant path.</p

Frequency at which small collections of simulated neurons fire within the same 20 ms time bin in response to inputs arriving at the observed temporal distribution of large mEPSCs.

<p><b><i>A</i></b>, Interval histogram for mEPSCs greater than 50 pA recorded from nine CA3b pyramidal neurons. <b><i>B</i></b>, Frequency at which the indicated numbers of neurons (arrow), from a simulation of 500 cells, fire during the same 20 ms time bin. Each cell in the model received the input shown in panel A. <b><i>C</i></b>, Frequency distribution of SPWs recorded from field CA3b under baseline conditions.</p

A type 2/3 metabotropic glutamate receptor agonist (DCG-IV) reduces the frequency of mEPSCs and SPWs.

<p><b><i>A</i></b>, mEPSCs collected from field CA3b prior to and after an infusion of DCG-IV (2 µM). <b><i>B</i></b>, DCG-IV caused a mark reduction in the frequency of high voltage SPWs and an increase in low voltage, fast activity. These effects reversed upon drug wash-out. <b><i>C</i></b>, A 30 min infusion of the agonist caused a rapid and reversible reduction (57%) in EEG power in the SPW frequency range (p<0.001, repeated measures ANOVA; n = 4 slices).</p

Minimal stimulation of the mossy fibers triggers CA3 sharp waves.

<p><b><i>A</i></b>, Stimulation pulses (arrows) were delivered to the infragranular zone of the hilus to activate the mossy fibers arising from a small portion of the granule cell population. This reliably triggered a negative-going, complex response in the apical dendrites (str. radiatum) of field CA3b; the size and shape of this response closely resembled those of spontaneous SPWs. High-pass filtered trace (100–400 Hz; time-locked to upper trace) showed that both the evoked response and spontaneous SPWs were accompanied by high frequency activity, particularly on their ascending phases. <b><i>B</i></b>, As with SPWs, the complex potentials elicited by mossy fiber stimulation were positive in sign when recorded at the boundary between str. lucidum and str. pyramidale. Note that a small mossy fiber response (asterisk) precedes the positive wave. The downward arrow denotes the stimulation pulse. <b><i>C</i></b>, The frequency distribution for the peak amplitude of the evoked waves (EWs) illustrates the highly variable nature of the responses over the course of a recording session. Note the extensive overlap for the evoked and spontaneous wave distributions.</p